Jennifer A Teske

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Scholarly Contributions

Chapters

• Perez‐Leighton, C. E., Lockridge, A., Teske, J. A., Alejandro, E. U., & Kotz, C. M. (2020). Rat Models of Obesity, Metabolic Syndrome, and Diabetes. In The Laboratory Rat. doi:10.1016/b978-0-12-814338-4.00027-1
• Teske, J. A. (2019). Orexin drives energy expenditure. In The Orexins/Hypocretins Systems: Functional Roles and Therapeutic Potential.. Elsevier Inc. doi:https://doi.org/10.1016/B978-0-12-813751-2.00003-6
• Teske, J. A. (2019). Rat models of obesity, metabolic syndrome and diabetes. In The Laboratory Rat, 3rd edition. Elsevier Inc.
• Nixonm, J., Kotz, C., Novak, C., Billington, C., & Teske, J. (2013). Neuropeptides controlling energy balance: orexins and neuromedins. In Handbook of Experimental Pharmacology(pp 77-109). Berlin, Heidelberg: Springer-Verlag.
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  Editor(s): Joost, HG
• Nixon, J., Kotz, C., Novak, C., Billington, C., & Teske, J. (2012). Neuropeptides controlling energy balance: orexins and neuromedins. In Handbook of Experimental Pharmacology(pp 77-109). Berlin, Heidelberg: Springer-Verlag.
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  Editor(s): Joost, HG
• Teske, J., & Mavanji, V. (2012). Energy expenditure: role of orexin. In Sleep Hormones(pp 91-109). Atlanta, GA: Elsevier Inc.
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  Editor(s): Litwack, G

Journals/Publications

• Kostiew, K. N., Tuli, D., Coborn, J. E., Sinton, C. M., & Teske, J. A. (2024). Behavioral phenotyping based on physical inactivity can predict sleep in female rats before, during, and after sleep disruption. Journal of neuroscience methods, 402, 110030.
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  A noninvasive method that can accurately quantify sleep before, during, and after sleep disruption (SD) has not been validated in female rats across their estrous cycle. In female rats, we hypothesized that the duration of physical inactivity (PIA) required to predict sleep would 1) change with the differences in baseline sleep between the circadian and estrous cycle phases and 2) predict sleep and the change in sleep (Δsleep) before, during, and after SD independent of circadian and estrous cycle phase.
• Kostiew, K. N., Tuli, D., Coborn, J., Sinton, C. M., & Teske, J. A. (2024). Behavioral phenotyping based on physical inactivity can predict sleep in female rats before, during, and after sleep disruption. J Neurosci Methods.. doi:10.1016/j.jneumeth.2023.110030
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  A noninvasive method that can accurately quantify sleep before, during, and after sleep disruption (SD) has not been validated in female rats across their estrous cycle. In female rats, we hypothesized that the duration of physical inactivity (PIA) required to predict sleep would 1) change with the differences in baseline sleep between the circadian and estrous cycle phases and 2) predict sleep and the change in sleep (Δsleep) before, during, and after SD independent of circadian and estrous cycle phase.EEG, EMG, physical activity and estrous cycle phase were measured in female Sprague-Dawley rats before, during, and after SD. Sleep was determined by two methods [EEG/EMG and a duration of continuous PIA (i.e., PIA criterion)]. Reliability between the methods was tested with a previously validated criterion (40 s). Sensitivity analyses and criterion-related validity analyses for sleep during SD and recovery were conducted across multiple PIA criteria (10 s-120 s). Predictability between the two methods and Δsleep was calculated.Three criteria (10 s, 20 s, 30 s) predicted baseline sleep independent of circadian and estrous cycle phase. Sleep during SD and recovery were predicted by two criteria (30 s and 10 s). Δsleep between study periods was not reliably predicted by a single PIA criterion.PIA predicted sleep independent of estrous cycle phase in female rats. However, the specific criterion was dependent upon the study period (before, during, and after SD) and circadian phase. Thus, prior work validating a PIA criterion in male rodents is not applicable to the female rat.
• Kostiew, K., Tuli, D., Coborn, J., Sinton, C., & Teske, J. (2024). Behavioral phenotyping based on physical inactivity can predict sleep in female rats before, during, and after sleep disruption. Journal of Neuroscience Methods, 402(402). doi:10.1016/j.jneumeth.2023.110030
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  Background: A noninvasive method that can accurately quantify sleep before, during, and after sleep disruption (SD) has not been validated in female rats across their estrous cycle. In female rats, we hypothesized that the duration of physical inactivity (PIA) required to predict sleep would 1) change with the differences in baseline sleep between the circadian and estrous cycle phases and 2) predict sleep and the change in sleep (Δsleep) before, during, and after SD independent of circadian and estrous cycle phase. New methods: EEG, EMG, physical activity and estrous cycle phase were measured in female Sprague-Dawley rats before, during, and after SD. Sleep was determined by two methods [EEG/EMG and a duration of continuous PIA (i.e., PIA criterion)]. Reliability between the methods was tested with a previously validated criterion (40 s). Sensitivity analyses and criterion-related validity analyses for sleep during SD and recovery were conducted across multiple PIA criteria (10 s–120 s). Predictability between the two methods and Δsleep was calculated. Results/comparison with existing methods: Three criteria (10 s, 20 s, 30 s) predicted baseline sleep independent of circadian and estrous cycle phase. Sleep during SD and recovery were predicted by two criteria (30 s and 10 s). Δsleep between study periods was not reliably predicted by a single PIA criterion. Conclusion: PIA predicted sleep independent of estrous cycle phase in female rats. However, the specific criterion was dependent upon the study period (before, during, and after SD) and circadian phase. Thus, prior work validating a PIA criterion in male rodents is not applicable to the female rat.
• Sandoval-Caballero, C., Jara, J., Luarte, L., Teske, J., Perez-Leighton, C., & Jiménez, Y. (2024). Control of motivation for sucrose in the paraventricular hypothalamic nucleus by dynorphin peptides and the kappa opioid receptor. Appetite, 200. doi:10.1016/j.appet.2024.107504
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  The dynorphin peptides are the endogenous ligands for the kappa opioid receptor (KOR) and regulate food intake. Administration of dynorphin-A1-13 (DYN) in the paraventricular hypothalamic nucleus (PVN) increases palatable food intake, and this effect is blocked by co-administration of the orexin-A neuropeptide, which is co-released with DYN in PVN from neurons located in the lateral hypothalamus. While PVN administration of DYN increases palatable food intake, whether it increases food-seeking behaviors has yet to be examined. We tested the effects of DYN and norBNI (a KOR antagonist) on the seeking and consumption of sucrose using a progressive ratio (PR) and demand curve (DC) tasks. In PVN, DYN did not alter the sucrose breaking point (BP) in the PR task nor the elasticity or intensity of demand for sucrose in the DC task. Still, DYN reduced the delay in obtaining sucrose and increased licks during sucrose intake in the PR task, irrespective of the co-administration of orexin-A. In PVN, norBNI increased the delay in obtaining sucrose and reduced licks during sucrose intake in the PR task while increasing elasticity without altering intensity of demand in the DC task. However, subcutaneous norBNI reduced the BP for sucrose and increased the delay in obtaining sucrose in the PR task while reducing the elasticity of demand. Together, these data show different effects of systemic and PVN blockade of KOR on food-seeking, consummatory behaviors, and incentive motivation for sucrose and suggest that KOR activity in PVN is necessary but not sufficient to drive seeking behaviors for palatable food.
• Wei, M., Teske, J. A., Mashaqi, S., & Combs, D. A. (2025). Obstructive Sleep Apnea, the NLRP3 inflammasome and the potential effects of incretin therapies. Frontiers in Sleep, 3.
• Houser, M. M., Coborn, J. E., Sinton, C. M., Perez-Leighton, C. E., & Teske, J. A. (2021). Stress does not account for weight gain during sleep disruption in male rats. Neuroscience Letters.
• Houser, M. M., Coborn, J. E., Sinton, C. M., Perez-Leighton, C. E., & Teske, J. A. (2023). Sleep loss in male rats contributes more to weight gain during sleep disruption than stress assessed by corticosterone. Neuroscience letters, 792, 136959.
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  Sleep disruption (SD) promotes stress which may mediate the effect of SD induced by noise on bodyweight gain and food intake. We determined if the change in bodyweight during SD caused by noise was driven by stress (assessed by corticosterone) and whether the effects of noise on SD, stress and bodyweight were specific to the method of SD or a consequence of SD per se. We isolated stress from SD due to noise by exposing rats to noise during the dark to test whether dark noise stimulated weight gain, stress and food intake. Male Sprague-Dawley rats slept undisturbed, were exposed to noise during both circadian phases (light vs dark) and light gentle handling. Bodyweight, food intake, physical activity, vigilance states, and plasma corticosterone were determined. Dark noise did not affect vigilance states. Unlike light noise, dark noise and light gentle handling did not stimulate weight gain or food intake. Only gentle handling significantly increased corticosterone levels. Noise during the light increasesed weight gain and food intake by causing SD and these effects were not driven by stress as assessed by corticosterone. These results may have significant implications for developing translational models of insomnia-induced obesity in humans.
• Mattar, P., Jaque, C., Teske, J. A., Morselli, E., Kerr, B., Cortés, V., Baudrand, R., & Perez-Leighton, C. E. (2023). Impact of short and long exposure to cafeteria diet on food intake and white adipose tissue lipolysis mediated by glucagon-like peptide 1 receptor. Frontiers in endocrinology, 14, 1164047.
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  The modern food environment facilitates excessive calorie intake, a major driver of obesity. Glucagon-like peptide 1 (GLP1) is a neuroendocrine peptide that has been the basis for developing new pharmacotherapies against obesity. The GLP1 receptor (GLP1R) is expressed in central and peripheral tissues, and activation of GLP1R reduces food intake, increases the expression of thermogenic proteins in brown adipose tissue (BAT), and enhances lipolysis in white adipose tissue (WAT). Obesity decreases the efficiency of GLP1R agonists in reducing food intake and body weight. Still, whether palatable food intake before or during the early development of obesity reduces the effects of GLP1R agonists on food intake and adipose tissue metabolism remains undetermined. Further, whether GLP1R expressed in WAT contributes to these effects is unclear.
• Mavanji, V., Teske, J. A., Kotz, C. M., & Pellizzer, G. (2023). Changes in sensorimotor cortex oscillatory activity by orexin-A in the ventrolateral preoptic area of the hypothalamus reflect increased muscle tone. Journal of neuroscience research, 101(8), 1305-1323.
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  Orexin-A (OXA) is a hypothalamic neuropeptide implicated in the regulation of wakefulness, appetite, reward processing, muscle tone, motor activity, and other physiological processes. The broad range of systems affected stems from the widespread projections of orexin neurons toward multiple brain regions regulating numerous physiological processes. Orexin neurons integrate nutritional, energetic, and behavioral cues and modulate the functions of target structures. Orexin promotes spontaneous physical activity (SPA), and we recently showed that orexin injected into the ventrolateral preoptic area (VLPO) of the hypothalamus increases behavioral arousal and SPA in rats. However, the specific mechanisms underlying the role of orexin in physical activity are unknown. Here we tested the hypothesis that OXA injected into the VLPO alters the oscillatory activity in the electroencephalogram (EEG) to reflect an increased excitability of the sensorimotor cortex, which may explain the associated increase in SPA. The results showed that OXA increased wakefulness following injections into the VLPO. In addition, OXA altered the power spectrum of the EEG during the awake state by decreasing the power of 5-19 Hz oscillations and increasing the power of >35 Hz oscillations, which are markers of increased sensorimotor excitability. Consistently, we found that OXA induced greater muscle activity. Furthermore, we found a similar change in power spectrum during slow-wave sleep, which suggests that OXA altered the EEG activity in a fundamental way, even in the absence of physical activity. These results support the idea that OXA increases the excitability of the sensorimotor system, which may explain the corresponding increase in awake time, muscle tone, and SPA.
