Benjamin J Renquist

Interests

Research

Obesity, Metabolic Syndrome, Type 2 diabetes, Hypertension, Control of food intake, Asthma, Neuroscience, Aquaculture, Heat Stress, Feed Efficiency

Teaching

Nutrition and Metabolism

Courses

Scholarly Contributions

Journals/Publications

• Klimentidis, Y. C., Arora, A., Newell, M., Zhou, J., Ordovas, J. M., Renquist, B. J., & Wood, A. C. (2019). Type-2 diabetes with low LDL-C: genetic insights into a unique phenotype. Diabetes.
• Bruggink, S. M., Kentch, K. P., Kronenfeld, J. M., & Renquist, B. J. (2021). Leak-Free Head-Out Plethysmography System to Accurately Assess Lung Function in Mice. BioRxiv. doi:https://doi.org/10.1101/2021.12.01.470843
• Bruggink, S., Kentch, K., Kronenfeld, J., & Renquist, B. J. (2022). A leak-free head-out plethysmography system to accurately assess lung function in mice. Journal of applied physiology (Bethesda, Md. : 1985), 133(1), 104-118.
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  Mice are a valuable model for elegant studies of complex, system-dependent diseases, including pulmonary diseases. Current tools to assess lung function in mice are either terminal or lack accuracy. We set out to develop a low-cost, accurate, head-out variable-pressure plethysmography system to allow for repeated, nonterminal measurements of lung function in mice. Current head-out plethysmography systems are limited by air leaks that prevent accurate measures of volume and flow. We designed an inflatable cuff that encompasses the mouse's neck preventing air leak. We wrote corresponding software to collect and analyze the data, remove movement artifacts, and automatically calibrate each dataset. This software calculates volume, inspiratory/expiratory time, breaths per minute, mid-expiratory flow, and end-inspiratory pause. To validate the use, we established that our plethysmography system accurately measured tidal breathing, the bronchoconstrictive response to methacholine, sex- and age-associated changes in breathing, and breathing changes associated with house dust mite sensitization. Our estimates of volume, flow, and timing of breaths are in line with published estimates, we observed dose-dependent decreases in volume and flow in response to methacholine ( < 0.05), increased lung volume, and decreased breathing rate with aging ( < 0.05), and that house dust mite sensitization decreased volume and flow ( < 0.05) while exacerbating the methacholine-induced increase in inspiratory time ( < 0.05). We describe an accurate, sensitive, low-cost, head-out plethysmography system that allows for longitudinal studies of pulmonary disease in mice. We describe a low-cost, variable-pressure head-out plethysmography system that can be used to assess lung function in mice. A balloon cuff is inflated around the mouse's neck to prevent air leak, allowing for accurate measurements of lung volume and air flow. Custom software facilitates system calibration, removes movement artifacts, and eases data analysis. The system was validated by measuring tidal breathing, responses to methacholine, and changes associated with house dust mite sensitization, sex, and aging.
• Geisler, C. E., Ghimire, S., Bruggink, S. M., Miller, K. E., Weninger, S. N., Kronenfeld, J. M., Yoshino, J., Klein, S., Duca, F. A., & Renquist, B. J. (2021). A critical role of hepatic GABA in the metabolic dysfunction and hyperphagia of obesity. Cell reports, 35(13), 109301.
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  Hepatic lipid accumulation is a hallmark of type II diabetes (T2D) associated with hyperinsulinemia, insulin resistance, and hyperphagia. Hepatic synthesis of GABA, catalyzed by GABA-transaminase (GABA-T), is upregulated in obese mice. To assess the role of hepatic GABA production in obesity-induced metabolic and energy dysregulation, we treated mice with two pharmacologic GABA-T inhibitors and knocked down hepatic GABA-T expression using an antisense oligonucleotide. Hepatic GABA-T inhibition and knockdown decreased basal hyperinsulinemia and hyperglycemia and improved glucose intolerance. GABA-T knockdown improved insulin sensitivity assessed by hyperinsulinemic-euglycemic clamps in obese mice. Hepatic GABA-T knockdown also decreased food intake and induced weight loss without altering energy expenditure in obese mice. Data from people with obesity support the notion that hepatic GABA production and transport are associated with serum insulin, homeostatic model assessment for insulin resistance (HOMA-IR), T2D, and BMI. These results support a key role for hepatocyte GABA production in the dysfunctional glucoregulation and feeding behavior associated with obesity.
• Geisler, C. E., Ghimire, S., Hepler, C., Miller, K. E., Bruggink, S. M., Kentch, K. P., Higgins, M. R., Banek, C. T., Yoshino, J., Klein, S., & Renquist, B. J. (2021). Hepatocyte membrane potential regulates serum insulin and insulin sensitivity by altering hepatic GABA release. Cell reports, 35(13), 109298.
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  Hepatic lipid accumulation in obesity correlates with the severity of hyperinsulinemia and systemic insulin resistance. Obesity-induced hepatocellular lipid accumulation results in hepatocyte depolarization. We have established that hepatocyte depolarization depresses hepatic afferent vagal nerve firing, increases GABA release from liver slices, and causes hyperinsulinemia. Preventing hepatic GABA release or eliminating the ability of the liver to communicate to the hepatic vagal nerve ameliorates the hyperinsulinemia and insulin resistance associated with diet-induced obesity. In people with obesity, hepatic expression of GABA transporters is associated with glucose infusion and disposal rates during a hyperinsulinemic euglycemic clamp. Single-nucleotide polymorphisms in hepatic GABA re-uptake transporters are associated with an increased incidence of type 2 diabetes mellitus. Herein, we identify GABA as a neuro-hepatokine that is dysregulated in obesity and whose release can be manipulated to mute or exacerbate the glucoregulatory dysfunction common to obesity.
• Geisler, C. E., Miller, K. E., Ghimire, S., & Renquist, B. J. (2021). The Role of GPR109a Signaling in Niacin Induced Effects on Fed and Fasted Hepatic Metabolism. International journal of molecular sciences, 22(8).
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  Signaling through GPR109a, the putative receptor for the endogenous ligand β-OH butyrate, inhibits adipose tissue lipolysis. Niacin, an anti-atherosclerotic drug that can induce insulin resistance, activates GPR109a at nM concentrations. GPR109a is not essential for niacin to improve serum lipid profiles. To better understand the involvement of GPR109a signaling in regulating glucose and lipid metabolism, we treated GPR109a wild-type (+/+) and knockout (-/-) mice with repeated overnight injections of saline or niacin in physiological states characterized by low (ad libitum fed) or high (16 h fasted) concentrations of the endogenous ligand, β-OH butyrate. In the fed state, niacin increased expression of apolipoprotein-A1 mRNA and decreased sterol regulatory element-binding protein 1 mRNA independent of genotype, suggesting a possible GPR109a independent mechanism by which niacin increases high-density lipoprotein (HDL) production and limits transcriptional upregulation of lipogenic genes. Niacin decreased fasting serum non-esterified fatty acid concentrations in both GPR109a +/+ and -/- mice. Independent of GPR109a expression, niacin blunted fast-induced hepatic triglyceride accumulation and peroxisome proliferator-activated receptor α mRNA expression. Although unaffected by niacin treatment, fasting serum HDL concentrations were lower in GPR109a knockout mice. Surprisingly, GPR109a knockout did not affect glucose or lipid homeostasis or hepatic gene expression in either fed or fasted mice. In turn, GPR109a does not appear to be essential for the metabolic response to the fasting ketogenic state or the acute effects of niacin.
• Renquist, B. J., Miller, K. E., Ghimire, S., & Geisler, C. E. (2021). The Role of GPR109a Signaling in Niacin Induced Effects on Fed and Fasted Hepatic Metabolism.. International journal of molecular sciences, 22(8), 4001. doi:10.3390/ijms22084001
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  Signaling through GPR109a, the putative receptor for the endogenous ligand β-OH butyrate, inhibits adipose tissue lipolysis. Niacin, an anti-atherosclerotic drug that can induce insulin resistance, activates GPR109a at nM concentrations. GPR109a is not essential for niacin to improve serum lipid profiles. To better understand the involvement of GPR109a signaling in regulating glucose and lipid metabolism, we treated GPR109a wild-type (+/+) and knockout (-/-) mice with repeated overnight injections of saline or niacin in physiological states characterized by low (ad libitum fed) or high (16 h fasted) concentrations of the endogenous ligand, β-OH butyrate. In the fed state, niacin increased expression of apolipoprotein-A1 mRNA and decreased sterol regulatory element-binding protein 1 mRNA independent of genotype, suggesting a possible GPR109a independent mechanism by which niacin increases high-density lipoprotein (HDL) production and limits transcriptional upregulation of lipogenic genes. Niacin decreased fasting serum non-esterified fatty acid concentrations in both GPR109a +/+ and -/- mice. Independent of GPR109a expression, niacin blunted fast-induced hepatic triglyceride accumulation and peroxisome proliferator-activated receptor α mRNA expression. Although unaffected by niacin treatment, fasting serum HDL concentrations were lower in GPR109a knockout mice. Surprisingly, GPR109a knockout did not affect glucose or lipid homeostasis or hepatic gene expression in either fed or fasted mice. In turn, GPR109a does not appear to be essential for the metabolic response to the fasting ketogenic state or the acute effects of niacin.
