Jennifer H Stern

Interests

Research

Aging and caloric restriction, Obesity and Type 2 Diabetes, sleep disturbance and metabolic dysfunction, Obesity related cancer development and progression

Teaching

Metabolism, Nutrition, and Diabetes

Courses

Scholarly Contributions

Journals/Publications

• Petersen, M. C., Smith, G. I., Palacios, H. H., Farabi, S. S., Yoshino, M., Yoshino, J., Cho, K., Davila-Roman, V. G., Shankaran, M., Barve, R. A., Yu, J., Stern, J. H., Patterson, B. W., Hellerstein, M. K., Shulman, G. I., Patti, G. J., & Klein, S. (2024). Cardiometabolic characteristics of people with metabolically healthy and unhealthy obesity. Cell metabolism, 36(4), 745-761.e5.
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  There is considerable heterogeneity in the cardiometabolic abnormalities associated with obesity. We evaluated multi-organ system metabolic function in 20 adults with metabolically healthy obesity (MHO; normal fasting glucose and triglycerides, oral glucose tolerance, intrahepatic triglyceride content, and whole-body insulin sensitivity), 20 adults with metabolically unhealthy obesity (MUO; prediabetes, hepatic steatosis, and whole-body insulin resistance), and 15 adults who were metabolically healthy lean. Compared with MUO, people with MHO had (1) altered skeletal muscle biology (decreased ceramide content and increased expression of genes involved in BCAA catabolism and mitochondrial structure/function); (2) altered adipose tissue biology (decreased expression of genes involved in inflammation and extracellular matrix remodeling and increased expression of genes involved in lipogenesis); (3) lower 24-h plasma glucose, insulin, non-esterified fatty acids, and triglycerides; (4) higher plasma adiponectin and lower plasma PAI-1 concentrations; and (5) decreased oxidative stress. These findings provide a framework of potential mechanisms responsible for MHO and the metabolic heterogeneity of obesity. This study was registered at ClinicalTrials.gov (NCT02706262).
• Martinez, T. M., Wachsmuth, H. R., Meyer, R. K., Weninger, S. N., Lane, A. I., Kangath, A., Schiro, G., Laubitz, D., Stern, J. H., & Duca, F. A. (2023). Differential effects of plant-based flours on metabolic homeostasis and the gut microbiota in high-fat fed rats. Nutrition & metabolism, 20(1), 44.
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  The gut microbiome is a salient contributor to the development of obesity, and diet is the greatest modifier of the gut microbiome, which highlights the need to better understand how specific diets alter the gut microbiota to impact metabolic disease. Increased dietary fiber intake shifts the gut microbiome and improves energy and glucose homeostasis. Dietary fibers are found in various plant-based flours which vary in fiber composition. However, the comparative efficacy of specific plant-based flours to improve energy homeostasis and the mechanism by which this occurs is not well characterized.
• Stern, J. H. (2023).

  Differential effects of plant-based flours on metabolic homeostasis and the gut microbiota in high-fat fed rats