• Sandoval-Caballero, C., Luarte, L., Jiménez, Y., Jaque, C., Cifuentes, F., Arenas, G. A., Figueroa, M., Jara, J., Olszewski, P. K., Teske, J. A., & Pérez-Leighton, C. E. (2023). Meta-analysis of pre-clinical studies on the effects of opioid receptor ligands on food intake, motivation, and choice. Neuroscience and biobehavioral reviews, 152, 105288.
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  The opioid receptors (OR) regulate food intake. Still, despite extensive pre-clinical research, the overall effects and individual contribution of the mu (MOR), kappa (KOR), and delta (DOR) OR subtypes to feeding behaviors and food intake remain unclear. To address this, we conducted a pre-registered systematic search and meta-analysis of rodent dose-response studies to evaluate the impact of central and peripheral administration of non-selective and selective OR ligands on intake, motivation, and choice of food. All studies had a high bias risk. Still, the meta-analysis confirmed the overall orexigenic and anorexigenic effects of OR agonists and antagonists, respectively. Our results support a larger orexigenic role for central MOR agonists among OR subtypes and that peripheral OR antagonists reduce motivation for and intake of preferred foods. In binary food choice studies, peripheral OR agonists selectively increase the intake of fat-preferred foods; in contrast, they did not increase the intake of sweet carbohydrate-preferred foods. Overall, these data support that OR regulation of intake, motivation, and choice is influenced by food macronutrient composition.
• Mattar, P., Uribe-Cerda, S., Pezoa, C., Guarnieri, T., Kotz, C. M., Teske, J. A., Morselli, E., & Perez-Leighton, C. (2022). Brain site-specific regulation of hedonic intake by orexin and DYN peptides: role of the PVN and obesity. Nutritional neuroscience, 25(5), 1105-1114.
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  The orexin peptides promote hedonic intake and other reward behaviors through different brain sites. The opioid dynorphin peptides are co-released with orexin peptides but block their effects on reward in the ventral tegmental area (VTA). We previously showed that in the paraventricular hypothalamic nucleus (PVN), dynorphin and not orexin peptides enhance hedonic intake, suggesting they have brain-site-specific effects. Obesity alters the expression of orexin and dynorphin receptors, but whether their expression across different brain sites is important to hedonic intake is unclear. We hypothesized that hedonic intake is regulated by orexin and dynorphin peptides in PVN and that hedonic intake in obesity correlates with expression of their receptors. Here we show that in mice, injection of DYN-A (an opioid dynorphin peptide) in the PVN enhanced hedonic intake, whereas in the VTA, injection of OXA (orexin-A, an orexin peptide) enhanced hedonic intake. In PVN, OXA blunted the increase in hedonic intake caused by DYN-A. In PVN, injection of norBNI (opioid receptor antagonist) reduced hedonic intake but a subsequent OXA injection failed to increase hedonic intake, suggesting that OXA activity in PVN is not influenced by endogenous opioid activity. In the PVN, DYN-A increased the intake of the less-preferred food in a two-food choice task. In obese mice fed a cafeteria diet, orexin 1 receptor mRNA across brain sites involved in hedonic intake correlated with fat preference but not caloric intake. Together, these data support that orexin and dynorphin peptides regulate hedonic intake in an opposing manner with brain-site-specific effects.
• Novak, C. M., Jiang, X., Wang, C., Teske, J. A., Kotz, C. M., & Levine, J. A. (2021). Caloric restriction and physical activity in zebrafish (Danio rerio). Neuroscience letters, 383(1-2), 99-104.
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  Understanding the mechanism of energy flux may be critical for explaining how obesity has emerged as a public health epidemic. It is known that changes in caloric intake predictably alter physical activity levels (PA) in mammals. Here, our goal was to test the hypothesis that fasting induces a biphasic pattern of change in PA by measuring PA before and after long-term food deprivation in zebrafish. Compared to control-fed fish, food-deprived fish showed a significant increase in PA levels during the first 2 days of food deprivation. Subsequently, however, fasted fish showed a significant chronic decrease in PA compared to fish fed at weight-maintenance levels. These data are comparable to those seen with mammals, which also show a biphasic response of PA to caloric restriction. In a separate group of fish, long-term food deprivation, associated with decreases in PA, induced a significant increase in brain preproorexin mRNA levels compared to fed controls. No change in orexin mRNA was seen after 2 days of food deprivation. The finding that orexin mRNA expression is altered only after long-term starvation suggests that orexin may be coupled with the changes in PA seen at this time. Thus, the association between negative energy balance and reductions in PA occurs across genera in biology and is associated with predictable neurological changes in brain gene expression.
• Mattar, P., Uribe-Cerda, S., Pezoa, C., Guarnieri, T., Kotz, C. M., Teske, J. A., Morselli, E., & Perez-Leighton, C. E. (2020). Brain site specific regulation of hedonic intake by orexin and DYN peptides: Role of the PVN and obesity. Nutritional Neuroscience, 5, 1-10. doi:doi: 10.1080/1028415X.2020.1840049.
• Coborn, J. E., Lessie, R. E., Sinton, C. M., Rance, N. E., Perez-Leighton, C. E., & Teske, J. A. (2019). Noise-induced sleep disruption increases weight gain and decreases energy metabolism in female rats. International journal of obesity, 43(9), 1759-1768. doi:10.1038/s41366-018-0293-9
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  Inadequate sleep increases obesity and environmental noise contributes to poor sleep. However, women may be more vulnerable to noise and hence more susceptible to sleep disruption-induced weight gain than men. In male rats, exposure to environmental (i.e. ambient) noise disrupts sleep and increases feeding and weight gain. However, the effects of environmental noise on sleep and weight gain in female rats are unknown. Thus, this study was designed to determine whether noise exposure would disturb sleep, increase feeding and weight gain and alter the length of the estrous cycle in female rats.
• Coborn, J., Lessie, R., Sinton, C., Rance, N., Perez-Leighton, C., & Teske, J. (2019). Noise-induced sleep disruption increases weight gain and decreases energy metabolism in female rats. International Journal of Obesity, 43(9). doi:10.1038/s41366-018-0293-9
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  Background/objectives: Inadequate sleep increases obesity and environmental noise contributes to poor sleep. However, women may be more vulnerable to noise and hence more susceptible to sleep disruption-induced weight gain than men. In male rats, exposure to environmental (i.e. ambient) noise disrupts sleep and increases feeding and weight gain. However, the effects of environmental noise on sleep and weight gain in female rats are unknown. Thus, this study was designed to determine whether noise exposure would disturb sleep, increase feeding and weight gain and alter the length of the estrous cycle in female rats. Subjects/methods: Female rats (12 weeks old) were exposed to noise for 17d (8 h/d during the light period) to determine the effects of noise on weight gain and food intake. In a separate set of females, estrous cycle phase and length, EEG, EMG, spontaneous physical activity and energy expenditure were recorded continuously for 27d during baseline (control, 9d), noise exposure (8 h/d, 9d) and recovery (9d) from sleep disruption. Results: Noise exposure significantly increased weight gain and food intake compared to females that slept undisturbed. Noise also significantly increased wakefulness, reduced sleep and resulted in rebound sleep during the recovery period. Total energy expenditure was significantly lower during both noise exposure and recovery due to lower energy expenditure during spontaneous physical activity and sleep. Notably, noise did not alter the estrous cycle length. Conclusions: As previously observed in male rats, noise exposure disrupted sleep and increased weight gain in females but did not alter the length of the estrous cycle. This is the first demonstration of weight gain in female rats during sleep disruption. We conclude that the sleep disruption caused by exposure to environmental noise is a significant tool for determining how sleep loss contributes to obesity in females.
• Teske, J. A., Coborn, J. E., & Sinton, C. M. (2019). 0057 Sex-dependent Effects of Suvorexant on Sleep Fragmentation During Sleep Disruption Due to Noise Exposure.. Sleep, 42(Supplement_1), A23-A24. doi:10.1093/sleep/zsz067.056
• Alvarez, B., Barrientos, T., Gac, L., Teske, J. A., & Perez-leighton, C. E. (2018). Effects on Hedonic Feeding, Energy Expenditure and Balance of the Non-opioid Peptide DYN-A2-17.. Neuroscience, 371, 337-345. doi:10.1016/j.neuroscience.2017.11.044
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  The dynorphin (DYN) peptide family includes opioid and non-opioid peptides, yet the physiological role of the non-opioid DYN peptides remains poorly understood. Recent evidence shows that administering the non-opioid peptide DYN-A2-17 into the paraventricular hypothalamic nucleus (PVN) simultaneously increased short-term intake of standard rodent chow and spontaneous physical activity (SPA). The present studies aimed to expand upon the mechanisms and role of DYN-A2-17 on food intake and energy expenditure. Injection of DYN-A2-17 in PVN increased SPA, energy expenditure and wheel running in the absence of food. Repeated DYN-A2-17 injection in PVN increased short-term chow intake, but this effect habituated over time and failed to alter cumulative food intake, body weight or adiposity. Pre-treatment with a CRF receptor antagonist into PVN blocked the effects of DYN-A2-17 on food intake while injection of DYN-A2-17 in PVN increased plasma ACTH. Finally, as DYN peptides are co-released with orexin peptides, we compared the effects of DYN-A2-17 to orexin-A and the opioid peptide DYN-A1-13 on food choice and intake in PVN when palatable snacks and chow were available. DYN-A1-13 selectively increased intake of palatable snacks. DYN-A2-17 and orexin-A decreased palatable snack intake while orexin-A also increased chow intake. These findings demonstrate that the non-opioid peptide DYN-A2-17 acutely regulates physical activity, energy expenditure and food intake without long-term effects on energy balance. These data also propose different roles of opioid, non-opioid DYN and orexin peptides on food choice and intake when palatable and non-palatable food options are available.
• Coborn, J. E., Lessie, R. E., Perez-Leighton, C. E., Sinton, C. M., & Teske, J. A. (2018). 0224 Sleep Disruption Due To Environmental Noise Exposure Increases Weight Gain By Modulating Energy Intake And Expenditure In Intact Female Rats. Sleep, 41(suppl_1), A87-A88. doi:10.1093/sleep/zsy061.223
• Alvarez, B., Barrientos, T., Gac, L., Teske, J. A., & Perez-Leighton, C. E. (2017). Effects on Hedonic Feeding, Energy Expenditure and Balance of the Non-opioid Peptide DYN-A2-17. Neuroscience, 371, 337-345.
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  The dynorphin (DYN) peptide family includes opioid and non-opioid peptides, yet the physiological role of the non-opioid DYN peptides remains poorly understood. Recent evidence shows that administering the non-opioid peptide DYN-A2-17 into the paraventricular hypothalamic nucleus (PVN) simultaneously increased short-term intake of standard rodent chow and spontaneous physical activity (SPA). The present studies aimed to expand upon the mechanisms and role of DYN-A2-17 on food intake and energy expenditure. Injection of DYN-A2-17 in PVN increased SPA, energy expenditure and wheel running in the absence of food. Repeated DYN-A2-17 injection in PVN increased short-term chow intake, but this effect habituated over time and failed to alter cumulative food intake, body weight or adiposity. Pre-treatment with a CRF receptor antagonist into PVN blocked the effects of DYN-A2-17 on food intake while injection of DYN-A2-17 in PVN increased plasma ACTH. Finally, as DYN peptides are co-released with orexin peptides, we compared the effects of DYN-A2-17 to orexin-A and the opioid peptide DYN-A1-13 on food choice and intake in PVN when palatable snacks and chow were available. DYN-A1-13 selectively increased intake of palatable snacks. DYN-A2-17 and orexin-A decreased palatable snack intake while orexin-A also increased chow intake. These findings demonstrate that the non-opioid peptide DYN-A2-17 acutely regulates physical activity, energy expenditure and food intake without long-term effects on energy balance. These data also propose different roles of opioid, non-opioid DYN and orexin peptides on food choice and intake when palatable and non-palatable food options are available.