• Yoshino, J., Renquist, B. J., Miller, K. E., Klein, S., Kentch, K. P., Higgins, M. R., Hepler, C., Ghimire, S., Geisler, C. E., Bruggink, S. M., & Banek, C. T. (2021). Hepatocyte membrane potential regulates serum insulin and insulin sensitivity by altering hepatic GABA release.. Cell reports, 35(13), 109298. doi:10.1016/j.celrep.2021.109298
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  Hepatic lipid accumulation in obesity correlates with the severity of hyperinsulinemia and systemic insulin resistance. Obesity-induced hepatocellular lipid accumulation results in hepatocyte depolarization. We have established that hepatocyte depolarization depresses hepatic afferent vagal nerve firing, increases GABA release from liver slices, and causes hyperinsulinemia. Preventing hepatic GABA release or eliminating the ability of the liver to communicate to the hepatic vagal nerve ameliorates the hyperinsulinemia and insulin resistance associated with diet-induced obesity. In people with obesity, hepatic expression of GABA transporters is associated with glucose infusion and disposal rates during a hyperinsulinemic euglycemic clamp. Single-nucleotide polymorphisms in hepatic GABA re-uptake transporters are associated with an increased incidence of type 2 diabetes mellitus. Herein, we identify GABA as a neuro-hepatokine that is dysregulated in obesity and whose release can be manipulated to mute or exacerbate the glucoregulatory dysfunction common to obesity.
• Yoshino, J., Weninger, S. N., Renquist, B. J., Miller, K. E., Kronenfeld, J. M., Klein, S., Ghimire, S., Geisler, C. E., Duca, F. A., & Bruggink, S. M. (2021). A Critical Role of Hepatic GABA in the Metabolic Dysfunction and Hyperphagia of Obesity. SSRN Electronic Journal. doi:10.2139/ssrn.3773795
• Yoshino, J., Weninger, S. N., Renquist, B. J., Miller, K. E., Kronenfeld, J. M., Klein, S., Ghimire, S., Geisler, C. E., Duca, F. A., & Bruggink, S. M. (2021). A critical role of hepatic GABA in the metabolic dysfunction and hyperphagia of obesity.. Cell reports, 35(13), 109301. doi:10.1016/j.celrep.2021.109301
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  Hepatic lipid accumulation is a hallmark of type II diabetes (T2D) associated with hyperinsulinemia, insulin resistance, and hyperphagia. Hepatic synthesis of GABA, catalyzed by GABA-transaminase (GABA-T), is upregulated in obese mice. To assess the role of hepatic GABA production in obesity-induced metabolic and energy dysregulation, we treated mice with two pharmacologic GABA-T inhibitors and knocked down hepatic GABA-T expression using an antisense oligonucleotide. Hepatic GABA-T inhibition and knockdown decreased basal hyperinsulinemia and hyperglycemia and improved glucose intolerance. GABA-T knockdown improved insulin sensitivity assessed by hyperinsulinemic-euglycemic clamps in obese mice. Hepatic GABA-T knockdown also decreased food intake and induced weight loss without altering energy expenditure in obese mice. Data from people with obesity support the notion that hepatic GABA production and transport are associated with serum insulin, homeostatic model assessment for insulin resistance (HOMA-IR), T2D, and BMI. These results support a key role for hepatocyte GABA production in the dysfunctional glucoregulation and feeding behavior associated with obesity.
• Klimentidis, Y. C., Arora, A., Newell, M., Zhou, J., Ordovas, J. M., Renquist, B. J., & Wood, A. C. (2020). Phenotypic and Genetic Characterization of Lower LDL Cholesterol and Increased Type 2 Diabetes Risk in the UK Biobank. Diabetes, 69(10), 2194-2205.
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  Although hyperlipidemia is traditionally considered a risk factor for type 2 diabetes (T2D), evidence has emerged from statin trials and candidate gene investigations suggesting that lower LDL cholesterol (LDL-C) increases T2D risk. We thus sought to more comprehensively examine the phenotypic and genotypic relationships of LDL-C with T2D. Using data from the UK Biobank, we found that levels of circulating LDL-C were negatively associated with T2D prevalence (odds ratio 0.41 [95% CI 0.39, 0.43] per mmol/L unit of LDL-C), despite positive associations of circulating LDL-C with HbA and BMI. We then performed the first genome-wide exploration of variants simultaneously associated with lower circulating LDL-C and increased T2D risk, using data on LDL-C from the UK Biobank ( = 431,167) and the Global Lipids Genetics Consortium ( = 188,577), and data on T2D from the Diabetes Genetics Replication and Meta-Analysis consortium ( = 898,130). We identified 31 loci associated with lower circulating LDL-C and increased T2D, capturing several potential mechanisms. Seven of these loci have previously been identified for this dual phenotype, and nine have previously been implicated in nonalcoholic fatty liver disease. These findings extend our current understanding of the higher T2D risk among individuals with low circulating LDL-C and of the underlying mechanisms, including those responsible for the diabetogenic effect of LDL-C-lowering medications.
• Matthew, V. P., Robert, C., Yao, X., Compart, D., Kay, R., Renquist, B. J., Leticia, C., & Diaz, D. (2020). Evaluation of Mid-Lactation Holstein Cows During Heat Stress in Response to a Dietary Feed Additive. Dairy and Vet Sci J., 14(5), 116-125. doi:DOI: 10.19080/JDVS.2020.14.555900
• Renquist, B. J. (2020). Feed intake–dependent and –independent effects of heat stress on lactation and mammary gland development. Journal of Dairy Science.
• Renquist, B. J., Kronenfeld, J., Kentch, K., & Bruggink, S. M. (2020). Determining the Role of Obesity and Muscarinic Signaling in Asthma. The FASEB Journal, 34(S1), 1-1. doi:10.1096/fasebj.2020.34.s1.05674
• Xiao, Y., Kronenfeld, J. M., & Renquist, B. J. (2020). Feed intake-dependent and -independent effects of heat stress on lactation and mammary gland development. Journal of dairy science, 103(12), 12003-12014.
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  With a growing population, a reliable food supply is increasingly important. Heat stress reduces livestock meat and milk production. Genetic selection of high-producing animals increases endogenous heat production, while climate change increases exogenous heat exposure. Both sources of heat exacerbate the risk of heat-induced depression of production. Rodents are valuable models to understand mechanisms conserved across species. Heat exposure suppresses feed intake across homeothermic species including rodents and production animal species. We assessed the response to early-mid lactation or late-gestation heat exposure on milk production and mammary gland development/function, respectively. Using pair-fed controls we experimentally isolated the feed intake-dependent and -independent effects of heat stress on mammary function and mass. Heat exposure (35°C, relative humidity 50%) decreased daily feed intake. When heat exposure occurred during lactation, hypophagia accounted for approximately 50% of the heat stress-induced hypogalactia. Heat exposure during middle to late gestation suppressed feed intake, which was fully responsible for the lowered mammary gland weight of dams at parturition. However, the impaired mammary gland function in heat-exposed dams measured by metabolic rate and lactogenesis could not be explained by depressed feed consumption. In conclusion, mice recapitulate the depressed milk production and mammary gland development observed in dairy species while providing insight regarding the role of feed intake. This opens the potential to apply genetic, experimental, and pharmacological models unique to mice to identify the mechanism by which heat is limiting animal production.
• Beckett, L., Rosemond, R., Renquist, B. J., & White, R. (2018). Technical note: a muscle biopsy technique for stratifying cattle by skeletal muscle nicotinamide adenine dinucleotide reduction rate. Journal of Dairy Science.
• Beckett, L., Rosemond, R., Renquist, B., & White, R. R. (2019). Technical note: A muscle biopsy technique for stratifying cattle by skeletal muscle metabolic activity. Journal of dairy science, 102(4), 3136-3141.