  . Nutrition and metabolism. doi:10.1186/s12986-023-00767-8
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  The gut microbiome is a salient contributor to the development of obesity, and diet is the greatest modifier of the gut microbiome, which highlights the need to better understand how specific diets alter the gut microbiota to impact metabolic disease. Increased dietary fiber intake shifts the gut microbiome and improves energy and glucose homeostasis. Dietary fibers are found in various plant-based flours which vary in fiber composition. However, the comparative efficacy of specific plant-based flours to improve energy homeostasis and the mechanism by which this occurs is not well characterized.In experiment 1, obese rats were fed a high fat diet (HFD) supplemented with four different plant-based flours for 12 weeks. Barley flour (BF), oat bran (OB), wheat bran (WB), and Hi-maize amylose (HMA) were incorporated into the HFD at 5% or 10% total fiber content and were compared to a HFD control. For experiment 2, lean, chow-fed rats were switched to HFD supplemented with 10% WB or BF to determine the preventative efficacy of flour supplementation.In experiment 1, 10% BF and 10% WB reduced body weight and adiposity gain and increased cecal butyrate. Gut microbiota analysis of WB and BF treated rats revealed increases in relative abundance of SCFA-producing bacteria. 10% WB and BF were also efficacious in preventing HFD-induced obesity; 10% WB and BF decreased body weight and adiposity, improved glucose tolerance, and reduced inflammatory markers and lipogenic enzyme expression in liver and adipose tissue. These effects were accompanied by alterations in the gut microbiota including increased relative abundance of Lactobacillus and LachnospiraceaeUCG001, along with increased portal taurodeoxycholic acid (TDCA) in 10% WB and BF rats compared to HFD rats.Therapeutic and preventative supplementation with 10%, but not 5%, WB or BF improves metabolic homeostasis, which is possibly due to gut microbiome-induced alterations. Specifically, these effects are proposed to be due to increased concentrations of intestinal butyrate and circulating TDCA.
• Peters, E. C., Safayan, L., Marx, T. J., Ngu, E., Vasileva, A., Zappia, I., Powell, W. H., Duca, F. A., & Stern, J. H. (2022). Metabolic and physical function are improved with lifelong 15% calorie restriction in aging male mice. Biogerontology, 23(6), 741-755.
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  Chronic calorie restriction (CR) results in lengthened lifespan and reduced disease risk. Many previous studies have implemented 30-40% calorie restriction to investigate these benefits. The goal of our study was to investigate the effects of calorie restriction, beginning at 4 months of age, on metabolic and physical changes induced by aging. Male C57BL/6NCrl calorie restricted and ad libitum fed control mice were obtained from the National Institute on Aging (NIA) and studied at 10, 18, 26, and 28 months of age to better understand the metabolic changes that occur in response to CR in middle age and advanced age. Food intake was measured in ad libitum fed controls to assess the true degree of CR (15%) in these mice. We found that 15% CR decreased body mass and liver triglyceride content, improved oral glucose clearance, and increased all limb grip strength in 10- and 18-month-old mice. Glucose clearance in ad libitum fed 26- and 28-month-old mice is enhanced relative to younger mice but was not further improved by CR. CR decreased basal insulin concentrations in all age groups and improved insulin sensitivity and rotarod time to fall in 28-month-old mice. The results of our study demonstrate that even a modest reduction (15%) in caloric intake may improve metabolic and physical health. Thus, moderate calorie restriction may be a dietary intervention to promote healthy aging with improved likelihood for adherence in human populations.
• Stern, J. H. (2022).