• Coborn, J. E., DePorter, D. P., Mavanji, V., Sinton, C. M., Kotz, C. M., Billington, C. J., & Teske, J. A. (2017). Role of orexin-A in the ventrolateral preoptic area on components of total energy expenditure. International journal of obesity (2005), 41(8), 1256-1262.
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  Identifying whether components of total energy expenditure (EE) are affected by orexin receptor (OXR1 and OXR2) stimulation or antagonism with dual orexin receptor antagonists (DORAs) has relevance for obesity treatment. Orexin receptor stimulation reduces weight gain by increasing total EE and EE during spontaneous physical activity (SPA).
• Coborn, J. E., Houser, M. M., Perez-Leighton, C. E., & Teske, J. A. (2017). Role of Sex and the Environment in Moderating Weight Gain Due to Inadequate Sleep. Current obesity reports, 6(4), 397-404.
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  The growing prevalence of obesity, inadequate sleep and sleep disorders together with the negative impact of lack of sleep on overall health highlights the need for therapies targeted towards weight gain due to sleep loss.
• DePorter, D. P., Coborn, J. E., & Teske, J. A. (2017). Partial Sleep Deprivation Reduces the Efficacy of Orexin-A to Stimulate Physical Activity and Energy Expenditure. Obesity (Silver Spring, Md.), 25(10), 1716-1722.
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  Sufficient sleep is required for weight maintenance. Sleep deprivation due to noise exposure stimulates weight gain by increasing hyperphagia and reducing energy expenditure (EE). Yet the mechanistic basis underlying the weight gain response is unclear. Orexin-A promotes arousal and negative energy balance, and orexin terminals project to the ventrolateral preoptic area (VLPO), which is involved in sleep-to-wake transitions. To determine whether sleep deprivation reduces orexin function in VLPO and to test the hypothesis that sleep deprivation would attenuate the orexin-A-stimulated increase in arousal, physical activity (PA), and EE.
• Kotz, C. M., Perez-Leighton, C. E., Teske, J. A., & Billington, C. J. (2017). Spontaneous Physical Activity Defends Against Obesity. Current obesity reports, 6(4), 362-370.
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  Spontaneous physical activity (SPA) is a physical activity not motivated by a rewarding goal, such as that associated with food-seeking or wheel-running behavior. SPA is often thought of as only "fidgeting," but that is a mischaracterization, since fidgety behavior can be linked to stereotypies in neurodegenerative disease and other movement disorders. Instead, SPA should be thought of as all physical activity behavior that emanates from an unconscious drive for movement.
• Mella, R., Schmidt, C. B., Romagnoli, P. P., Teske, J. A., & Perez-Leighton, C. (2017). The Food Environment, Preference, and Experience Modulate the Effects of Exendin-4 on Food Intake and Reward. Obesity (Silver Spring, Md.), 25(11), 1844-1851.
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  The obesogenic food environment facilitates access to multiple palatable foods. Exendin-4 (EX4) is a glucagon-like peptide 1 receptor (GLP1R) agonist that inhibits food intake and has been proposed as an obesity therapy. This study tested whether the composition of the food environment and experience with palatable foods modulate the effects of EX4 on food intake and reward.
• Parrish, J. B., & Teske, J. A. (2017). Acute partial sleep deprivation due to environmental noise increases weight gain by reducing energy expenditure in rodents. Obesity (Silver Spring, Md.), 25(1), 141-146.
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  Chronic partial sleep deprivation (SD) by environmental noise exposure increases weight gain and feeding in rodents, which contrasts weight loss after acute SD by physical methods. This study tested whether acute environmental noise exposure reduced sleep and its effect on weight gain, food intake, physical activity, and energy expenditure (EE). It was hypothesized that acute exposure would (1) increase weight gain and feeding and (2) reduce sleep, physical activity, and EE (total and individual components); and (3) behavioral changes would persist throughout recovery from SD.
• Teske, J. A., Coborn, J. E., & DePorter, D. P. (2017). Partial Sleep Deprivation Reduces the Efficacy of Orexin-A to Stimulate Physical Activity and Energy Expenditure: Sleep Deprivation Dampens EE During Physical Activity. Obesity, 25(10), 1716-1722. doi:10.1002/oby.21944
• Teske, J. A., Mella, R., Schmidt, C. B., Romagnoli, P., & Perez-Leighton, C. (2017). The Food Environment, Preference, and Experience Modulate the Effects of Exendin-4 on Food Intake and Reward: Food Preference and Experience Regulate EX4 Effect. Obesity, 25(11), 1844-1851. doi:10.1002/oby.21939
• Gac, L., Butterick, T., Duffy, C., Teske, J., & Perez-Leighton, C. (2016). Role of the non-opioid dynorphin peptide des-Tyr-dynorphin (DYN-A2-17) in food intake and physical activity, and its interaction with orexin-A.. Peptides, 76. doi:10.1016/j.peptides.2015.12.001
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  Food intake and physical activity are regulated by multiple neuropeptides, including orexin and dynorphin (DYN). Orexin-A (OXA) is one of two orexin peptides with robust roles in regulation of food intake and spontaneous physical activity (SPA). DYN collectively refers to several peptides, some of which act through opioid receptors (opioid DYN) and some whose biological effects are not mediated by opioid receptors (non-opioid DYN). While opioid DYN is known to increase food intake, the effects of non-opioid DYN peptides on food intake and SPA are unknown. Neurons that co-express and release OXA and DYN are located within the lateral hypothalamus. Limited evidence suggests that OXA and opioid DYN peptides can interact to modulate some aspects of behaviors classically related to orexin peptide function. The paraventricular hypothalamic nucleus (PVN) is a brain area where OXA and DYN peptides might interact to modulate food intake and SPA. We demonstrate that injection of des-Tyr-dynorphin (DYN-A2-17, a non opioid DYN peptide) into the PVN increases food intake and SPA in adult mice. Co-injection of DYN-A2-17 and OXA in the PVN further increases food intake compared to DYN-A2-17 or OXA alone. This is the first report describing the effects of non-opioid DYN-A2-17 on food intake and SPA, and suggests that DYN-A2-17 interacts with OXA in the PVN to modulate food intake. Our data suggest a novel function for non-opioid DYN-A2-17 on food intake, supporting the concept that some behavioral effects of the orexin neurons result from combined actions of the orexin and DYN peptides.
• Mullington, J. M., Abbott, S. M., Carroll, J. E., Davis, C. J., Dijk, D., Dinges, D. F., Gehrman, P. R., Ginsburg, G. S., Gozal, D., Haack, M., Lim, D. C., Macrea, M., Pack, A. I., Plante, D. T., Teske, J. A., & Zee, P. C. (2016). Developing Biomarker Arrays Predicting Sleep and Circadian-Coupled Risks to Health. Sleep, 39(4), 727-36.
• Teske, J. A., & Parrish, J. B. (2016). Acute partial sleep deprivation due to environmental noise increases weight gain by reducing energy expenditure in rodents: Acute Partial Sleep Deprivation Reduces Energy Expenditure. Obesity, 25(1), 141-146. doi:10.1002/oby.21703
• Teske, J. A., Perez-Leighton, C. E., Noble, E. E., Wang, C., Billington, C. J., & Kotz, C. M. (2016). Effect of Housing Types on Growth, Feeding, Physical Activity, and Anxiety-Like Behavior in Male Sprague-Dawley Rats. Frontiers in nutrition, 3, 4.
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  Animal welfare and accurate data collection are equally important in rodent research. Housing influences study outcomes and can challenge studies that monitor feeding, so housing choice needs to be evidence-based. The goal of these studies was to (1) compare established measures of well-being between rodents housed in wire grid-bottom floors with a resting platform compared to solid-bottom floors with bedding and (2) determine whether presence of a chewable device (Nylabone) affects orexin-A-induced hyperphagia.
• Gac, L., Butterick, T. A., Duffy, C. M., Teske, J. A., & Perez-Leighton, C. E. (2015). Role of the non-opioid dynorphin peptide des-Tyr-dynorphin (DYN-A2-17) in food intake and physical activity, and its interaction with orexin-A. Peptides.
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  Food intake and physical activity are regulated by multiple neuropeptides, including orexin and dynorphin (DYN). Orexin-A (OXA) is one of two orexin peptides with robust roles in regulation of food intake and spontaneous physical activity (SPA). DYN collectively refers to a class of several peptides, some of which act through opioid receptors (opioid DYN) and some whose biological effects are not mediated by opioid receptors (non-opioid DYN). While opioid DYN is known to increase food intake, the effects of non-opioid DYN peptides on food intake and SPA are unknown. Neurons that co-express and release OXA and DYN are located within the lateral hypothalamus. Limited evidence suggests that OXA and opioid DYN peptides can interact to modulate some aspects of behaviors classically related to orexin peptide function. The paraventricular hypothalamic nucleus (PVN) is a brain area where OXA and DYN peptides might interact to modulate food intake and SPA. We demonstrate that injection of des-Tyr-dynorphin (DYN-A2-17, a non opioid DYN peptide) into the PVN increases food intake and SPA in adult mice. Co-injection of DYN-A2-17 and OXA in the PVN further increases food intake compared to DYN-A2-17 or OXA alone. This is the first report describing the effects of non-opioid DYN-A2-17 on food intake and SPA, and suggests that DYN-A2-17 interacts with OXA in the PVN to modulate food intake. Our data suggest a novel function for non-opioid DYN-A2-17 on food intake, supporting the concept that some behavioral effects of the orexin neurons result from combined actions of the orexin and DYN peptides.
• Gac, L., Kanaly, V., Ramirez, V., Teske, J. A., Pinto, M. P., & Perez-Leighton, C. E. (2015). Behavioral characterization of a model of differential susceptibility to obesity induced by standard and personalized cafeteria diet feeding. Physiology & behavior, 152(Pt A), 315-22.
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  Despite the increase in obesity prevalence over the last decades, humans show large inter-individual variability for susceptibility to diet-induced obesity. Understanding the biological basis of this susceptibility could identify new therapeutic alternatives against obesity. We characterized behavioral changes associated with propensity to obesity induced by cafeteria (CAF) diet consumption in mice. We show that Balb/c mice fed a CAF diet display a large inter-individual variability in susceptibility to diet-induced obesity, such that based on changes in adiposity we can classify mice as obesity prone (OP) or obesity resistant (OR). Both OP and OR were hyperphagic relative to control-fed mice but caloric intake was similar between OP and OR mice. In contrast, OR had a larger increase in locomotor activity following CAF diet compared to OP mice. Obesity resistant and prone mice showed similar intake of sweet snacks, but OR ate more savory snacks than OP mice. Two bottle sucrose preference tests showed that OP decreased their sucrose preference compared to OR mice after CAF diet feeding. Finally, to test the robustness of the OR phenotype in response to further increases in caloric intake, we fed OR mice with a personalized CAF (CAF-P) diet based on individual snack preferences. When fed a CAF-P diet, OR increased their calorie intake compared to OP mice fed the standard CAF diet, but did not reach adiposity levels observed in OP mice. Together, our data show the contribution of hedonic intake, individual snack preference and physical activity to individual susceptibility to obesity in Balb/c mice fed a standard and personalized cafeteria-style diet.