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  Tissue biopsy metabolic activity, assessed using the oxidation-reduction indicator resazurin, may serve as a proxy to assess energy expenditure associated with maintenance in nongrowing animals or growth rate in growing animals. Herein, we evaluate the repeatability, practicality, and sensitivity of a resazurin-based assay for ranking bovine skeletal muscle biopsies based on metabolic activity. Six yearling Holstein heifers (body weight = 330 ± 11.3 kg) were fed 4 dietary treatments consisting of high or low rumen-degradable starch and fiber arranged factorially in a partially replicated Latin square design. Periods were 18 d, consisting of 3 d for diet transition, 14 d for diet adaptation, and 1 d for sample collection. Semitendinosus biopsies were collected into ice-cold Dulbecco's modified Eagle medium (Fisher Scientific, Hampton, NH) from each heifer during each period. Analysis was initiated within an hour of sample collection. To assess tissue metabolic rate, biopsies were transferred to Dulbecco's modified Eagle medium with resazurin and incubated at 37°C. Fluorescence of each sample was read at time 0 and at 15-min intervals for 2 h. Change in fluorescence was representative of skeletal muscle reducing equivalent production. Fluorescent signal strength increased with time and relative rank of treatments did not change with time; accordingly, future studies may compare fluorescence at a single time point. Change in fluorescence at 120 min was used for analysis of the fixed effects of fiber, starch, and animal when accounting for a random effect of period. Samples collected when animals were on a high-ruminally degradable starch diet were more metabolically active than samples collected from animals on low-starch diets. Significant differences in metabolic activity among individual animals were also identified. Average relative fluorescence was correlated with dry matter intake, average daily gain, and feed-to-gain ratio. The relative fluorescence tended to correlate with average daily gain (r = 0.749) and feed-to-gain ratio (r = -0.783); change in fluorescence did not correlate with dry matter intake. Although evaluated on a small sample size, this technique shows promise as a potential means of ranking animals by growth or feed efficiency. Further work on a larger experimental population is needed to confirm the usefulness of this assay as a consistent and reliable predictor of these important phenotypic parameters.
• Geisler, C. E., Ghimire, S., Bogan, R. L., & Renquist, B. J. (2018). The Role of Ketone Signaling in the Hepatic Response to Fasting. American Journal of Physiology: Gastrointestinal and Liver Physiology.
• Geisler, C. E., Ghimire, S., Bogan, R. L., & Renquist, B. J. (2019). Role of ketone signaling in the hepatic response to fasting. American journal of physiology. Gastrointestinal and liver physiology, 316(5), G623-G631.
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  Ketosis is a metabolic adaptation to fasting, nonalcoholic fatty liver disease (NAFLD), and prolonged exercise. β-OH butyrate acts as a transcriptional regulator and at G protein-coupled receptors to modulate cellular signaling pathways in a hormone-like manner. While physiological ketosis is often adaptive, chronic hyperketonemia may contribute to the metabolic dysfunction of NAFLD. To understand how β-OH butyrate signaling affects hepatic metabolism, we compared the hepatic fasting response in control and 3-hydroxy-3-methylglutaryl-CoA synthase II (HMGCS2) knockdown mice that are unable to elevate β-OH butyrate production. To establish that rescue of ketone metabolic/endocrine signaling would restore the normal hepatic fasting response, we gave intraperitoneal injections of β-OH butyrate (5.7 mmol/kg) to HMGCS2 knockdown and control mice every 2 h for the final 9 h of a 16-h fast. In hypoketonemic, HMGCS2 knockdown mice, fasting more robustly increased mRNA expression of uncoupling protein 2 (UCP2), a protein critical for supporting fatty acid oxidation and ketogenesis. In turn, exogenous β-OH butyrate administration to HMGCS2 knockdown mice decreased fasting UCP2 mRNA expression to that observed in control mice. Also supporting feedback at the transcriptional level, β-OH butyrate lowered the fasting-induced expression of HMGCS2 mRNA in control mice. β-OH butyrate also regulates the glycemic response to fasting. The fast-induced fall in serum glucose was absent in HMGCS2 knockdown mice but was restored by β-OH butyrate administration. These data propose that endogenous β-OH butyrate signaling transcriptionally regulates hepatic fatty acid oxidation and ketogenesis, while modulating glucose tolerance. Ketogenesis regulates whole body glucose metabolism and β-OH butyrate produced by the liver feeds back to inhibit hepatic β-oxidation and ketogenesis during fasting.
• Geisler, C. E., Ghimire, S., Higgins, M. R., & Renquist, B. J. (2017). The Role of Ketone Signaling in the Hepatic Response to Fasting. Am. J. Physiol.: Gastrointestinal and Liver Physiology.
• Ghimire, S., Renquist, B. J., Ghimire, S., & Geisler, C. E. (2019). 289-LB: Hepatic Gamma-Amino Butyric Acid Release Drives Hyperinsulinemia and Insulin Resistance. Diabetes, 68(Supplement 1), 289-LB. doi:10.2337/db19-289-lb
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  The degree of hepatic lipid accumulation in obesity directly correlates with the severity of hyperinsulinemia and systemic insulin resistance. Here, we propose a mechanism that explains this associative link, whereby, hepatic steatosis dysregulates glucose and insulin homeostasis. Obesity-induced lipid accumulation results in hepatocyte depolarization. We have established that hepatocyte depolarization depresses hepatic vagal afferent nerve (HVAN) firing (22.9 ± 7.6%; P Disclosure C. Geisler: None. S. Ghimire: None. B.J. Renquist: None. Funding Arizona Biomedical Research Commission (ADHS14-082986, ADHS18-201472 to B.J.R.); American Heart Association (15BGIA25090300 to B.J.R.)
• Renquist, B. J. (2019). Hypophagia and hypogalactia associated with heat stress. Applied Animal Science, 35, 49-56. doi:https://doi.org/10.15232/aas.2018-01773
• Renquist, B. J. (2019). Invited Review: Hypophagia and Hypogalactia Associated with Heat Stress. Applied Animal Science, 35(1), 49-56.
• Renquist, B. J. (2019). Role of ketone signaling in the hepatic response to fasting. American Journal of Physiology-Gastrointestinal and Liver Physiology.
• Bhagwandin, C., Ashbeck, E. L., Whalen, M., Bandola-Simon, J., Roche, P. A., Szajman, A., Truong, S. M., Wertheim, B. C., Klimentidis, Y. C., Ishido, S., Renquist, B. J., & Lybarger, L. (2018). The E3 ubiquitin ligase MARCH1 regulates glucose-tolerance and lipid storage in a sex-specific manner. PloS one, 13(10), e0204898.
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  Type 2 diabetes is typified by insulin-resistance in adipose tissue, skeletal muscle, and liver, leading to chronic hyperglycemia. Additionally, obesity and type 2 diabetes are characterized by chronic low-grade inflammation. Membrane-associated RING-CH-1 (MARCH1) is an E3 ubiquitin ligase best known for suppression of antigen presentation by dendritic and B cells. MARCH1 was recently found to negatively regulate the cell surface levels of the insulin receptor via ubiquitination. This, in turn, impaired insulin sensitivity in mouse models. Here, we report that MARCH1-deficient (knockout; KO) female mice exhibit excessive weight gain and excessive visceral adiposity when reared on standard chow diet, without increased inflammatory cell infiltration of adipose tissue. By contrast, male MARCH1 KO mice had similar weight gain and visceral adiposity to wildtype (WT) male mice. MARCH1 KO mice of both sexes were more glucose tolerant than WT mice. The levels of insulin receptor were generally higher in insulin-responsive tissues (especially the liver) from female MARCH1 KO mice compared to males, with the potential to account in part for the differences between male and female MARCH1 KO mice. We also explored a potential role for MARCH1 in human type 2 diabetes risk through genetic association testing in publicly-available datasets, and found evidence suggestive of association. Collectively, our data indicate an additional link between immune function and diabetes, specifically implicating MARCH1 as a regulator of lipid metabolism and glucose tolerance, whose function is modified by sex-specific factors.
• Bhagwandin, C., Ashbeck, E. L., Whalen, M., Szajman, A., Truong, S. M., Wertheim, B. C., Klimentidis, Y. C., Ishido, S., Renquist, B. J., & Lybarger, L. P. (2018). The E3 ubiquitin ligase MARCH1 regulates glucose-tolerance and lipid storage in a sex-specific manner. PlosOne.
• Diaz, D., Vander Poel, M., Xiao, Y., Renquist, B., Wright, A., Collier, R., & Compart, D. (2018). Environmental chamber heat stress responses and adaptations in crossbred Hereford steers. Translational animal science, 2(Suppl 1), S185-S188.
• Geisler, C. E., Hepler, C., Ghimire, S., Higgins, M. R., Fregosi, R. F., & Renquist, B. J. (2018). Hyperinsulinemia and Insulin Resistance is a Result of Steatosis Induced Hepatocyte γ-Amino Butyric Acid Production and Release. BioRxiv. doi:https://doi.org/10.1101/475608
• Renquist, B. J., Madanayake, T. W., Ghimire, S., Geisler, C. E., Xu, Y., & Bogan, R. L. (2018). Transmembrane Protein 135 (TMEM135) is a Liver X Receptor Target Gene that Mediates an Auxiliary Peroxisome Matrix Protein Import Pathway. BioRxiv. doi:https://doi.org/10.1101/334979
• Vander Poel, M., Diaz, D., Xiao, Y., Renquist, B. J., Wright, A., Collier, R., & Compart, D. (2018). Environmental chamber heat stress responses and adaptations in crossbred Hereford steers. Translational Animal Science (TAS), Supplement 1, S185-S188.
• White, R. R., Rosemond, R., Renquist, B. J., & Beckett, L. (2018). Evaluating a Novel Strategy for Measuring Basal Metabolic Rate of Bovine Skeletal Muscle.. Journal of Animal Science, 96(suppl_1), 47-48. doi:10.1093/jas/sky027.090
• Xiao, Y., & Renquist, B. J. (2018). Abstract P103: Hepatocyte Depolarization Induces a Pressor Response. Hypertension, 72(Suppl_1). doi:10.1161/hyp.72.suppl_1.p103
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  Obesity and the resulting hepatic lipid accumulation increase the incidence of hypertension. In obese adults, the prevalence of excessive hepatic lipid accumulation exceeds 80%. Hepatic lipid accum...
• Collier, R. J., Renquist, B. J., & Xiao, Y. (2017).