  Glucagon Receptor Signaling at White Adipose Tissue Does Not Regulate Lipolysis

  . American Journal of Physiology Endocrinology and Metabolism, E389-E401. doi:10.1152/ajpendo.00078.2022
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  Abstract Objective Although the physiologic role of glucagon receptor signaling in the liver is well defined, the impact of glucagon receptor (Gcgr) signaling at white adipose tissue (WAT) continues to be debated. While numerous studies propose glucagon stimulates WAT lipolysis, we lack evidence that physiological concentrations of glucagon regulate WAT lipolysis. Glucagon receptor antagonists are proposed as a treatment to lower blood glucose in people with type 2 diabetes, yet concerns on how these treatments may affect lipid homeostasis have led to questions regarding the potential safety and efficacy of such therapeutics. Tight regulation of adipose tissue lipolysis is critical for whole body lipid homeostasis. In turn, we used WAT Gcgr knockout mice to determine if glucagon regulates lipolysis at WAT in the mouse. Methods We assessed the effects of fasting and acute exogenous glucagon administration in wildtype C57BL/6J and Gcgr Adipocyte+/+ vs Gcgr Adipocyte-/- mice. Using an ex vivo lipolysis protocol, we further examined the direct effects of glucagon on physiologically (fasted) and pharmacologically stimulated lipolysis. Results Adipocyte Gcgr expression did not affect fasting induced lipolysis or hepatic lipid accumulation in lean or diet induced obese (DIO) mice. Acute glucagon administration did not affect serum non-esterified fatty acids (NEFA), leptin, or adiponectin concentration, but did increase serum glucose and FGF21, regardless of genotype. Glucagon did not affect ex vivo lipolysis in explants from either Gcgr Adipocyte+/+ or Gcgr Adipocyte-/- mice. Gcgr expression did not affect fasting-induced or isoproterenol-stimulated lipolysis from WAT explants. Moreover, glucagon receptor signaling at WAT does not affect body weight or glucose homeostasis in lean or DIO mice. Conclusions We have established that glucagon does not regulate WAT lipolysis, either directly or indirectly. Unlike the crucial role of hepatic glucagon receptor signaling in maintaining glucose and lipid homeostasis, we observed no metabolic consequence of WAT glucagon receptor deletion.
• Vasileva, A., Vasileva, A., Marx, T., Marx, T., Beaudry, J. L., Beaudry, J. L., Stern, J. H., & Stern, J. H. (2022). Glucagon receptor signaling at white adipose tissue does not regulate lipolysis. American journal of physiology. Endocrinology and metabolism, 323(4), E389-E401.
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  Although the physiological role of glucagon receptor signaling in the liver is well defined, the impact of glucagon receptor (Gcgr) signaling on white adipose tissue (WAT) continues to be debated. Although numerous studies propose that glucagon stimulates WAT lipolysis, we lack evidence that physiological concentrations of glucagon regulate WAT lipolysis. In turn, we performed studies in both wild-type and WAT knockout mice to determine if glucagon regulates lipolysis at WAT in the mouse. We assessed the effects of fasting and acute exogenous glucagon administration in wild-type C57BL/6J and versus mice. Using an ex vivo lipolysis protocol, we further examined the direct effects of glucagon on physiologically (fasted) and pharmacologically stimulated lipolysis. We found that adipocyte expression did not affect fasting-induced lipolysis or hepatic lipid accumulation in lean or diet-induced obese (DIO) mice. Acute glucagon administration did not affect serum nonesterified fatty acids (NEFA), leptin, or adiponectin concentration, but did increase serum glucose and FGF21, regardless of genotype. Glucagon did not affect ex vivo lipolysis in explants from either or mice. expression did not affect fasting-induced or isoproterenol-stimulated lipolysis from WAT explants. Moreover, glucagon receptor signaling at WAT did not affect body weight or glucose homeostasis in lean or DIO mice. Our studies have established that physiological levels of glucagon do not regulate WAT lipolysis, either directly or indirectly. Given that glucagon receptor agonism can improve dyslipidemia and decrease hepatic lipid accumulation, it is critical to understand the tissue-specific effects of glucagon receptor action. Unlike the crucial role of hepatic glucagon receptor signaling in maintaining glucose and lipid homeostasis, we observed no metabolic consequence of WAT glucagon receptor deletion. It has been postulated that glucagon stimulates lipolysis and fatty acid release from white adipose tissue. We observed no metabolic effects of eliminating or activating glucagon receptor signaling at white adipose tissue.
• Marx, T., Vasileva, A., Hutchison, S., & Stern, J. H. (2021).

  Metabolic Adaptations to Aerobic Exercise in Aged Mice

  . Innovation in Aging. doi:10.1093/geroni/igab046.2046
• Willis, W., Willis, E., Kuzmiak-Glancy, S., Kras, K., Hudgens, J., Barakati, N., Stern, J., & Mandarino, L. (2021). Oxidative phosphorylation KADP in vitro depends on substrate oxidative capacity: Insights from a luciferase-based assay to evaluate ADP kinetic parameters. Biochimica et biophysica acta. Bioenergetics, 1862(8), 148430.
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  The KADP of oxidative phosphorylation (OxPhos) identifies the cytosolic ADP concentration which elicits one-half the maximum OxPhos rate. This kinetic parameter is commonly measured to assess mitochondrial metabolic control sensitivity. Here we describe a luciferase-based assay to evaluate the ADP kinetic parameters of mitochondrial ATP production from OxPhos, adenylate kinase (AK), and creatine kinase (CK). The high sensitivity, reproducibility, and throughput of the microplate-based assay enabled a comprehensive kinetic assessment of all three pathways in mitochondria isolated from mouse liver, kidney, heart, and skeletal muscle. Carboxyatractyloside titrations were also performed with the assay to estimate the flux control strength of the adenine nucleotide translocase (ANT) over OxPhos in human skeletal muscle mitochondria. ANT flux control coefficients were 0.91 ± 0.07, 0.83 ± 0.06, and 0.51 ± 0.07 at ADP concentrations of 6.25, 12.5, and 25 μM, respectively, an [ADP] range which spanned the KADP. The oxidative capacity of substrate combinations added to drive OxPhos was found to dramatically influence ADP kinetics in mitochondria from several tissues. In mouse skeletal muscle ten different substrate combinations elicited a 7-fold range of OxPhos V, which correlated positively (R = 0.963) with KADP values ranging from 2.3 ± 0.2 μM to 11.9 ± 0.6 μM. We propose that substrate-enhanced capacity to generate the protonmotive force increases the OxPhos KADP because flux control at ANT increases, thus KADP rises toward the dissociation constant, KADP, of ADP-ANT binding. The findings are discussed in the context of top-down metabolic control analysis.
• Beaudry, J. L., Kaur, K. D., Varin, E. M., Baggio, L. L., Cao, X., Mulvihill, E. E., Stern, J. H., Campbell, J. E., Scherer, P. E., & Drucker, D. J. (2019). The brown adipose tissue glucagon receptor is functional but not essential for control of energy homeostasis in mice. Molecular metabolism, 22, 37-48.
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  Administration of glucagon (GCG) or GCG-containing co-agonists reduces body weight and increases energy expenditure. These actions appear to be transduced by multiple direct and indirect GCG receptor (GCGR)-dependent mechanisms. Although the canonical GCGR is expressed in brown adipose tissue (BAT) the importance of BAT GCGR activity for the physiological control of body weight, or the response to GCG agonism, has not been defined.
• Stern, J. H. (2019).