• Mavanji, V., Perez-Leighton, C. E., Kotz, C. M., Billington, C. J., Parthasarathy, S., Sinton, C. M., & Teske, J. A. (2015). Promotion of Wakefulness and Energy Expenditure by Orexin-A in the Ventrolateral Preoptic Area. Sleep, 38(9), 1361-70.
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  The ventrolateral preoptic area (VLPO) and the orexin/hypocretin neuronal system are key regulators of sleep onset, transitions between vigilance states, and energy homeostasis. Reciprocal projections exist between the VLPO and orexin/hypocretin neurons. Although the importance of the VLPO to sleep regulation is clear, it is unknown whether VLPO neurons are involved in energy balance. The purpose of these studies was to determine if the VLPO is a site of action for orexin-A, and which orexin receptor subtype(s) would mediate these effects of orexin-A. We hypothesized that orexin-A in the VLPO modulates behaviors (sleep and wakefulness, feeding, spontaneous physical activity [SPA]) to increase energy expenditure.
• Nixon, J. P., Mavanji, V., Butterick, T. A., Billington, C. J., Kotz, C. M., & Teske, J. A. (2015). Sleep disorders, obesity, and aging: The role of orexin. Ageing Res Rev., 63-73. doi:10.1016/j.arr.2014.11.001
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  The hypothalamic neuropeptides orexin A and B (hypocretin 1 and 2) are important homeostatic mediators of central control of energy metabolism and maintenance of sleep/wake states. Dysregulation or loss of orexin signaling has been linked to narcolepsy, obesity, and age-related disorders. In this review, we present an overview of our current understanding of orexin function, focusing on sleep disorders, energy balance, and aging, in both rodents and humans. We first discuss animal models used in studies of obesity and sleep, including loss of function using transgenic or viral-mediated approaches, gain of function models using exogenous delivery of orexin receptor agonist, and naturally-occurring models in which orexin responsiveness varies by individual. We next explore rodent models of orexin in aging, presenting evidence that orexin loss contributes to age-related changes in sleep and energy balance. In the next section, we focus on clinical importance of orexin in human obesity, sleep, and aging. We include discussion of orexin loss in narcolepsy and potential importance of orexin in insomnia, correlations between animal and human studies of age-related decline, and evidence for orexin involvement in age-related changes in cognitive performance. Finally, we present a summary of recent studies of orexin in neurodegenerative disease. We conclude that orexin acts as an integrative homeostatic signal influencing numerous brain regions, and that this pivotal role results in potential dysregulation of multiple physiological processes when orexin signaling is disrupted or lost.
• Teske, J. A., Parthasarathy, S., Mavanji, V., Perez-Leighton, C. E., Kotz, C. M., Billington, C. J., & Sinton, C. M. (2015). Promotion of Wakefulness and Energy Expenditure by Orexin-A in the Ventrolateral Preoptic Area. Sleep, 38(9), 1361-1370. doi:10.5665/sleep.4970
• Nixon, J. P., Mavanji, V., Butterick, T. A., Billington, C. J., Kotz, C. M., & Teske, J. A. (2014). Sleep disorders, obesity, and aging: The role of orexin. Ageing research reviews.
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  The hypothalamic neuropeptides orexin A and B (hypocretin 1 and 2) are important homeostatic mediators of central control of energy metabolism and maintenance of sleep/wake states. Dysregulation or loss of orexin signaling has been linked to narcolepsy, obesity, and age-related disorders. In this review, we present an overview of our current understanding of orexin function, focusing on sleep disorders, energy balance, and aging, in both rodents and humans. We first discuss animal models used in studies of obesity and sleep, including loss of function using transgenic or viral-mediated approaches, gain of function models using exogenous delivery of orexin receptor agonist, and naturally-occurring models in which orexin responsiveness varies by individual. We next explore rodent models of orexin in aging, presenting evidence that orexin loss contributes to age-related changes in sleep and energy balance. In the next section, we focus on clinical importance of orexin in human obesity, sleep, and aging. We include discussion of orexin loss in narcolepsy and potential importance of orexin in insomnia, correlations between animal and human studies of age-related decline, and evidence for orexin involvement in age-related changes in cognitive performance. Finally, we present a summary of recent studies of orexin in neurodegenerative disease. We conclude that orexin acts as an integrative homeostatic signal influencing numerous brain regions, and that this pivotal role results in potential dysregulation of multiple physiological processes when orexin signaling is disrupted or lost.
• Teske, J. A., Billington, C. J., & Kotz, C. M. (2014). Mechanisms underlying obesity resistance associated with high spontaneous physical activity. Neuroscience, 256, 91-100.
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  Abstract: Obesity resistance due to elevated orexin signaling is accompanied by high levels of spontaneous physical activity (SPA). The behavioral and neural mechanisms underlying this observation have not been fully worked out. We determined the contribution of hypothalamic orexin receptors (OXRs) to SPA stimulated by orexin A (OXA), whether OXA-stimulated SPA was secondary to arousal and whether voluntary wheel running led to compensations in 24-h SPA. We further tested whether orexin action on dopamine one receptors (DA1R) in the substantia nigra (SN) plays an important role in the generation of SPA. To test this, SPA response was determined in lean and obese rats with cannulae targeted toward the rostral lateral hypothalamus (rLH) or SN. Sleep/wake states were also measured in rats with rLH cannula and electroencephalogram/electromyogram radiotelemetry transmitters. SPA in lean rats was more sensitive to antagonism of the OX1R and in the early response to the orexin 2 agonist. OXA increased arousal equally in lean and obese rodents, which is discordant from the greater SPA response in lean rats. Obesity-resistant rats ran more and wheel running was directly related to 24-h SPA levels. The OX1R antagonist, SB-334867-A, and the DA1R antagonist, SCH3390, in SN more effectively reduced SPA stimulated by OXA in obesity-resistant rats. These data suggest OXA-stimulated SPA is not secondary to enhanced arousal, propensity for SPA parallels inclination to run and that orexin action on dopaminergic neurons in SN may participate in the mediation of SPA and running wheel activity. © 2013.
• Teske, J. A., Perez-Leighton, C. E., Billington, C. J., & Kotz, C. M. (2014). Methodological considerations for measuring spontaneous physical activity in rodents. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 306(10), R714-R721. doi:10.1152/ajpregu.00479.2013
• Teske, J. A., Perez-Leighton, C. E., Billington, C. J., & Kotz, C. M. (2014). Methodological considerations for measuring spontaneous physical activity in rodents. American journal of physiology. Regulatory, integrative and comparative physiology, 306(10), R714-21.
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  When exploring biological determinants of spontaneous physical activity (SPA), it is critical to consider whether methodological factors differentially affect rodents and the measured SPA. We determined whether acclimation time, sensory stimulation, vendor, or chamber size affected measures in rodents with varying propensity for SPA. We used principal component analysis to determine which SPA components (ambulatory and vertical counts, time in SPA, and distance traveled) best described the variability in SPA measurements. We compared radiotelemetry and infrared photobeams used to measure SPA and exploratory activity. Acclimation time, sensory stimulation, vendor, and chamber size independently influenced SPA, and the effect was moderated by the propensity for SPA. A 24-h acclimation period prior to SPA measurement was sufficient for habituation. Principal component analysis showed that ambulatory and vertical measurements of SPA describe different dimensions of the rodent's SPA behavior. Smaller testing chambers and a sensory attenuation cubicle around the chamber reduced SPA. SPA varies between rodents purchased from different vendors. Radiotelemetry and infrared photobeams differ in their sensitivity to detect phenotypic differences in SPA and exploratory activity. These data highlight methodological considerations in rodent SPA measurement and a need to standardize SPA methodology.
• Kumar, V., Teske, J., Billington, C., & Kotz, C. (2012). Partial sleep deprivation by environmental noise increases food intake and body weight in obesity resistant rats. Obesity.
• Mavanji, V., Teske, J. A., Billington, C. J., & Kotz, C. M. (2013). Partial sleep deprivation by environmental noise increases food intake and body weight in obesity-resistant rats. Obesity, 21(7), 1396-1405.
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  PMID: 23666828;PMCID: PMC3742663;Abstract: Objective Sleep restriction in humans increases risk for obesity, but previous rodent studies show weight loss following sleep deprivation, possibly due to stressful methods used to prevent sleep. Obesity-resistant (OR) rats exhibit consolidated-sleep and resistance to weight gain. It was hypothesized that sleep disruption by a less-stressful method would increase body weight, and the effect of partial sleep deprivation (PSD) on body weight in OR and Sprague-Dawley (SD) rats was examined. Design and Methods OR and SD rats (n = 12/group) were implanted with transmitters to record sleep/wake. After baseline recording, six SD and six OR rats underwent 8 h PSD during light phase for 9 days. Sleep was reduced using recordings of random noise. Sleep/wake states were scored as wakefulness (W), slow-wave-sleep (SWS), and rapid-eye-movement-sleep (REMS). Total number of transitions between stages, SWS-delta-power, food intake, and body weight were documented. Results Exposure to noise decreased SWS and REMS time, while increasing W time. Sleep-deprivation increased the number of transitions between stages and SWS-delta-power. Further, PSD during the rest phase increased recovery sleep during the active phase. The PSD SD and OR rats had greater food intake and body weight compared to controls Conclusions PSD by less-stressful means increases body weight in rats. Also, PSD during the rest phase increases active period sleep. Copyright © 2012 The Obesity Society.
• McNay, E. C., Teske, J. A., Kotz, C. M., Dunn-Meynell, A., Levin, B. E., McCrimmon, R. J., & Sherwin, R. S. (2013). Long-term, intermittent, insulin-induced hypoglycemia produces marked obesity without hyperphagia or insulin resistance: a model for weight gain with intensive insulin therapy. American journal of physiology. Endocrinology and metabolism, 304(2), E131-8.
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  A major side effect of insulin treatment of diabetes is weight gain, which limits patient compliance and may pose additional health risks. Although the mechanisms responsible for this weight gain are poorly understood, it has been suggested that there may be a link to the incidence of recurrent episodes of hypoglycemia. Here we present a rodent model of marked weight gain associated with weekly insulin-induced hypoglycemic episodes in the absence of diabetes. Insulin treatment caused a significant increase in both body weight and fat mass, accompanied by reduced motor activity, lowered thermogenesis in response to a cold challenge, and reduced brown fat uncoupling protein mRNA. However, there was no effect of insulin treatment on total food intake nor on hypothalamic neuropeptide Y or proopiomelanocortin mRNA expression, and insulin-treated animals did not become insulin-resistant. Our results suggest that repeated iatrogenic hypoglycemia leads to weight gain, and that such weight gain is associated with a multifaceted deficit in metabolic regulation rather than to a chronic increase in caloric intake.
• McNay, E., Teske, J., Kotz, C., Dunn-Meynell, A., Levin, B., McCrimmon, R., & Sherwin, R. (2012). Long-term, intermittent, insulin-induced hypoglycemia produces marked obesity in the absence of hyperphagia or insulin resistance: a model for weight gain associated with intensive insulin therapy. American Journal of Physiology Endocrinology and Metabolism.
• Teske, J. A., Billington, C. J., & Kotz, C. M. (2013). Mechanisms underlying obesity resistance associated with high spontaneous physical activity. Neuroscience, 256.