  A 100-Year Review: Stress physiology including heat stress

  . Journal of Dairy Science. doi:10.3168/jds.2017-13676
• Collier, R. J., Renquist, B. J., & Xiao, Y. (2017). A 100-Year Review: Stress physiology including heat stress. Journal of dairy science, 100(12), 10367-10380.
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  Stress is an external event or condition that places a strain on a biological system. The animal response to a stress involves the expenditure of energy to remove or reduce the impact of the stress. This increases maintenance requirements of the animal and results in loss of production. The biological response to stress is divided into acute and chronic phases, with the acute phase lasting hours to a few days and the chronic phase lasting several days to weeks. The acute response is driven by homeostatic regulators of the nervous and endocrine systems and the chronic phase by homeorhetic regulators of the endocrine system. Both responses involve alterations in energy balance and metabolism. Thermal environment affects all animals and therefore represents the largest single stressor in animal production. Other types of stressors include housing conditions, overcrowding, social rank, disease, and toxic compounds. "Acclimation" to a stress is a phenotypic response developed by the animal to an individual stressor within the environment. However, under natural conditions, it is rare for only one environmental variable to change over time. "Acclimatization" is the process by which an animal adapts to several stressors within its natural environment. Acclimation is a homeorhetic process that takes several weeks to occur and occurs via homeorhetic, not homeostatic, mechanisms. It is a phenotypic change that disappears when the stress is removed. When the stress is severe and not relieved by acclimatization or management changes, the animal is considered chronically stressed and is susceptible to increased incidence of disease and poor health. Milk yield and reproduction are extremely sensitive to stress because of the high energy and protein demands of lactation and the complexity of the reproductive process and multiple organs that are involved. Improvements in protection of animals against stress require improved education of producers to recognize stress and methods for estimating degree of stress on animals.
• Geisler, C. E., & Renquist, B. J. (2017). Hepatic lipid accumulation: cause and consequence of dysregulated glucoregulatory hormones. The Journal of endocrinology, 234(1), R1-R21.
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  Fatty liver can be diet, endocrine, drug, virus or genetically induced. Independent of cause, hepatic lipid accumulation promotes systemic metabolic dysfunction. By acting as peroxisome proliferator-activated receptor (PPAR) ligands, hepatic non-esterified fatty acids upregulate expression of gluconeogenic, beta-oxidative, lipogenic and ketogenic genes, promoting hyperglycemia, hyperlipidemia and ketosis. The typical hormonal environment in fatty liver disease consists of hyperinsulinemia, hyperglucagonemia, hypercortisolemia, growth hormone deficiency and elevated sympathetic tone. These endocrine and metabolic changes further encourage hepatic steatosis by regulating adipose tissue lipolysis, liver lipid uptake, de novo lipogenesis (DNL), beta-oxidation, ketogenesis and lipid export. Hepatic lipid accumulation may be induced by 4 separate mechanisms: (1) increased hepatic uptake of circulating fatty acids, (2) increased hepatic de novo fatty acid synthesis, (3) decreased hepatic beta-oxidation and (4) decreased hepatic lipid export. This review will discuss the hormonal regulation of each mechanism comparing multiple physiological models of hepatic lipid accumulation. Nonalcoholic fatty liver disease (NAFLD) is typified by increased hepatic lipid uptake, synthesis, oxidation and export. Chronic hepatic lipid signaling through PPARgamma results in gene expression changes that allow concurrent activity of DNL and beta-oxidation. The importance of hepatic steatosis in driving systemic metabolic dysfunction is highlighted by the common endocrine and metabolic disturbances across many conditions that result in fatty liver. Understanding the mechanisms underlying the metabolic dysfunction that develops as a consequence of hepatic lipid accumulation is critical to identifying points of intervention in this increasingly prevalent disease state.
• Geisler, C. E., Kentch, K. P., & Renquist, B. J. (2017). Non-Mammalian Vertebrates: Distinct Models to Assess the Role of Ion Gradients in Energy Expenditure. Frontiers in endocrinology, 8, 224.
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  Animals store metabolic energy as electrochemical gradients. At least 50% of mammalian energy is expended to maintain electrochemical gradients across the inner mitochondrial membrane (H+), the sarcoplasmic reticulum (Ca++), and the plasma membrane (Na+/K+). The potential energy of these gradients can be used to perform work (e.g., transport molecules, stimulate contraction, and release hormones) or can be released as heat. Because ectothermic species adapt their body temperature to the environment, they are not constrained by energetic demands that are required to maintain a constant body temperature. In fact, ectothermic species expend seven to eight times less energy than similarly sized homeotherms. Accordingly, ectotherms adopt low metabolic rates to survive cold, hypoxia, and extreme bouts of fasting that would result in energy wasting, lactic acidosis and apoptosis, or starvation in homeotherms, respectively. Ectotherms have also evolved unique applications of ion gradients to allow for localized endothermy. Endothermic avian species, which lack brown adipose tissue, have been integral in assessing the role of H+ and Ca++ cycling in skeletal muscle thermogenesis. Accordingly, the diversity of non-mammalian vertebrate species allows them to serve as unique models to better understand the role of ion gradients in heat production, metabolic flux, and adaptation to stressors, including obesity, starvation, cold, and hypoxia.
• Ditzel, E. J., Li, H., Foy, C. E., Perrera, A. B., Parker, P., Renquist, B. J., Cherrington, N. J., & Camenisch, T. D. (2016). Altered Hepatic Transport by Fetal Arsenite Exposure in Diet-Induced Fatty Liver Disease. Journal of biochemical and molecular toxicology, 30(7), 321-30.
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  Non-alcoholic fatty liver disease can result in changes to drug metabolism and disposition potentiating adverse drug reactions. Furthermore, arsenite exposure during development compounds the severity of diet-induced fatty liver disease. This study examines the effects of arsenite potentiated diet-induced fatty liver disease on hepatic transport in male mice. Changes were detected for Mrp2/3/4 hepatic transporter gene expression as well as for Oatp1a4/2b1/1b2. Plasma concentrations of Mrp and Oatp substrates were increased in arsenic exposure groups compared with diet-only controls. In addition, murine embryonic hepatocytes and adult primary hepatocytes show significantly altered transporter expression after exposure to arsenite alone: a previously unreported phenomenon. These data indicate that developmental exposure to arsenite leads to changes in hepatic transport which could increase the risk for ADRs during fatty liver disease.
• Geisler, C. E., Hepler, C., Higgins, M. R., & Renquist, B. J. (2016). Hepatic adaptations to maintain metabolic homeostasis in response to fasting and refeeding in mice. Nutrition & metabolism, 13, 62.
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  The increased incidence of obesity and associated metabolic diseases has driven research focused on genetically or pharmacologically alleviating metabolic dysfunction. These studies employ a range of fasting-refeeding models including 4-24 h fasts, "overnight" fasts, or meal feeding. Still, we lack literature that describes the physiologically relevant adaptations that accompany changes in the duration of fasting and re-feeding. Since the liver is central to whole body metabolic homeostasis, we investigated the timing of the fast-induced shift toward glycogenolysis, gluconeogenesis, and ketogenesis and the meal-induced switch toward glycogenesis and away from ketogenesis.
• Hepler, C., Foy, C. E., Higgins, M. R., & Renquist, B. J. (2016). The hypophagic response to heat stress is not mediated by GPR109A or peripheral β-OH butyrate. American Journal of Physiology: Regulatory, Integrative, and Comparative Physiology.
• Hepler, C., Foy, C. E., Higgins, M. R., & Renquist, B. J. (2016). The hypophagic response to heat stress is not mediated by GPR109A or peripheral β-OH butyrate. American journal of physiology. Regulatory, integrative and comparative physiology, 310(10), R992-8.
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  Rising temperatures resulting from climate change will increase the incidence of heat stress, negatively impacting the labor force and food animal production. Heat stress elevates circulating β-OH butyrate, which induces vasodilation through GPR109a. Interestingly, both heat stress and intraperitoneal β-OH butyrate administration induce hypophagia. Thus, we aimed to investigate the role of β-OH butyrate in heat stress hypophagia in mice. We found that niacin, a β-OH butyrate mimetic that cannot be oxidized to generate ATP, also reduces food intake. Interestingly, the depression in food intake as a result of 8-h intraperitoneal niacin or 48-h heat exposure did not result from changes in hypothalamic expression of orexigenic or anorexigenic signals (AgRP, NPY, or POMC). Genetically eliminating GPR109a expression did not prevent the hypophagic response to heat exposure, intraperitoneal β-OH butyrate (5.7 mmol/kg), or niacin (0.8 mmol/kg). Hepatic vagotomy eliminated the hypophagic response to β-OH butyrate and niacin but did not affect the hypophagic response to heat exposure. We subsequently hypothesized that the hypophagic response to heat stress may depend on direct effects of β-OH butyrate at the central nervous system: β-OH butyrate induced hormonal changes (hyperinsulinemia, hypercorticosteronemia, and hyperleptinemia), or gene expression changes. To test these possibilities, we blocked expression of hepatic hydroxyl methyl glutaryl CoA synthase II (HMGCS2) to prevent hepatic β-OH butyrate synthesis. Mice that lack HMGCS2 maintain a hypophagic response to heat stress. Herein, we establish that the hypophagia of heat stress is independent of GPR109a, the hepatic vagus afferent nerve, and hepatic ketone body synthesis.
• Williams, S. Y., & Renquist, B. J. (2016). High Throughput Danio Rerio Energy Expenditure Assay. Journal of visualized experiments : JoVE, e53297.
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  Zebrafish are an important model organism with inherent advantages that have the potential to make zebrafish a widely applied model for the study of energy homeostasis and obesity. The small size of zebrafish allows for assays on embryos to be conducted in a 96- or 384-well plate format, Morpholino and CRISPR based technologies promote ease of genetic manipulation, and drug treatment by bath application is viable. Moreover, zebrafish are ideal for forward genetic screens allowing for novel gene discovery. Given the relative novelty of zebrafish as a model for obesity, it is necessary to develop tools that fully exploit these benefits. Herein, we describe a method to measure energy expenditure in thousands of embryonic zebrafish simultaneously. We have developed a whole animal microplate platform in which we use 96-well plates to isolate individual fish and we assess cumulative NADH2 production using the commercially available cell culture viability reagent alamarBlue. In poikilotherms the relationship between NADH2 production and energy expenditure is tightly linked. This energy expenditure assay creates the potential to rapidly screen pharmacological or genetic manipulations that directly alter energy expenditure or alter the response to an applied drug (e.g. insulin sensitizers).
• Renquist, B. J., Zhang, C., Williams, S. Y., & Cone, R. D. (2013). Development of an assay for high-throughput energy expenditure monitoring in the zebrafish. Zebrafish, 10(3), 343-352.
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  PMID: 23705823;PMCID: PMC3806375;Abstract: Energy homeostasis is maintained by balancing energy intake and expenditure. Many signals regulating energy intake are conserved between the human and teleost. However, before this work, there was no sensitive high-throughput system to monitor energy expenditure in the teleost. We exploit the nonfluorescent and fluorescent properties of resazurin and its reduced form resorufin (alamarBlue®) to monitor energy expenditure responses to drug application and genetic manipulation. We show that leptin, insulin, and alpha-melanocyte-stimulating hormone (α-MSH) increase energy expenditure dose dependently in the larval zebrafish. As previously established in the mouse, etomoxir, a carnitine palmitoyl transferase I inhibitor, blocks leptin-induced energy expenditure in the zebrafish. Metformin, the most commonly prescribed insulin sensitizer, increases the insulin-induced metabolic rate. Using genetic knockdown, we observed that α-MSH treatment increases the metabolic rate, as does knockdown of the melanocortin antagonist, agouti-related protein. The agouti-related protein and multiple melanocortin receptors are shown to be involved in these effects. These studies confirm that aspects of hormonal regulation of energy expenditure are conserved in the teleost, and suggest that this assay may provide a unique tool to perform in vivo screens for drugs or genes that affect the metabolic rate, including insulin or leptin sensitizers. © Copyright 2013, Mary Ann Liebert, Inc.
• Renquist, B. J., Zhang, C., Williams, S. Y., & Cone, R. D. (2013). Development of an assay for high-throughput energy expenditure monitoring in the zebrafish. Zebrafish, 10(3).
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  Energy homeostasis is maintained by balancing energy intake and expenditure. Many signals regulating energy intake are conserved between the human and teleost. However, before this work, there was no sensitive high-throughput system to monitor energy expenditure in the teleost. We exploit the nonfluorescent and fluorescent properties of resazurin and its reduced form resorufin (alamarBlue(®)) to monitor energy expenditure responses to drug application and genetic manipulation. We show that leptin, insulin, and alpha-melanocyte-stimulating hormone (α-MSH) increase energy expenditure dose dependently in the larval zebrafish. As previously established in the mouse, etomoxir, a carnitine palmitoyl transferase I inhibitor, blocks leptin-induced energy expenditure in the zebrafish. Metformin, the most commonly prescribed insulin sensitizer, increases the insulin-induced metabolic rate. Using genetic knockdown, we observed that α-MSH treatment increases the metabolic rate, as does knockdown of the melanocortin antagonist, agouti-related protein. The agouti-related protein and multiple melanocortin receptors are shown to be involved in these effects. These studies confirm that aspects of hormonal regulation of energy expenditure are conserved in the teleost, and suggest that this assay may provide a unique tool to perform in vivo screens for drugs or genes that affect the metabolic rate, including insulin or leptin sensitizers.
• Renquist, B. J., Murphy, J. G., Larson, E. A., Olsen, D., Klein, R. F., Ellacott, K. L., & Cone, R. D. (2012). Melanocortin-3 receptor regulates the normal fasting response. Proceedings of the National Academy of Sciences of the United States of America, 109(23), E1489-98.
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  The melanocortin-3 receptor-deficient (MC3-R(-/-)) mouse exhibits mild obesity without hyperphagia or hypometabolism. MC3-R deletion is reported to increase adiposity, reduce lean mass and white adipose tissue inflammation, and increase sensitivity to salt-induced hypertension. We show here that the MC3-R(-/-) mouse exhibits defective fasting-induced white adipose tissue lipolysis, fasting-induced liver triglyceride accumulation, fasting-induced refeeding, and fasting-induced regulation of the adipostatic and hypothalamic-adrenal-pituitary axes. Close examination of the hypothalamic-pituitary-adrenal axis showed that MC3-R(-/-) mice exhibit elevated nadir corticosterone as well as a blunted fasting-induced activation of the axis. The previously described phenotypes of this animal and the reduced bone density reported here parallel those of Cushing syndrome. Thus, MC3-R is required for communicating nutritional status to both central and peripheral tissues involved in nutrient partitioning, and this defect explains much of the metabolic phenotype in the model.
• Renquist, B. J., Murphy, J. G., Larson, E. A., Olsen, D., Klein, R. F., L., K., & Cone, R. D. (2012). Melanocortin-3 receptor regulates the normal fasting response. Proceedings of the National Academy of Sciences of the United States of America, 109(23), E1489-E1498.
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  PMID: 22573815;PMCID: PMC3384161;Abstract: The melanocortin-3 receptor-deficient (MC3-R-/-) mouse exhibits mild obesity without hyperphagia or hypometabolism. MC3-R deletion is reported to increase adiposity, reduce lean mass and white adipose tissue inflammation, and increase sensitivity to salt-induced hypertension. We show here that the MC3-R-/-mouse exhibits defective fasting-induced white adipose tissue lipolysis, fasting-induced liver triglyceride accumulation, fasting-induced refeeding, and fasting-induced regulation of the adipostatic and hypothalamic-adrenal-pituitary axes. Close examination of the hypothalamic-pituitary-adrenal axis showed that MC3-R-/-mice exhibit elevated nadir corticosterone as well as a blunted fasting-induced activation of the axis. The previously described phenotypes of this animal and the reduced bone density reported here parallel those of Cushing syndrome. Thus, MC3-R is required for communicating nutritional status to both central and peripheral tissues involved in nutrient partitioning, and this defect explains much of the metabolic phenotype in the model.
• Renquist, B., Murphy, J., Larson, E., Olsen, D., Klein, R., Ellacott, K., & Cone, R. (2012). Melanocortin-3 receptor regulates the normal fasting response. Proc Natl Acad Sci U S A, 109(23), 1489-1498.
• Renquist, B. J., Lippert, R. N., Sebag, J. A., Ellacott, K. L., & Cone, R. D. (2011). Physiological roles of the melanocortin MC₃ receptor. European Journal of Pharmacology, 660(1), 13-20.
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  PMID: 21211527;PMCID: PMC3095771;Abstract: The melanocortin MC3 receptor remains the most enigmatic of the melanocortin receptors with regard to its physiological functions. The receptor is expressed both in the CNS and in multiple tissues in the periphery. It appears to be an inhibitory autoreceptor on proopiomelanocortin neurons, yet global deletion of the receptor causes an obesity syndrome. Knockout of the receptor increases adipose mass without a readily measurable increase in food intake or decrease in energy expenditure. And finally, no melanocortin MC 3 receptor null humans have been identified and associations between variant alleles of the melanocortin MC3 receptor and diseases remain controversial, so the physiological role of the receptor in humans remains to be determined. © 2011 Elsevier B.V. All rights reserved.
• Renquist, B. J., Lippert, R. N., Sebag, J. A., Ellacott, K. L., & Cone, R. D. (2011). Physiological roles of the melanocortin MC₃ receptor. European journal of pharmacology, 660(1), 13-20.
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  The melanocortin MC(3) receptor remains the most enigmatic of the melanocortin receptors with regard to its physiological functions. The receptor is expressed both in the CNS and in multiple tissues in the periphery. It appears to be an inhibitory autoreceptor on proopiomelanocortin neurons, yet global deletion of the receptor causes an obesity syndrome. Knockout of the receptor increases adipose mass without a readily measurable increase in food intake or decrease in energy expenditure. And finally, no melanocortin MC(3) receptor null humans have been identified and associations between variant alleles of the melanocortin MC(3) receptor and diseases remain controversial, so the physiological role of the receptor in humans remains to be determined.
• Renquist, B. J., Adams, T. E., Adams, B. M., & Calvert, C. C. (2008). Dietary restriction reduces the rate of estradiol clearance in sheep (Ovis aries). Journal of Animal Science, 86(5), 1124-1131.
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  PMID: 18272858;Abstract: Three experiments were designed to test the effect of dietary restriction on clearance of 17β-estradiol (E2) in sheep. A preliminary experiment examined the effect of a 4-d fast on the rate of E2 clearance in wethers. The second experiment tested the hypothesis that either long-term restriction (7 wk) or a 5-d fast would increase steroid-binding capacity of serum by increasing the concentration of sex hormone-binding globulin (SHBG) in the blood of ovariectomized ewes. In Exp. 3, we hypothesized that nutrition-dependent regulation of E2 clearance by the liver would result in divergence in biliary extraction of E2 in fed and fasted wethers receiving comparable levels of exogenous E2. A marked difference in E2 clearance between fed and fasted wethers was noted in the preliminary study. Relative to ad libitum-fed wethers, a 4-d fast decreased E2 clearance by 52%. Serum concentrations of SHBG were increased in long-term energy-restricted and fasted ewes, relative to the concentration in maintenance-fed ewes (P = 0.015). Furthermore, a 5-d fast nearly doubled serum steroid-binding capacity in wethers. The E2 concentration in bile was 2 times greater in fasted than in fed wethers. This fasting-dependent increase in biliary E2 may be reflective of the increased serum E2 in fasted animals, because each 1 pg/mL increase in serum E2 increased bile E2 by 0.86 ± 0.12 pg/mL, independent of nutrition (P = 0.002). Our results demonstrate that the rate of clearance of E2 is decreased during nutritional restriction. Additionally, these data indicate that altered SHBG expression, enterohepatic recirculation, or both are involved in the decreased E2 clearance during dietary restriction. ©2008 American Society of Animal Science. All rights reserved.
• Renquist, B. J., Adams, T. E., Adams, B. M., & Calvert, C. C. (2008). Dietary restriction reduces the rate of estradiol clearance in sheep (Ovis aries). Journal of animal science, 86(5), 1124-31.
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  Three experiments were designed to test the effect of dietary restriction on clearance of 17beta-estradiol (E(2)) in sheep. A preliminary experiment examined the effect of a 4-d fast on the rate of E(2) clearance in wethers. The second experiment tested the hypothesis that either long-term restriction (7 wk) or a 5-d fast would increase steroid-binding capacity of serum by increasing the concentration of sex hormone-binding globulin (SHBG) in the blood of ovariectomized ewes. In Exp. 3, we hypothesized that nutrition-dependent regulation of E(2) clearance by the liver would result in divergence in biliary extraction of E(2) in fed and fasted wethers receiving comparable levels of exogenous E(2). A marked difference in E(2) clearance between fed and fasted wethers was noted in the preliminary study. Relative to ad libitumfed wethers, a 4-d fast decreased E(2) clearance by 52%. Serum concentrations of SHBG were increased in long-term energy-restricted and fasted ewes, relative to the concentration in maintenancefed ewes (P = 0.015). Furthermore, a 5-d fast nearly doubled serum steroid-binding capacity in wethers. The E(2) concentration in bile was 2 times greater in fasted than in fed wethers. This fasting-dependent increase in biliary E(2) may be reflective of the increased serum E(2) in fasted animals, because each 1 pg/mL increase in serum E(2) increased bile E(2) by 0.86 +/- 0.12 pg/mL, independent of nutrition (P = 0.002). Our results demonstrate that the rate of clearance of E(2) is decreased during nutritional restriction. Additionally, these data indicate that altered SHBG expression, enterohepatic recirculation, or both are involved in the decreased E(2) clearance during dietary restriction.
• Renquist, B. J., Calvert, C. C., Adams, B. M., & Adams, T. E. (2008). Circulating estradiol suppresses luteinizing hormone pulse frequency during dietary restriction. Domestic Animal Endocrinology, 34(3), 301-310.