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  Obesity resistance due to elevated orexin signaling is accompanied by high levels of spontaneous physical activity (SPA). The behavioral and neural mechanisms underlying this observation have not been fully worked out. We determined the contribution of hypothalamic orexin receptors (OXRs) to SPA stimulated by orexin A (OXA), whether OXA-stimulated SPA was secondary to arousal and whether voluntary wheel running led to compensations in 24-h SPA. We further tested whether orexin action on dopamine one receptors (DA1R) in the substantia nigra (SN) plays an important role in the generation of SPA. To test this, SPA response was determined in lean and obese rats with cannulae targeted toward the rostral lateral hypothalamus (rLH) or SN. Sleep/wake states were also measured in rats with rLH cannula and electroencephalogram/electromyogram radiotelemetry transmitters. SPA in lean rats was more sensitive to antagonism of the OX1R and in the early response to the orexin 2 agonist. OXA increased arousal equally in lean and obese rodents, which is discordant from the greater SPA response in lean rats. Obesity-resistant rats ran more and wheel running was directly related to 24-h SPA levels. The OX1R antagonist, SB-334867-A, and the DA1R antagonist, SCH3390, in SN more effectively reduced SPA stimulated by OXA in obesity-resistant rats. These data suggest OXA-stimulated SPA is not secondary to enhanced arousal, propensity for SPA parallels inclination to run and that orexin action on dopaminergic neurons in SN may participate in the mediation of SPA and running wheel activity.
• Teske, J. A., Mavanji, V., Billington, C. J., & Kotz, C. M. (2013). Partial sleep deprivation by environmental noise increases food intake and body weight in obesity-resistant rats: Sleep Deprivation and Obesity. Obesity, 21(7), 1396-1405. doi:10.1002/oby.20182
• Teske, J. A., McNay, E. C., Kotz, C. M., Dunn-Meynell, A., Levin, B. E., McCrimmon, R. J., & Sherwin, R. S. (2013). Long-term, intermittent, insulin-induced hypoglycemia produces marked obesity without hyperphagia or insulin resistance: A model for weight gain with intensive insulin therapy. American Journal of Physiology-Endocrinology and Metabolism, 304(2), E131-E138. doi:10.1152/ajpendo.00262.2012
• Teske, J. A., Perez-Leighton, C. E., Billington, C. J., & Kotz, C. M. (2013). Role of the locus coeruleus in enhanced orexin A-induced spontaneous physical activity in obesity-resistant rats. American Journal of Physiology - Regulatory Integrative and Comparative Physiology, 305(11), R1337-R1345.
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  PMID: 24089383;Abstract: Orexin/hypocretin terminals innervate noradrenergic locus coeruleus (LC) neurons that project to the prefrontral cortex, which may influence spontaneous physical activity (SPA) and energy balance. Obesity-resistant (OR) rats have higher orexin receptors (OXR) mRNA in the LC and other brain regions, as well as lower adiposity compared with obese rats. These findings led us to hypothesize that orexin activity in the LC is relevant for the OR phenotype. We compared OR rats to Sprague-Dawley rats. We predicted that: 1) brain OXR expression pattern is sufficient to differentiate OR from non-bred Sprague-Dawley rats; 2) nonresting energy expenditure (NREE) and orexin A (OXA)-stimulated SPA after injection in LC would be greater in OR rats; and 3) the effect of OXA on SPA would be greater than its effect on feeding. OXR mRNA from 11 brain sites and the SPA and feeding responses to OXA in the LC were determined. Body composition, basal SPA, and EE were determined. Principal component analysis of the OXR expression pattern differentiates OR and Sprague-Dawley rats and suggests the OXR mRNA in the LC is important in defining the OR phenotype. Compared with Sprague-Dawley rats, OR rats had greater SPA and NREE and lower resting EE and adiposity. SPA responsivity to OXA in the LC was greater in OR rats compared with Sprague-Dawley rats. OXA in the LC did not stimulate feeding in OR or Sprague-Dawley rats. These data suggest that the LC is a prominent site modulating OXA-stimulated SPA, which promotes lower adiposity and higher nonresting EE.
• Teske, J. A., Perez-Leighton, C. E., Billington, C. J., & Kotz, C. M. (2013). Role of the locus coeruleus in enhanced orexin A-induced spontaneous physical activity in obesity-resistant rats. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 305(11), R1337-R1345. doi:10.1152/ajpregu.00229.2013
• Teske, J. A., Perez-Leighton, C. E., Billington, C. J., & Kotz, C. M. (2013). Role of the locus coeruleus in enhanced orexin A-induced spontaneous physical activity in obesity-resistant rats. American journal of physiology. Regulatory, integrative and comparative physiology, 305(11).
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  Orexin/hypocretin terminals innervate noradrenergic locus coeruleus (LC) neurons that project to the prefrontral cortex, which may influence spontaneous physical activity (SPA) and energy balance. Obesity-resistant (OR) rats have higher orexin receptors (OXR) mRNA in the LC and other brain regions, as well as lower adiposity compared with obese rats. These findings led us to hypothesize that orexin activity in the LC is relevant for the OR phenotype. We compared OR rats to Sprague-Dawley rats. We predicted that: 1) brain OXR expression pattern is sufficient to differentiate OR from non-bred Sprague-Dawley rats; 2) nonresting energy expenditure (NREE) and orexin A (OXA)-stimulated SPA after injection in LC would be greater in OR rats; and 3) the effect of OXA on SPA would be greater than its effect on feeding. OXR mRNA from 11 brain sites and the SPA and feeding responses to OXA in the LC were determined. Body composition, basal SPA, and EE were determined. Principal component analysis of the OXR expression pattern differentiates OR and Sprague-Dawley rats and suggests the OXR mRNA in the LC is important in defining the OR phenotype. Compared with Sprague-Dawley rats, OR rats had greater SPA and NREE and lower resting EE and adiposity. SPA responsivity to OXA in the LC was greater in OR rats compared with Sprague-Dawley rats. OXA in the LC did not stimulate feeding in OR or Sprague-Dawley rats. These data suggest that the LC is a prominent site modulating OXA-stimulated SPA, which promotes lower adiposity and higher nonresting EE.
• Kotz, C., Nixon, J., Butterick, T., Perez-Leighton, C., Teske, J., & Billington, C. (2012). Brain orexin promotes obesity resistance. Annals of the New York Academy of Sciences, 1264(1), 72-86.
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  PMID: 22803681;PMCID: PMC3464355;Abstract: Resistance to obesity is becoming an exception rather than the norm, and understanding mechanisms that lead some to remain lean in spite of an obesigenic environment is critical if we are to find new ways to reverse this trend. Levels of energy intake and physical activity both contribute to body weight management, but it is challenging for most to adopt major long-term changes in either factor. Physical activity outside of formal exercise, also referred to as activity of daily living, and in stricter form, spontaneous physical activity (SPA), may be an attractive modifiable variable for obesity prevention. In this review, we discuss individual variability in SPA and NEAT (nonexercise thermogenesis, or the energy expended by SPA) and its relationship to obesity resistance. The hypothalamic neuropeptide orexin (hypocretin) may play a key role in regulating SPA and NEAT. We discuss how elevated orexin signaling capacity, in the context of a brain network modulating SPA, may play a major role in defining individual variability in SPA and NEAT. Greater activation of this SPA network leads to a lower propensity for fat mass gain and therefore may be an attractive target for obesity prevention and therapy. © 2012 New York Academy of Sciences.
• Kotz, C., Nixon, J., Butterick, T., Perez-Leighton, C., Teske, J., & Billington, C. (2012). Brain orexin promotes obesity resistance. Annals of the New York Academy of Sciences, 1264, 72-86.
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  Resistance to obesity is becoming an exception rather than the norm, and understanding mechanisms that lead some to remain lean in spite of an obesigenic environment is critical if we are to find new ways to reverse this trend. Levels of energy intake and physical activity both contribute to body weight management, but it is challenging for most to adopt major long-term changes in either factor. Physical activity outside of formal exercise, also referred to as activity of daily living, and in stricter form, spontaneous physical activity (SPA), may be an attractive modifiable variable for obesity prevention. In this review, we discuss individual variability in SPA and NEAT (nonexercise thermogenesis, or the energy expended by SPA) and its relationship to obesity resistance. The hypothalamic neuropeptide orexin (hypocretin) may play a key role in regulating SPA and NEAT. We discuss how elevated orexin signaling capacity, in the context of a brain network modulating SPA, may play a major role in defining individual variability in SPA and NEAT. Greater activation of this SPA network leads to a lower propensity for fat mass gain and therefore may be an attractive target for obesity prevention and therapy.
• Kotz, C., Nixon, J., Perez-Leighton, C., Butterick-Peterson, T., Teske, J., & Billington, C. (2012). Brain orexin promotes obesity resistance. Annals of the New York Academy of Sciences, 1264(1), 72-86.
• Mavanji, V., Billington, C. J., Kotz, C. M., & Teske, J. A. (2012). Sleep and obesity: A focus on animal models. Neuroscience and Biobehavioral Reviews, 36(3), 1015-1029.
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  PMID: 22266350;PMCID: PMC3288260;Abstract: The rapid rise in obesity prevalence in the modern world parallels a significant reduction in restorative sleep (. Agras et al., 2004; Dixon et al., 2007, 2001; Gangwisch and Heymsfield, 2004; Gupta et al., 2002; Sekine et al., 2002; Vioque et al., 2000; Wolk et al., 2003). Reduced sleep time and quality increases the risk for obesity, but the underlying mechanisms remain unclear (. Gangwisch et al., 2005; Hicks et al., 1986; Imaki et al., 2002; Jennings et al., 2007; Moreno et al., 2006). A majority of the theories linking human sleep disturbances and obesity rely on self-reported sleep. However, studies with objective measurements of sleep/wake parameters suggest a U-shaped relationship between sleep and obesity. Studies in animal models are needed to improve our understanding of the association between sleep disturbances and obesity. Genetic and experimenter-induced models mimicking characteristics of human obesity are now available and these animal models will be useful in understanding whether sleep disturbances determine propensity for obesity, or result from obesity. These models exhibit weight gain profiles consistently different from control animals. Thus a careful evaluation of animal models will provide insight into the relationship between sleep disturbances and obesity in humans.In this review we first briefly consider the fundamentals of sleep and key sleep disturbances, such as sleep fragmentation and excessive daytime sleepiness (EDS), observed in obese individuals. Then we consider sleep deprivation studies and the role of circadian alterations in obesity. We describe sleep/wake changes in various rodent models of obesity and obesity resistance. Finally, we discuss possible mechanisms linking sleep disturbances with obesity. © 2012 Elsevier Ltd.
• Nixon, J. P., Kotz, C. M., Novak, C. M., Billington, C. J., & Teske, J. A. (2012). Neuropeptides controlling energy balance: Orexins and neuromedins. Handbook of Experimental Pharmacology, 209, 77-109.
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  PMID: 22249811;Abstract: In this chapter, we review the feeding and energy expenditure effects of orexin (also known as hypocretin) and neuromedin. Orexins are multifunctional neuropeptides that affect energy balance by participating in regulation of appetite, arousal, and spontaneous physical activity. Central orexin signaling for all functions originates in the lateral hypothalamus-perifornical area and is likely functionally differentiated based on site of action and on interacting neural influences. The effect of orexin on feeding is likely related to arousal in some ways but is nonetheless a separate neural process that depends on interactions with other feeding-related neuropeptides. In a pattern distinct from other neuropeptides, orexin stimulates both feeding and energy expenditure. Orexin increases in energy expenditure are mainly by increasing spontaneous physical activity, and this energy expenditure effect is more potent than the effect on feeding. Global orexin manipulations, such as in transgenic models, produce energy balance changes consistent with a dominant energy expenditure effect of orexin. Neuromedins are gut-brain peptides that reduce appetite. There are gut sources of neuromedin, but likely the key appetite-related neuromedin-producing neurons are in the hypothalamus and parallel other key anorectic neuropeptide expression in the arcuate to paraventricular hypothalamic projection. As with other hypothalamic feeding-related peptides, hindbrain sites are likely also important sources and targets of neuromedin anorectic action. Neuromedin increases physical activity in addition to reducing appetite, thus producing a consistent negative energy balance effect. Together with the other various neuropeptides, neurotransmitters, neuromodulators, and neurohormones, neuromedin and orexin act in the appetite network to produce changes in food intake and energy expenditure, which ultimately influences the regulation of body weight. © 2012 Springer-Verlag Berlin Heidelberg.