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  PMID: 17904783;Abstract: The influence of dietary restriction on the negative feedback potency of 17-β-estradiol (E2) was evaluated in both castrated male (wethers) and female sheep (OVX ewes) during the breeding season. In study 1, OVX ewes received maintenance or restricted dietary energy for 7 weeks or maintenance energy for 6 weeks prior to a 5 day fast (n = 12 ewes/feeding group). Estradiol (0.31 μg E2/50 kg/h) or vehicle (10% EtOH-saline) was continuously infused into half the animals in each dietary treatment for the final 54 h of the study. The dynamic pattern of LH secretion was assessed during the final 6 h of infusion. Estradiol inhibited luteinizing hormone (LH) pulse amplitude independent of nutrition (P = 0.02); fasting increased mean LH, LH peak height, and LH nadir in the absence of E2 (P = 0.004, P = 0.02, and P = 0.02, respectively); while E2 inhibited pulse frequency (P = 0.02) and increased peak width (P = 0.04) in restricted ewes. Interestingly, despite uniform E2 delivery, serum concentrations of E2 differed with feeding status. Therefore, 12 wethers were infused with 0.31 μg E2/50 kg/h (6 fed, 6 fasted) and six wethers received 0.19 μg E2/50 kg/h (fasted) to establish similar serum concentrations of E2 in fed (0.31 μg/50 kg/h) and fasted (0.19 μg/50 kg/h) wethers. When fed and fasted wethers had uniform serum concentrations of E2 LH pulse frequency was suppressed (P < 0.05) in fasted relative to fed animals, supporting the postulate that energy restriction enhances the E2 negative feedback potency. Collectively, these studies demonstrate that nutrition affects E2 feedback potency and clearance. © 2007 Elsevier Inc. All rights reserved.
• Renquist, B. J., Calvert, C. C., Adams, B. M., & Adams, T. E. (2008). Circulating estradiol suppresses luteinizing hormone pulse frequency during dietary restriction. Domestic animal endocrinology, 34(3), 301-10.
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  The influence of dietary restriction on the negative feedback potency of 17-beta-estradiol (E2) was evaluated in both castrated male (wethers) and female sheep (OVX ewes) during the breeding season. In study 1, OVX ewes received maintenance or restricted dietary energy for 7 weeks or maintenance energy for 6 weeks prior to a 5 day fast (n=12ewes/feeding group). Estradiol (0.31microg E2/50kg/h) or vehicle (10% EtOH-saline) was continuously infused into half the animals in each dietary treatment for the final 54h of the study. The dynamic pattern of LH secretion was assessed during the final 6h of infusion. Estradiol inhibited luteinizing hormone (LH) pulse amplitude independent of nutrition (P=0.02); fasting increased mean LH, LH peak height, and LH nadir in the absence of E2 (P=0.004, P=0.02, and P=0.02, respectively); while E2 inhibited pulse frequency (P=0.02) and increased peak width (P=0.04) in restricted ewes. Interestingly, despite uniform E2 delivery, serum concentrations of E2 differed with feeding status. Therefore, 12 wethers were infused with 0.31microg E2/50kg/h (6 fed, 6 fasted) and six wethers received 0.19microg E2/50kg/h (fasted) to establish similar serum concentrations of E2 in fed (0.31microg/50kg/h) and fasted (0.19microg/50kg/h) wethers. When fed and fasted wethers had uniform serum concentrations of E2 LH pulse frequency was suppressed (P
• Renquist, B. J., Oltjen, J. W., Sainz, R. D., & Calvert, C. C. (2006). Effects of age on body condition and production parameters of multiparous beef cows. Journal of Animal Science, 84(7), 1890-1895.
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  PMID: 16775073;Abstract: Pregnancy rate, calving interval, birth weight, weaning weight, and quarterly BCS were collected for 5 consecutive years on 454 fall-calving multiparous British crossbred cattle (3 to 10 yr of age) to evaluate associations of age with BCS and production parameters. Body weight and BCS were collected precalving, prebreeding, at weaning, and midway through the second trimester of pregnancy (August). Body condition score was correlated with age during all seasons (P < 0.01). At calving, breeding, and in August, 3-yr-old cows had the lowest BW and BCS, whereas 8-yr-old cows had the greatest. At weaning, these values were maximal in 10-yr-old cows. Pregnancy rate was near 80% up to 9 yr of age but decreased to 57% in 10-yr-old cows. The relationship of pregnancy rate with age appears to be correlated with the BCS decrease at breeding in the older cows, supported by the fact that inclusion of BCS at breeding in the statistical model eliminated the effect of age on pregnancy rate (P = 0.42). Calving interval was longer in 3-yr-old cows compared with 4- to 9-yr-old cows (P = 0.02); however, among older cows, there was little change in the calving interval. Birth weight reached a maximum at 8 yr of age (35 ± 0.9 kg) and a minimum in 3-yr-old cows (32 ± 0.7 kg). Birth weights of calves born to both 3- and 4-yr-old cows were lower than for those born to 5-, 6-, 7-, or 8-yr-old cows (P < 0.05). Ten-year-old cows weaned lighter calves (205-d adjusted weaning weight) than younger dams. Furthermore, 3-yr-old cows weaned calves 9 ± 2.1 and 14 ± 2.4 kg lighter than 4- and 5-yr-old cows, respectively (P < 0.001). Interpretation of the age analyses of calving interval, birth weight, and weaning weight was independent of the inclusion of BCS in the model. This study documents the effects of age on calving interval, birth weight, and weaning weight that are independent of BCS. ©2006 American Society of Animal Science. All rights reserved.
• Renquist, B. J., Oltjen, J. W., Sainz, R. D., & Calvert, C. C. (2006). Effects of age on body condition and production parameters of multiparous beef cows. Journal of animal science, 84(7), 1890-5.
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  Pregnancy rate, calving interval, birth weight, weaning weight, and quarterly BCS were collected for 5 consecutive years on 454 fall-calving multiparous British crossbred cattle (3 to 10 yr of age) to evaluate associations of age with BCS and production parameters. Body weight and BCS were collected pre-calving, prebreeding, at weaning, and midway through the second trimester of pregnancy (August). Body condition score was correlated with age during all seasons (P < 0.01). At calving, breeding, and in August, 3-yr-old cows had the lowest BW and BCS, whereas 8-yr-old cows had the greatest. At weaning, these values were maximal in 10-yr-old cows. Pregnancy rate was near 80% up to 9 yr of age but decreased to 57% in 10-yr-old cows. The relationship of pregnancy rate with age appears to be correlated with the BCS decrease at breeding in the older cows, supported by the fact that inclusion of BCS at breeding in the statistical model eliminated the effect of age on pregnancy rate (P = 0.42). Calving interval was longer in 3-yr-old cows compared with 4- to 9-yr-old cows (P = 0.02); however, among older cows, there was little change in the calving interval. Birth weight reached a maximum at 8 yr of age (35 +/- 0.9 kg) and a minimum in 3-yr-old cows (32 +/- 0.7 kg). Birth weights of calves born to both 3- and 4-yr-old cows were lower than for those born to 5-, 6-, 7-, or 8-yr-old cows (P < 0.05). Ten-year-old cows weaned lighter calves (205-d adjusted weaning weight) than younger dams. Furthermore, 3-yr-old cows weaned calves 9 +/- 2.1 and 14 +/- 2.4 kg lighter than 4- and 5-yr-old cows, respectively (P < 0.001). Interpretation of the age analyses of calving interval, birth weight, and weaning weight was independent of the inclusion of BCS in the model. This study documents the effects of age on calving interval, birth weight, and weaning weight that are independent of BCS.
• Renquist, B. J., Oltjen, J. W., Sainz, R. D., & Calvert, C. C. (2006). Relationship between body condition score and production of multiparous beef cows. Livestock Science, 104(1-2), 147-155.
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  Abstract: Pregnancy rate, calving interval, weaning weight, birth weight and quarterly body condition score (BCS) were collected on fall calving multiparous English crossbred cattle (ages 3 to 10) from 1994 to 2001 to evaluate the critical time of cow condition measurements that predict production. The study was initiated with 260 cows. Replacement animals entered the study at first calving (2 years of age), with 45, 54, 27, 68, 54, and 45 animals added in years two through seven, respectively. Body condition score was measured in association with calving, breeding, weaning, and midway between weaning and calving (August). Regression of the logit of the probability of pregnancy (Y) showed that pregnancy outcome was quadratically related to BCS at breeding (P < 0.0001, Y = - 4.81X2 - 0.52X - 4.339) and linearly related to BCS at calving (P = 0.009, Y = 0.32X + 4.17), but was not associated with either the pre- or postpartum change in condition (P > 0.05). Calving interval varied cubically with BCS at calving and quadratically with BCS at breeding (P < 0.0001 and P = 0.002, respectively). The largest decreases in calving interval were associated with increases in body condition score at calving from 3.5 to 4.5 and from 7 to 8. Calf weight at 205 days was related to both the BCS at breeding and the change in BCS from breeding to weaning (P = 0.01 and P = 0.004). Calf weight at 205 days was also associated with BCS at weaning (P = 0.0003). Cows with either low or high BCS at weaning tended to wean lighter calves than cows with moderate condition (4.5 and 5.5). Moreover, BCS at weaning (≈ 6 months prior to calving) was related to birth weight (P = 0.01). Dams with a BCS at weaning of 7 birthed heavier calves than dams with low (3 to 4) or high (8.5) BCS. The relationship of BCS at breeding with pregnancy rate, calving interval, and weaning weight suggests that maintenance of adequate BCS immediately before, during, and after the breeding season may be most critical to sustaining adequate reproductive performance and calf gains in animals subject to the seasonal forage production associated with a Mediterranean climate. © 2006 Elsevier B.V. All rights reserved.
• Renquist, B. J., Oltjen, J. W., Sainz, R. D., Connor, J. M., & Calvert, C. C. (2005). Effects of supplementation and stocking rate on body condition and production parameters of multiparous beef cows. Animal Science, 81(3), 403-411.
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  Abstract: Fall-calving multiparous Angus x Hereford cows 3 to 10 years of age were stratified by age in a three by two factorial treatment arrangement to evaluate the efficacy of modifying stocking rate and supplementation strategy to manage cow body condition and production parameters over a 5-year study. Efficacy was evaluated quarterly in association with calving, breeding, weaning, and mid way between weaning and calving (i.e. in August). Three protein supplementation strategies (none, standard, strategic) were imposed across both a moderate (0.3 cows per ha) and a high (0.4 cows per ha) stocking rate. In the strategically supplemented group, protein supplement was provided to cows with a body condition score < 5.5 at the quarterly evaluations. There was an effect of supplementation on pregnancy rate, which in combination with previously established culling practices resulted in different age profiles amongst supplementation strategies in years 2 to 5 (P < 0.01). Two statistical analyses were therefore conducted to dissociate the confounding effects of supplementation strategy and age. One model included the effect of stocking rate, supplementation strategy, production year, and all interactions; the second included the addition of age and its interactive effects. Stocking rate and supplementation strategy affected pregnancy rate in each of the models (P = 0.003 and P = 0.10, respectively). Standard, non-supplemented and strategically supplemented animals had estimated pregnancy rates of 0.83, 0.76, and 0.79, respectively (P = 0.10). The effects of nutrition on both calving interval and birth weight were independent of the model employed. Animals that were not supplemented had extended calving intervals (P = 0.06), but there was no effect of stocking rate (P = 0.10). Birth weight was not affected by supplementation strategy or stocking rate (P>0.10). The lower 205-day weights of calves on a heavy compared with moderate stocking rate was independent of age (P = 0.02). However, the increased 205-day weight of calves born to strategically supplemented cows compared with those born to unsupplemented cows was only evident when data were not corrected for differences in age among groups (P = 0.03). Likewise, analyses of cow condition parameters using models without and with age resulted in different interpretations. These results suggest that strategic and standard supplementation result in similar animal performance and that the improvement in herd productivity associated with altering stocking rate and supplementation may partially be due to altered herd age dynamics. © 2005 British Society of Animal Science.