• Nixon, J. P., Kotz, C. M., Novak, C. M., Billington, C. J., & Teske, J. A. (2012). Neuropeptides controlling energy balance: orexins and neuromedins. Handbook of experimental pharmacology, 77-109.
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  In this chapter, we review the feeding and energy expenditure effects of orexin (also known as hypocretin) and neuromedin. Orexins are multifunctional neuropeptides that affect energy balance by participating in regulation of appetite, arousal, and spontaneous physical activity. Central orexin signaling for all functions originates in the lateral hypothalamus-perifornical area and is likely functionally differentiated based on site of action and on interacting neural influences. The effect of orexin on feeding is likely related to arousal in some ways but is nonetheless a separate neural process that depends on interactions with other feeding-related neuropeptides. In a pattern distinct from other neuropeptides, orexin stimulates both feeding and energy expenditure. Orexin increases in energy expenditure are mainly by increasing spontaneous physical activity, and this energy expenditure effect is more potent than the effect on feeding. Global orexin manipulations, such as in transgenic models, produce energy balance changes consistent with a dominant energy expenditure effect of orexin. Neuromedins are gut-brain peptides that reduce appetite. There are gut sources of neuromedin, but likely the key appetite-related neuromedin-producing neurons are in the hypothalamus and parallel other key anorectic neuropeptide expression in the arcuate to paraventricular hypothalamic projection. As with other hypothalamic feeding-related peptides, hindbrain sites are likely also important sources and targets of neuromedin anorectic action. Neuromedin increases physical activity in addition to reducing appetite, thus producing a consistent negative energy balance effect. Together with the other various neuropeptides, neurotransmitters, neuromodulators, and neurohormones, neuromedin and orexin act in the appetite network to produce changes in food intake and energy expenditure, which ultimately influences the regulation of body weight.
• Perez-Leighton, C. E., Boland, K., Teske, J. A., Billington, C., & Kotz, C. M. (2012). Behavioral responses to orexin, orexin receptor gene expression, and spontaneous physical activity contribute to individual sensitivity to obesity. American Journal of Physiology - Endocrinology and Metabolism, 303(7), E865-E874.
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  PMID: 22829584;PMCID: PMC3469621;Abstract: There is significant variability in diet-induced obesity (DIO) among humans and rodents, which has been associated with differences in intrinsic spontaneous physical activity (SPA). The orexin neuropeptides positively modulate SPA through multiple brain sites, but the effects of DIO on orexin's activity are not well understood. In this study, we tested the hypothesis that DIO sensitivity is mediated by decreased SPA and changes in the function of the orexins. As a DIO model, we used male Sprague-Dawley rats fed a high-fat (HF; 45% kcal from fat) or a low-fat (LF; 10% kcal from fat) diet for 10 wk. We measured SPA before and after HF or LF feeding and expression of orexin receptors by real-time PCR after dietary treatments. We tested DIO effects on orexin signaling by measuring SPA after injection of orexin A in the rostral lateral hypothalamus (RLH) before and after 10 wk of HF feeding. Finally, we tested whether daily orexin A RLH injections prevent DIO caused by HF feeding. Our results show that resistance to DIO is associated with an increase in SPA, SPA after injection of orexin A in RLH, and orexin receptor expression in sites that mediate orexin's effect on SPA, including RLH. We show that daily injections of orexin peptide in RLH prevent DIO without altering food intake. We estimate that the energetic cost of SPA after orexin A RLH injection accounts for approximately 61% of the extra caloric intake associated with HF intake, suggesting additional effects of orexins. In summary, our results suggest that variability in DIO sensitivity is mediated through adaptations in the activity of the orexin peptides and their receptors.
• Perez-Leighton, C. E., Boland, K., Teske, J. A., Billington, C., & Kotz, C. M. (2012). Behavioral responses to orexin, orexin receptor gene expression, and spontaneous physical activity contribute to individual sensitivity to obesity. American journal of physiology. Endocrinology and metabolism, 303(7), E865-74.
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  There is significant variability in diet-induced obesity (DIO) among humans and rodents, which has been associated with differences in intrinsic spontaneous physical activity (SPA). The orexin neuropeptides positively modulate SPA through multiple brain sites, but the effects of DIO on orexin's activity are not well understood. In this study, we tested the hypothesis that DIO sensitivity is mediated by decreased SPA and changes in the function of the orexins. As a DIO model, we used male Sprague-Dawley rats fed a high-fat (HF; 45% kcal from fat) or a low-fat (LF; 10% kcal from fat) diet for 10 wk. We measured SPA before and after HF or LF feeding and expression of orexin receptors by real-time PCR after dietary treatments. We tested DIO effects on orexin signaling by measuring SPA after injection of orexin A in the rostral lateral hypothalamus (RLH) before and after 10 wk of HF feeding. Finally, we tested whether daily orexin A RLH injections prevent DIO caused by HF feeding. Our results show that resistance to DIO is associated with an increase in SPA, SPA after injection of orexin A in RLH, and orexin receptor expression in sites that mediate orexin's effect on SPA, including RLH. We show that daily injections of orexin peptide in RLH prevent DIO without altering food intake. We estimate that the energetic cost of SPA after orexin A RLH injection accounts for approximately 61% of the extra caloric intake associated with HF intake, suggesting additional effects of orexins. In summary, our results suggest that variability in DIO sensitivity is mediated through adaptations in the activity of the orexin peptides and their receptors.
• Teske, J. A., & Mavanji, V. (2012). Energy Expenditure. Role of Orexin.. Vitamins and Hormones, 89, 91-109.
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  PMID: 22640610;Abstract: The orexins/hypocretins are endogenous, modulatory and multifunctional neuropeptides with prominent influence on several physiological processes. The influence of orexins on energy expenditure is highlighted with focus on orexin action on individual components of energy expenditure. As orexin stabilizes and maintains normal states of arousal and the sleep/wake cycle, we also highlight orexin mediation of sleep and how sleep interacts with energy expenditure. © 2012 Elsevier Inc..
• Teske, J. A., Billington, C. J., Kuskowski, M. A., & Kotz, C. M. (2012). Spontaneous physical activity protects against fat mass gain. International Journal of Obesity, 36(4), 603-613.
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  PMID: 21610695;PMCID: PMC3163117;Abstract: Objective: It is unclear whether elevated spontaneous physical activity (SPA, very low-intensity physical activity) positively influences body composition long term. We determined whether SPA and caloric intake were differentially related to the growth curve trajectories of body weight, fat mass (FM) and fat-free mass (FFM) between obesity resistant and Sprague-Dawley rats at specific age intervals. Design and Subjects: Body composition, SPA and caloric intake were measured in selectively-bred obesity-resistant and out-bred Sprague-Dawley rats from 1 to 18 months. Data from development throughout maturation were analyzed by longitudinal growth curve modeling to determine the rate and acceleration of body weight, FM- and FFM-gain. Results: Obesity-resistant rats had a lower rate of FM gain overall, a lower acceleration in body weight early in life, significantly greater SPA and lower cumulative caloric intake. Greater SPA in obesity-resistant rats was significantly associated with a lower rate of FM gain overall and lower acceleration in body weight early in life. Obesity resistant rats lost less FFM compared with Sprague-Dawley rats despite that obesity-resistant rats had a lower acceleration in FFM gain early in life. Obesity-resistant rats gained less FM and more FFM per gram body weight and were less energy efficient than Sprague-Dawley rats. Caloric intake was significantly and positively related to body weight, FM and FFM gain in both groups. Circadian patterns of caloric intake were group and age-dependent. Our data demonstrate that elevated and sustained SPA during development and over the lifespan are related to the reduced the rate of FM gain and may preserve FFM. Conclusion: These data support the idea that SPA level is a reproducible marker that reliably predicts propensity for obesity in rats, and that elevated levels of SPA maintained during the lifespan promote a lean phenotype. © 2012 Macmillan Publishers Limited All rights reserved.
• Teske, J. A., Perez-Leighton, C. E., Boland, K., Billington, C., & Kotz, C. M. (2012). Behavioral responses to orexin, orexin receptor gene expression, and spontaneous physical activity contribute to individual sensitivity to obesity. American Journal of Physiology-Endocrinology and Metabolism, 303(7), E865-E874. doi:10.1152/ajpendo.00119.2012
• Teske, J., Billington, C., Kuskowski, M., & Kotz, C. M. (2012). Spontaneous physical activity protects against fat mass gain. International Journal of Obesity, 36(4), 603-613.
• Teske, J., Kotz, C., Nixon, J., Butterick, T., Perez‐Leighton, C., & Billington, C. (2012). Brain orexin promotes obesity resistance. Annals of the New York Academy of Sciences, 1264(1), 72-86. doi:10.1111/j.1749-6632.2012.06585.x
• Teske, J. A., Billington, C. J., Kuskowski, M. A., & Kotz, C. M. (2011). Spontaneous physical activity protects against fat mass gain. Int J Obes (Lond). doi:10.1038/ijo.2011.108
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  It is unclear whether elevated spontaneous physical activity (SPA, very low-intensity physical activity) positively influences body composition long term. We determined whether SPA and caloric intake were differentially related to the growth curve trajectories of body weight, fat mass (FM) and fat-free mass (FFM) between obesity resistant and Sprague–Dawley rats at specific age intervals. Body composition, SPA and caloric intake were measured in selectively-bred obesity-resistant and out-bred Sprague–Dawley rats from 1 to 18 months. Data from development throughout maturation were analyzed by longitudinal growth curve modeling to determine the rate and acceleration of body weight, FM- and FFM-gain. Obesity-resistant rats had a lower rate of FM gain overall, a lower acceleration in body weight early in life, significantly greater SPA and lower cumulative caloric intake. Greater SPA in obesity-resistant rats was significantly associated with a lower rate of FM gain overall and lower acceleration in body weight early in life. Obesity resistant rats lost less FFM compared with Sprague–Dawley rats despite that obesity-resistant rats had a lower acceleration in FFM gain early in life. Obesity-resistant rats gained less FM and more FFM per gram body weight and were less energy efficient than Sprague–Dawley rats. Caloric intake was significantly and positively related to body weight, FM and FFM gain in both groups. Circadian patterns of caloric intake were group and age-dependent. Our data demonstrate that elevated and sustained SPA during development and over the lifespan are related to the reduced the rate of FM gain and may preserve FFM. These data support the idea that SPA level is a reproducible marker that reliably predicts propensity for obesity in rats, and that elevated levels of SPA maintained during the lifespan promote a lean phenotype.
• Mavanji, V., Teske, J. A., Billington, C. J., & Kotz, C. M. (2010). Elevated sleep quality and orexin receptor mRNA in obesity-resistant rats. International Journal of Obesity, 34(11), 1576-1588.