Proceedings Publications

• Collier, R. J., Renquist, B. J., & Bilby, T. R. (2017, May). Emerging Trends in Agriculture. In 5th International Symposium on Dairy Cow Nutrition and Milk Quality, 5th.
• Foy, C. E., Hepler, C., Higgins, M. R., & Renquist, B. J. (2016, Spring). GPR109a Signaling Alters the Hepatic Response to Fasting. In Experimental Biology.
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  Elevated hepatic ketogenesis and gluconeogenesis are integral to the metabolic adaptation to fasting. The increase in ketone body production allows for feedback inhibition of adipose tissue lipolysis through Gαi coupled GPR109a, the β-OH butyrate receptor. To better understand the role of this feedback we investigated the hepatic metabolic response to fasting in sibling GPR109a +/+ and -/- mice that were injected every 2 hours for 8 hours with either saline (0.1 ml/10 g body weight) or niacin (100 mg/kg in 0.1 ml saline/10 g body weight), a non-metabolizable GPR109a agonist. In wildtype mice, niacin completely eliminated the rise in serum NEFAs during a fast and significantly (p
• Renquist, B. J. (2013, February). Development of a high-throughput assay to monitor metabolic rate in zebrafish: Future impact in aquacultural species. In World Aquaculture Society.
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  Abstract and Presentation at World Aquaculture Society Meetings 2013
• Renquist, B. J. (2012, February). Stress Mediated Regulation of Feed Intake. In Southwest Nutrition and Management Conference, 27, 116-125.