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  PMID: 20498657;PMCID: PMC2929312;Abstract: Objective: To determine if resistance to weight gain is associated with alterations in sleep-wake states and orexin receptor gene expression.Design: Three-month-old obesity-susceptible Sprague-Dawley (SD) and obesity-resistant (OR) rats were fed standard rodent chow. Sleep-wake cycle was measured by radiotelemetry and orexin receptor profiles in sleep-wake regulatory areas of the brain were quantified by quantitative reverse transcriptase-PCR.Subjects: Adult male obesity-susceptible SD and selectively bred OR rats.Measurements:Body weight, food intake, energy efficiency, percent time spent in active wake (AW), quiet wake (QW), slow-wave sleep (SWS), rapid eye movement (REM) sleep, number and mean duration of sleep-wake episodes, number of stage transitions, SWS sleep delta power and orexin receptor mRNA levels were measured. Results: OR rats weighed significantly less and had lower energy efficiency than SD rats. Food intake was not different between SD and OR rats. Time spent in QW was similar between groups, and therefore AW and QW were combined and are referred to as wakefulness. OR rats spent significantly more time in wakefulness and less time in SWS compared with SD rats during the 24-h recording period. Relative to SD rats, OR rats had significantly fewer sleep-wake episodes and the duration of the episodes were prolonged, indicating less fragmented sleep. Furthermore, OR rats had fewer transitions between sleep stages, which indicates that OR rats were behaviorally more stable and had more consolidated sleep than obesity-susceptible SD rats. OR rats showed lower delta power during SWS, indicating a lower sleep drive. Our results showed greater orexin receptor gene expression in sleep regulatory brain areas in OR rats. Conclusion: These results show that prolonged wakefulness, better sleep quality, lower sleep drive and greater orexin signaling may confer protection against obesity. © 2010 Macmillan Publishers Limited All rights reserved.
• Teske, J. A., Billington, C. J., & Kotz, C. M. (2010). Hypocretin/orexin and energy expenditure. Acta Physiologica, 198(3), 303-312.
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  PMID: 20070282;Abstract: The hypocretins or orexins are endogenous neuropeptides synthesized in discrete lateral, perifornical and dorsal hypothalamic neurones. These multi-functional neuropeptides modulate energy homeostasis, arousal, stress, reward, reproduction and cardiovascular function. This review summarizes the role of hypocretins in modulating non-sleep-related energy expenditure with specific focus on the augmentation of whole body energy expenditure as well as hypocretin-induced physical activity and sympathetic outflow. We compare the efficacy of hypocretin-1 and 2 on energy expenditure and evaluate whether the literature implicates hypocretin signalling though the hypocretin-1 and -2 receptor as having shared and or functionally specific physiological effects. Thus far data suggest that hypocretin-1 has a more robust stimulatory effect relative to hypocretin-2. Furthermore, hypocretin-1 receptor predominantly mediates behaviours known to influence energy expenditure. Further studies on the hypocretin-2 receptor are needed. © 2010 Scandinavian Physiological Society.
• Teske, J. A., & Kotz, C. M. (2009). Effect of acute and chronic caloric restriction and metabolic glucoprivation on spontaneous physical activity in obesity-prone and obesity-resistant rats. American Journal of Physiology - Regulatory Integrative and Comparative Physiology, 297(1), R176-R184.
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  PMID: 19420294;Abstract: Caloric restriction (CR) and metabolic glucoprivation affect spontaneous physical activity (SPA), but it's unknown whether these treatments similarly affect SPA in selectively bred obesity-prone (OP) and -resistant (OR) rats. OR rats have greater basal SPA and are more responsive to treatments that modulate SPA, such as orexin A administration. We hypothesized that OR rats would be more sensitive to other treatments modulating SPA. To test this, continuous 24-h SPA was measured before and during acute (24 h) and chronic (8 wk) CR in OR, OP, and Sprague-Dawley rats. Pharmacological glucoprivation was produced by injection of 2-deoxyglucose (2-DG), and SPA was measured 5 h postinjection. Acute CR increased SPA in all groups; however, the effect was dependent on the index of SPA and time interval during the 24-h time period. In contrast to OR rats, chronic CR increased distance traveled, ambulatory episodes, and time spent in ambulation and stereotypy during the time interval preceding anticipation of food in OP and Sprague-Dawley rats. Although the effects of 2-DG treatment on SPA were minimal, OR rats had significantly greater SPA than OP and Sprague-Dawley rats independent of treatment. That chronic CR failed to result in significant changes in SPA in OR rats suggests that these rats may be especially unresponsive to treatments modulating feeding. This insensitivity coupled with elevated basal SPA levels may in part mediate phenotypic traits of lean rats.
• Kotz, C. M., Teske, J. A., & Billington, C. J. (2008). Neuroregulation of nonexercise activity thermogenesis and obesity resistance. American Journal of Physiology - Regulatory Integrative and Comparative Physiology, 294(3), R699-R710.
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  PMID: 18160530;Abstract: High levels of spontaneous physical activity in lean people and the nonexercise activity thermogenesis (NEAT) derived from that activity appear to protect lean people from obesity during caloric challenge, while obesity in humans is characterized by dramatically reduced spontaneous physical activity. We have similarly demonstrated that obesity-resistant rats have significantly greater spontaneous physical activity than obesity-prone rats, and that spontaneous physical activity predicts body weight gain. Although the energetic cost of activity varies between types of activity and may be regulated, individual level of spontaneous physical activity is important in determining propensity for obesity. We review the current status of knowledge about the brain mechanisms involved in controlling the level of spontaneous physical activity and the NEAT so generated. Focus is on potential neural mediators of spontaneous physical activity and NEAT, including orexin A (also known as hypocretin 1), agouti-related protein, ghrelin, and neuromedin U, in addition to brief mention of neuropeptide Y, corticotrophin releasing hormone, cholecystokinin, estrogen, leptin, and dopamine effects on spontaneous physical activity. We further review evidence that strain differences in orexin stimulation pathways for spontaneous physical activity and NEAT appear to track with the body weight phenotype, thus providing a potential mechanistic explanation for reduced activity and weight gain.
• Perry, C. A., Pravetoni, M., Teske, J. A., Aguado, C., Erickson, D. J., Medrano, J. F., Luján, R., Kotz, C. M., & Wickman, K. (2008). Predisposition to late-onset obesity in GIRK4 knockout mice. Proceedings of the National Academy of Sciences of the United States of America, 105(23), 8148-8153.
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  PMID: 18523006;PMCID: PMC2430374;Abstract: G protein-gated inwardly rectifying potassium (GIRK/Kir3) channels mediate the inhibitory effects of many neurotransmitters on excitable cells. Four Girk genes have been identified (Girk1-4). Whereas GIRK4 is associated with the cardiac GIRK channel, Girk4 expression has been detected in a few neuron populations. Here, we used a transgenic mouse expressing enhanced green fluorescent protein (EGFP) under the control of the Girk4 gene promoter to clarify the expression pattern of Girk4 in the brain. Although small subsets of EGFP-positive neurons were evident in some areas, prominent labeling was seen in the hypothalamus. EGFP expression was most pronounced in the ventromedial, paraventricular, and arcuate nuclei, neuron populations implicated in energy homeostasis. Consistent with a contribution of GIRK4-containing channels to energy balance, Girk4 knockout (-/-) mice were predisposed to late-onset obesity. By 9 months, Girk4-/- mice were ≈25% heavier than wild-type controls, a difference attributed to greater body fat. Before the development of overweight, Girk4-/- mice exhibited a tendency toward greater food intake and an increased propensity to work for food in an operant task. Girk4-/- mice also exhibited reduced net energy expenditure, despite displaying elevated resting heart rates and core body temperatures. These data implicate GIRK4-containing channels in signaling crucial to energy homeostasis and body weight. © 2008 by The National Academy of Sciences of the USA.
• Teske, J. A., Billington, C. J., & Kotz, C. M. (2007). Neuropeptidergic mediators of spontaneous physical activity and non-exercise activity thermogenesis. Neuroendocrinology, 87(2), 71-90.
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  PMID: 17984627;Abstract: Lean individuals have high levels of spontaneous physical activity (SPA) and the energy expenditure derived from that activity, termed non-exercise activity thermogenesis or NEAT, appears to protect them from obesity. Conversely, obesity in different human populations is characterized by low levels of SPA and NEAT. Like in humans, elevated SPA in rats appears to protect against obesity: obesity-resistant rats have significantly greater SPA and NEAT than obesity-prone rats. We review the literature on brain mechanisms important in mediating SPA and NEAT. The focus is on neuropeptides, including cholecystokinin, corticotropin-releasing hormone (also known as corticotropin-releasing factor), neuromedin U, neuropeptide Y, leptin, agouti-related protein, orexin-A (also known as hypocretin-1), and ghrelin. We also review information regarding interactions between these neuropeptides and dopamine, a neurotransmitter important in mediating motor function. Finally, we present evidence that elevated signaling of pathways mediating SPA and NEAT may protect against weight gain and obesity. Copyright © 2007 S. Karger AG.
• Kotz, C. M., Wang, C., Teske, J. A., Thorpe, A. J., Novak, C. M., Kiwaki, K., & Levine, J. A. (2006). Orexin A mediation of time spent moving in rats: Neural mechanisms. Neuroscience, 142(1), 29-36.
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  PMID: 16809007;Abstract: The brain regulates energy balance and spontaneous physical activity, including both small- and large-motor activities. Neural mediators of spontaneous physical activity are currently undefined, although the amount of time spent in sedentary positions versus standing and ambulating may be important in the energetics of human obesity. Orexin A, a neuropeptide produced in caudal hypothalamic areas and projecting throughout the neuraxis, enhances arousal and spontaneous physical activity. To test the hypothesis that orexin A affects the amount of time spent moving, we injected orexin A (0-1000 pmol) into three orexin projection sites in male Sprague-Dawley rats: hypothalamic paraventricular nucleus, rostral lateral hypothalamic area and substantia nigra pars compacta, and measured spontaneous physical activity. Orexin A affects local GABA release and we co-injected orexin A with a GABA agonist, muscimol, in each brain site. Dopamine signaling is important to substantia nigra function and so we also co-injected a dopamine 1 receptor antagonist (SCH 23390) in the substantia nigra pars compacta. In all brain sites orexin A significantly increased time spent vertical and ambulating. Muscimol significantly and dose-dependently inhibited orexin A effects on time spent moving only when administered to the rostral lateral hypothalamic area. In the substantia nigra pars compacta, SCH 23390 completely blocked orexin A-induced ambulation. These data indicate that orexin A influences time spent moving, in three brain sites utilizing separate signaling mechanisms. That orexin A modulation of spontaneous physical activity occurs in brain areas with multiple roles indicates generalization across brain site, and may reflect a fundamental mechanism for enhancing activity levels. This potential for conferring physical activity stimulation may be useful for inducing shifts in time spent moving, which has important implications for obesity. © 2006 IBRO.
• Teske, J. A., Levine, A. S., Kuskowski, M., Levine, J. A., & Kotz, C. M. (2006). Elevated hypothalamic orexin signaling, sensitivity to orexin A, and spontaneous physical activity in obesity-resistant rats. American Journal of Physiology - Regulatory Integrative and Comparative Physiology, 291(4), R889-R899.
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  PMID: 16763079;Abstract: Selectively-bred obesity-resistant [diet resistant (DR)] rats weigh less than obesity-prone [diet-induced obese (DIO)] rats, despite comparable daily caloric intake, suggesting phenotypic energy expenditure differences. Human data suggest that obesity is maintained by reduced ambulatory or spontaneous physical activity (SPA). The neuropeptide orexin A robustly stimulates SPA. We hypothesized that DR rats have greater: 1) basal SPA, 2) orexin A-induced SPA, and 3) preproorexin, orexin 1 and 2 receptor (OX1R and OX2R) mRNA, compared with DIO rats. A group of age-matched out-bred Sprague-Dawley rats were used as additional controls for the behavioral studies. DIO, DR, and Sprague-Dawley rats with dorsal-rostral lateral hypothalamic (rLHa) cannulas were injected with orexin A (0, 31.25, 62.5, 125, 250, and 500 pmol/0.5 μl). SPA and food intake were measured for 2 h after injection. Preproorexin, OX1R and OX2R mRNA in the rLHa, and whole hypothalamus were measured by real-time RT-PCR. Orexin A significantly stimulated feeding in all rats. Orexin A-induced SPA was significantly greater in DR and Sprague-Dawley rats than in DIO rats. Two-mo-old DR rats had significantly greater rLHa OX1R and OX2R mRNA than DIO rats but comparable preproorexin levels. Eight-moold DR rats had elevated OX1R and OX2R mRNA compared with DIO rats, although this increase was significant for OX2R only at this age. Thus DR rats show elevated basal and orexin A-induced SPA associated with increased OX1R and OX2R gene expression, suggesting that differences in orexin A signaling through OX1R and OX2R may mediate DIO and DR phenotypes.
• Novak, C. M., Jiang, X., Wang, C., Teske, J. A., Kotz, C. M., & Levine, J. A. (2005). Caloric restriction and physical activity in zebrafish (Danio rerio). Neuroscience Letters, 383(1-2), 99-104.
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  PMID: 15936519;Abstract: Understanding the mechanism of energy flux may be critical for explaining how obesity has emerged as a public health epidemic. It is known that changes in caloric intake predictably alter physical activity levels (PA) in mammals. Here, our goal was to test the hypothesis that fasting induces a biphasic pattern of change in PA by measuring PA before and after long-term food deprivation in zebrafish. Compared to control-fed fish, food-deprived fish showed a significant increase in PA levels during the first 2 days of food deprivation. Subsequently, however, fasted fish showed a significant chronic decrease in PA compared to fish fed at weight-maintenance levels. These data are comparable to those seen with mammals, which also show a biphasic response of PA to caloric restriction. In a separate group of fish, long-term food deprivation, associated with decreases in PA, induced a significant increase in brain preproorexin mRNA levels compared to fed controls. No change in orexin mRNA was seen after 2 days of food deprivation. The finding that orexin mRNA expression is altered only after long-term starvation suggests that orexin may be coupled with the changes in PA seen at this time. Thus, the association between negative energy balance and reductions in PA occurs across genera in biology and is associated with predictable neurological changes in brain gene expression. © 2005 Elsevier Ireland Ltd. All rights reserved.
• Thorpe, A. J., Teske, J. A., & Kotz, C. M. (2005). Orexin A-induced feeding is augmented by caloric challenge. American Journal of Physiology - Regulatory Integrative and Comparative Physiology, 289(2 58-2), R367-R372.
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  PMID: 15947069;Abstract: Orexin neurons are stimulated by conditions that are glucoprivic, suggesting that orexin signaling may be increased during nutritional duress. We have previously shown that injection of orexin A (OxA) into the rostral lateral hypothalamic area (rLHa) robustly and dose-dependently increases feeding behavior. Thus we hypothesized that exogenous administration of orexin A would induce a greater feeding response after acute food deprivation or perceived caloric duress achieved through 2-deoxyglucose (2DG) administration. To test our hypothesis, male Sprague-Dawley rats implanted with internal guide cannulas directed to the rLHa were exposed to varying degrees of food deprivation (0, 3, 12, 24 h) and 2DG (200 mg/kg) before intra-rLHa OxA (500 pmol) infusion. We also performed a dose-response study using graded doses of OxA (0, 31.25, 125, and 500 pmol) in fed and 24-h fasted rats. OxA administration in conjunction with the highest level of prior food deprivation (24 h) resulted in the greatest feeding response (above baseline means; 0 h deprivation: 1.9 ± 0.6; 24 h deprivation: 4.4 ± 0.8; P = 0.0034) and showed a dose-dependent enhancement of feeding. Additionally, 2DG administration before OxA administration resulted in a significantly higher feeding response (above baseline means: 2DG = 1.8 ± 0.5; OxA = 1.8 ± 0.4; 2DG + OxA = 5.1 ± 0.6; P < 0.0001). These data support the hypothesis that orexin signaling may be important in modulating the feeding network under times of nutritional duress.
• Kotz, C. M., Teske, J. A., Levine, J. A., & Wang, C. (2002). Feeding and activity induced by orexin A in the lateral hypothalamus in rats. Regulatory Peptides, 104(1-3), 27-32.
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  PMID: 11830273;Abstract: Orexin A injected into the lateral hypothalamus (LH) stimulates feeding and activates neurons in brain sites regulating feeding and arousal. The feeding effects of orexin A have been demonstrated during the light cycle, a time when rats are normally resting, and the effect of orexin A on activity after injection into the LH has not been previously measured. Thus, it is unclear whether LH orexin A-induced feeding is secondary to enhanced arousal. To address this, LH-cannulated rats habituated to a running wheel were injected with either orexin A (1000 pmol) or vehicle during light and dark cycles. Food intake and running wheel rotations were measured for 2 h. Spontaneous physical activity (SPA) was also measured during the dark cycle. During the light cycle, orexin A in the LH stimulated feeding in the presence and absence of a running wheel and increased number of running wheel rotations in the presence and absence of food. During the dark cycle, orexin A in the LH induced SPA (±presence of food), but had no effect on feeding. These data show that LH orexin A stimulation of feeding is not always coincident with increased activity, suggesting that feeding induced by LH-injected orexin A is not consequent to enhanced arousal. Published by Elsevier Science B.V.

Presentations

• Teske, J. A. (2016, January). Sleep extension & weight gain: role of energy intake and energy expenditure. Winter Conference on Brain Research. Breckenridge, CO: Winter Conference on Brain Research.
• Teske, J. A. (2012). Obesity...What does the brain got to do with it?. University of Minnesota, School of Public Health, Obesity Consortium of Minnesota. Minneapolis, MN, USA: University of Minnesota, School of Public Health, Obesity Consortium of Minnesota.
• Teske, J. A. (2012). Role of sleep in a rodent model of obesity. University of Arizona Pulmonary and Critical Care Medical Section. Tucson, AZ, USA: University of Arizona Pulmonary and Critical Care Medical Section.
• Teske, J. A., Teske, J. A., Billington, C., & Kotz, C. (2012). Spontaneous physical activity and sleep for obesity prevention in a rodent model. International Conference on Obesity and Weight Management. Philadelphia, PA, USA: International Conference on Obesity and Weight Management.
• Teske, J., Perez-Leighton, C., Grace, M., Billington, C., & Kotz, C. (2012). Orexin A reduces body weight gain and obesity resistant rats have elevated non-resting energy expenditure. 30th Annual Meeting of the Obesity Society. San Antonio, TX, USA: 30th Annual Meeting of the Obesity Society.

Poster Presentations

• Coborn, J. E., Sinton, C. M., & Teske, J. A. (2019, June). Sex-dependent effects of suvorexant on sleep fragmentation during sleep disruption due to noise exposure.. Presented at the 33nd Annual Meeting of the Associated Sleep Society. San Antonio, Tx. USA: Associated Sleep Society.
• Coborn, J. E., Yu, J. C., Flores, A. C., Snapp, V. R., & Teske, J. A. (2019, May). Exposure to an obesogenic diet prevents differences in calorie intake across phases of the estrous cycle and stimulates weight gain in female rats.. Poster presented at the Organization for the Study of Sex Differences. Washington, DC: Organization for the Study of Sex Differences.
• Pillai, R., Pastora, K., Flores, A. C., Sinton, C. M., Rance, N. E., & Teske, J. A. (2019, November). Estradiol mediates weight gain during sleep disruption in female rats.. Presented at the Annual Meeting of the Obesity Society. Las Vegas, NV. USA: Obesity Society.
• Snapp, V. R., Flrores, A. C., & Teske, J. A. (2019, June). Effects of sleep disruption by environmental noise on preference, weight and estrous cycle in female and male Sprague-Dawley rats.. Presented at the 33nd Annual Meeting of the Associated Sleep Society. San Antonio, Tx. USA: Associated Sleep Society.
• Coborn, J. E., & Teske, J. A. (2018, October). Sleep disruption due to environmental noise exposure increases weight gain by modulating energy intake and expenditure in intact female rats. National Institutes of Health Research Conference on Sleep and the Health of Women. Bethesda, MD: National Institutes of Health Research.
• Coborn, J. E., Lessie, R. E., & Teske, J. A. (2018, June). Sleep disruption due to environmental noise exposure increases weight gain by modulating energy intake and expenditure in intact female rats. 32nd Annual Meeting of the Associated Sleep Society. Baltimore, MD: Associated Sleep Society.
• Flores, A. C., & Teske, J. A. (2018, July). Effects of sleep disruption by environmental noise preference, weight and estrous cycle in female and male Sprague-Dawley rats. Undergraduate Research Opportunities Consortium Minority Health Disparities Program annual research symposium. Tucson, AZ: University of Az.
• Flores, A. C., & Teske, J. A. (2018, November). Role of Sex Modulating Weight Gain Due to Sleep Disruption. Annual Biomedical Research Conference for Minority Students. Indianapolis, IN.: Annual Biomedical Research Conference for Minority Students.
• Houser, M. M., & Teske, J. A. (2018, June). Role of diet in modulating the effects of sodium oxybate on weight gain through feeding and energy expenditure in male Sprague-Dawley rats. 32nd Annual Meeting of the Associated Sleep Society. Baltimore, MD: Associated Sleep Society.
• Muslmani, S., & Teske, J. A. (2018, July). Expression of IL-6 and TNF⍺ in Perennial White Adipose Tissue of Sleep Disrupted Male Sprague-Dawley. Keeping Engaged Youth In Sciences annual research symposium. Tucson, AZ: University of AZ.
• Prabakaran, G., & Teske, J. A. (2018, July). Effects of sleep disruption by environmental noise on food preferences. Keeping Engaged Youth In Sciences annual research symposium. Tucson, AZ: University of AZ.
• Teske, J. A. (2018, April). The Role of Adequate Sleep on Eating Patterns and Body weight. Meeting of the Southern Arizona Academy of Nutrition and Dietetics. Tucson, AZ: Southern Arizona Academy of Nutrition and Dietetics.
• Yu, J., & Teske, J. A. (2018, July). Sleep disruption modifies preference for hedonic foods in rats fed a cafeteria diet.. Annual conference for the Society for the Study of Ingestive Behavior. Bonita Springs, FL: Society for the Study of Ingestive Behavior.
• Yu, J., & Teske, J. A. (2018, November). Weight gain and feeding due to noise exposure is driven by sleep disruption independent of stress. Obesity Society. Nashville, TN: Obesity Soceity.
• Teske, J. A. (2016, May). The alteration of sensorimotor rhythms by hypothalamic orexin-A reflects motor preparedness. Minneapolis VA Health Care System Research Day. Minneapolis, MN: Minneapolis VA Health Care System.
• Teske, J. A. (2016, November). Des-Try DYN, a non-opioid DYN peptide regulates physical activity, energy expenditure and hedonic food intake in the paraventricular hypothalamic nucleus. Society for Neuroscience. San Diego, CA: Society for Neuroscience.
• Teske, J. A. (2013, spring). Orexin A in the ventrolateral preoptic area promotes wakefulness in rodents. Experimental Biology.
• Mavanji, V., Teske, J., Billington, C., & Kotz, C. (2012, June). High fat diet feeding increase active-period sleep and sleep fragmentation in rats. 26th Annual Meeting of the Associated Sleep Society. Boston, MA, USA.
• Chiney, C., Tam, H., Butterick-Peterson, T., Teske, J., & Johnson, L. (2011, September). Xanthine Oxidase Enzyme Activity is Elevated in Rat Model of Diet Induced Obesity. The Obesity Society annual meeting. Orlando, FL.

Others

• Teske, J. A. (2016, december). Journal = Science. Research Innovation.