Presentations

• Ngu, E., Renquist, B. J., & Stern, J. H. (2023, March). Investigating the Impact of GABA in NAFLD-Associated HCC: Model Development. . University of Arizona College of Medicine Research Day. Selected short talk.. Tucson, AZ: University of Arizona COM-T.
• Brugging, S. M., & Renquist, B. J. (2021, Fall). Development and Validation of a Leak-Free Head-Out Plethysmography System to Assess Breathing in Mice. Asthma and Airway Disease Research Center Seminar Series. Online: Asthma and Airway Disease Research Center.
• Bruggink, S. M., Geisler, C. E., Ghimire, S., & Renquist, B. J. (2021, Fall). Identifying a Mechanism by Which Hepatic Steatosis Drives Hypertension Development. The Obesity Society Meetings. Online: The Obesity Society.
• Renquist, B. J. (2021, Fall). Hepatic GABA Release Drives Hyperinsulinemia and Insulin Resistance. Kansas University Medical Center. Kansas University Medical Center Seminar. Kansas City, Kansas: Kansas University Medical Center.
• Renquist, B. J. (2021, Fall). Studies in Mice to Better Understand the Mechanism by Which Heat Suppresses Growth and Milk Production. University of Georgia Dairy Science Seminar Series. Online: University of Georia.
• Renquist, B. J. (2021, September). Tools to Advance Genetics in Aquaculture. Global Aquaculture Alliance. Online: Global Aquaculture Alliance.
• Geisler, C. E., Ghimire, S., & Renquist, B. J. (2019, Spring). Hepatic Gamma-Amino Butyric Acid Release Drives Hyperinsulinemia and Insulin Resistance. Arizona Biomedical Research Commission. Pheonix, AZ: Arizona Biomedical Research Commission.
• Kentch, K., & Renquist, B. J. (2018, Fall). Measuring Metabolic Rate to Improve Genetics for Growth and Feed Efficiency. Triennial World Aquaculture Society Meeting: Aquaculture 2019. New Orleans, LA: World Aquaculture Society.
• Renquist, B. J. (2019, Fall). GentiRate. IdeaFunding Tucson. Tucson, AZ: Start-up Tucson.
• Renquist, B. J. (2019, Fall). Natural Selection to Drive Sustainable Production. Aquaculture Innovation Summit. London, UK: Kiasco Research.
• Renquist, B. J. (2019, Spring). Informed Natural Selection to Improve Sustainability and Production. North Atlantic Seafood Forum. Bergen, Norway: Aquaculture Industry.
• Renquist, B. J. (2019, Spring). Informed Natural Selection to Improve Sustainable Production. Aquaculture America. New Orleans, LA: World Aquaculture Society.
• Beckett, L., Rosemond, R., Renquist, B. J., & White, R. (2018, February). Evaluating a Novel Strategy for Measuring Basal Metabolic Rate of Bovine Skeletal Muscle. American Society of Animal Science Southern Section. Forth Worth, TX: American Society of Animal Science.
• Beckett, L., Rosemond, R., Renquist, B. J., & White, R. R. (2017, Fall). Evaluating a Novel Strategy for Measuring Basal Metabolic Rate of Bovine Skeletal Muscle. American Society of Animal Science Southern Section. Fort Worth, TX: American Society of Animal Science.
• Diaz, D., Vander Poel, M., Xiao, Y., Renquist, B. J., Wright, A., Collier, R. J., & Compart, D. (2018, Summer). Environmental chamber heat stress responses and adaptations in crossbred Hereford steers. American Society of Animal Science Western Section. Bend, OR: American Society of Animal Science.
• Renquist, B. J. (2018, Summer). Hepatic Neurotransmitter Release Drives Hyperinsulinemia and Insulin Resistance. University of Cincinnati Endocrinology Seminar Series. Cincinnati, OH: University of Cincinnati.
• Vander Poel, M., Xiao, Y., Renquist, B. J., Wright, A., Collier, R. J., Compart, D., & Diaz, D. (2018, April). Evaluation of the efficacy of a feed supplement (BeefAbate) in attenuating the effects of heat stress on growing steers. Plains Nutrition Council. San Antonio, TX: Plains Nutrition Council.
• Xiao, Y., & Renquist, B. J. (2018, June). Heat Stress: Hypophagia and Hypogalactia. Symposium: Ruminant Nutrition: Interface of Environment and Nutrition – Targeted Nutrition to Overcome Heat Stress. American Dairy Science Association. Knoxville, TN: American Dairy Science Association.
• Xiao, Y., & Renquist, B. J. (2018, Summer). Assessing Tissue Specific Metabolic Rate to Predict Production. American Dairy Science Association Annual Meeting. Knoxville, TN: American Dairy Science Association.
• Xiao, Y., & Renquist, B. J. (2018, Summer). Heat Stress: Hypophagia and Hypogalactia. Symposium: Ruminant Nutrition: Interface of Environment and Nutrition – Targeted Nutrition to Overcome Heat Stress. American Dairy Science Association Annual Meeting. Knoxville, TN: American Dairy Science Association.
• Geisler, C. E., & Renquist, B. J. (2017, June). Hepatic Uncoupling Protein 2 is Essential to the Development of High Fat Diet Induced Hyperinsulinemia and Insulin Resistance.. American Diabetes Association. San Diego, CA: American Diabetes Association.
• Kentch, K. P., Geisler, C. E., & Renquist, B. J. (2017, February/Spring). Measuring Metabolic Rate of Embryonic Fish to Predict Growth Rate. Aquaculture America. San Antonio: World Aquaculture Society.
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  Selected for Oral Presentation
• Renquist, B. J. (2017, April). Obesity Induced Pathophysiologies: Diabetes, Hypertension, and Cancer. Translational Genomics Research Institute Seminar Series. Phoenix, AZ: Translational Genomics Research Institute.
• Renquist, B. J. (2017, May). The Role of the Liver in Hyperinsulinemia, Insulin Resistance, and Glucose Intolerance. City of Hope/Translational Genomics Research Institute Diabetes Symposium. Pheonix, AZ: City of Hope/Translational Genomics Research Institute Diabetes Symposium.
• Renquist, B. J. (2017, Spring). Measuring Metabolic Rate to Predict Growth and Feed Efficiency. Trout Growers Meeting. USDA Hagerman Fish Culture Experiment Station: USDA.
• Renquist, B. J., & Geisler, C. E. (2017, January). Hepatic Lipids: Insulin Resistance, Hyperinsulinemia, and Hypertension. Nutritional Sciences Seminar Series. UofA Campus Marley Building: Nutritional Science.
• Renquist, B. J., & Geisler, C. E. (2017, Spring). Hepatic Lipids: Hyperinsulinemia, Insulin Resistance, and Hypertension. Endocrine Grand Rounds. Tucson, AZ: Division of Endocrinology, College of Medicine.
• Renquist, B. J., & Geisler, C. E. (2017, Spring). Hepatic Lipids: Hyperinsulinemia, Insulin Resistance, and Hypertension. Nutritional Science Seminar Series. Tucson, AZ: Nutritional Sciences Graduate Group.
• Renquist, B. J., Collier, R. J., & Bilby, T. R. (2017, May). Emerging Trends in Agriculture. 5th International Symposium on Dairy Cow Nutrition and Milk Quality. Beijing, China: American Dairy Science Association and Chinese National Academy.
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  Keynote Address.
• Renquist, B. J. (2016, Spring). Studies in Endocrinology to Address Societal Issues: Obesity, Global Warming, and Food Production. Animal Science Seminar Series. Davis, CA: University of California, Davis.
• Renquist, B. J. (2016, Summer). Applying a Test Developed to Combat Obesity and Diabetes to Improve Growth in Fish, Shellfish, and Crustaceans. eXtension. Webinar on eXtension: eXtension.org.
• Renquist, B., Overturf, K., & Freitag, G. (2012, October). Efficient, Rapid Assay for Predicting the Growth Rate of Aquaculture Species Based on Metabolic Rate of the Fertilized Egg. Spokane, WA: Western Regional Aquaculture Center.

Poster Presentations

• Bruggink, S. M., Geisler, C. E., Ghimire, S., Strom, J., Xiao, Y., & Renquist, B. J. (2022, April). An Underlying Mechanism by which Hepatic Steatosis Drives the Development of Hypertension. Experimental Biology. Philadelphia, PA: American Physiological Society.
• Bruggink, S. M., Kentch, K. P., Kronenfeld, J. M., Pederson, W., Ledford, J., & Renquist, B. J. (2021, October). Utilizing variable-pressure head-out plethysmography to assess obesity-associate alterations in lung function. Metabesity. Online: Metabesity Conference.
• Fenwick, J. M., & Renquist, B. J. (2021, Fall). Improved cardiac output improves microvascular blood flow and skeletal muscle glucose uptake. Metabesity. Online: Metabesity Conference.
• Ghimire, S., Miller, K. E., Geisler, C. E., & Renquist, B. J. (2021, October). The role of liver GABA shunt enzymes and GABA transporters in the regulation of liver slice GABA release and glucose homeostasis. Metabesity. Online: Metabesity Conference.
• Miller, K. E., Kentch, K. P., Kronenfeld, J. M., Escobedo, A., & Renquist, B. J. (2021, October). The direction of GABA shunt flux is driven by substrate and product concentrations. Metabesity. Online: Metabesity Conference.
• Bruggink, S., Kentch, K., Kronenfeld, J., & Renquist, B. J. (2020, Spring). Determining the Role of Obesity and Muscarinic Signaling in Asthma. Experimental Biology. San Diego: American Physiological Society.
• Geisler, C. E., Ghimire, S., & Renquist, B. J. (2019, June). Hepatic Gamma-Amino Butyric Acid Release Drives Hyperinsulinemia and Insulin Resistance. American Diabetes Association. San Francisco CA: American Diabetes Association.
• Xiao, Y., & Renquist, B. J. (2018, October). Hepatocyte Depolarization Induces a Pressor Response. American Heart Association Hypertension. Chicago, IL: American Heart Association.
• Geisler, C. E., Hepler, C., Ghimire, S., Higgins, M. R., & Renquist, B. J. (2017, Spring). Targeting the Hepatocyte/Vagal Nerve Communication to Develop Therapeutics for Type 2 Diabetes. Arizona Biomedical Research Commission/Flinn Foundation Research Symposium. Phoenix, AZ: Arizona Biomedical Research Commission and Flinn Foundation.
• Geisler, C. E., Higgins, M. R., & Renquist, B. J. (2016, May). GPR109a Signaling Alters the Hepatic Response to Fasting. Experimental Biology 2016. San Diego, CA: Federation of American Societies for Experimental Biology.
• Geisler, C. E., Higgins, M. R., & Renquist, B. J. (2016, Spring). Targeting the hepatocyte/vagal nerve communication to develop therapeutics for Type 2 Diabetes. Arizona Biomedical Research Commission/Flinn Foundation Research Symposium. Phoenix, AZ: Arizona Biomedical Research Commission.

Others

• Renquist, B. J. (2020, April). A Critical Role of Hepatic GABA in The Metabolic Dysfunction and Hyperphagia of Obesity. https://doi.org/10.1101/2020.04.02.022699
• Renquist, B. J. (2020, April). Food intake dependent and independent effects of heat stress on lactation and mammary gland development. https://doi.org/10.1101/2020.04.03.024679
• Renquist, B. J. (2018, November). Hepatocyte Membrane Potential Regulates Serum Insulin and Insulin Sensitivity by Altering Hepatic GABA Release. https://doi.org/10.1101/475608