  Fasting and Glucose-Stimulated Changes in Plasma Glucagon in Pancreatic Cancer

  . Pancreas. doi:10.1097/mpa.0000000000001208
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  Stern, Jennifer H. PhD; Arriaga, Yull MD; Gupta, Arjun MD; Verma, Udit MD; Karri, Sirisha MD; Syed, Samira MD; Khosama, Leticia NP; Mansour, John MD; Meyer, Jeffrey MD; Scherer, Philipp E. PhD; Beg, Muhammad S. MD Author Information
• Stern, J. H., Arriaga, Y., Gupta, A., Verma, U., Karri, S., Syed, S., Khosama, L., Mansour, J., Meyer, J., Scherer, P. E., & Beg, M. S. (2019). Fasting and Glucose-Stimulated Changes in Plasma Glucagon in Pancreatic Cancer: Potential Biomarkers for Detection?. Pancreas, 48(1), e1-e3.
• Stern, J. H., Smith, G., Chen, S., Unger, R., Klein, S., & Scherer, P. E. (2019). Obesity dysregulates fasting-induced changes in glucagon secretion. The Journal of endocrinology.
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  Hyperglucagonemia, a hallmark in obesity and insulin resistance promotes hepatic glucose output, exacerbating hyperglycemia and thus predisposing to the development type 2 diabetes. As such, glucagon signaling is a key target for new therapeutics to manage insulin resistance. We evaluated glucagon homeostasis in lean and obese mice and people. In lean mice, fasting for 24h caused a rise in glucagon. In contrast, a decrease in serum glucagon compared to baseline was observed in diet-induced obese mice between 8 and 24h of fasting. Fasting decreased serum insulin in both lean and obese mice. Accordingly, the glucagon:insulin ratio was unaffected by fasting in obese mice but increased in lean mice. Re-feeding (2h) restored hyperglucagonemia in obese mice. Pancreatic perfusion studies confirm that fasting (16h) decreases pancreatic glucagon secretion in obese mice. Consistent with our findings in the mouse, a mixed meal increased serum glucagon and insulin concentrations in obese humans, both of which decreased with time after a meal. Consequently, fasting and re-feeding less robustly affected glucagon:insulin ratios in obese compared to lean participants. The glucoregulatory disturbance in obesity may be driven by inappropriate regulation of glucagon by fasting and a static glucagon:insulin ratio.
• Stern, J. H., Smith, G. I., Unger, R. H., Klein, S., & Scherer, P. E. (2018). Fasting-Induced Changes in Glucagon Secretion Are Dysregulated in Obesity. Diabetes, 67(Supplement_1). doi:10.2337/db18-271-lb
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  Hyperglucagonemia is a hallmark in obesity and type 2 diabetes (T2DM). Suppression of glucagon signaling improves glycemic control in T2DM. We evaluated glucagon homeostasis in lean and obese mice and people. Discordant with the canonical rise in glucagon with fasting, our studies show that fasting (4, 8, 16 and 24 h) caused a progressive decrease in serum glucagon in diet-induced obese, hyperglucagonemic mice (P Disclosure J.H. Stern: None. G.I. Smith: None. R.H. Unger: None. S. Klein: Stock/Shareholder; Self; Aspire Bariatrics. Consultant; Self; Pfizer Inc.. Research Support; Self; Merck & Co., Inc., Johnson & Johnson Services, Inc., REMD Biotherapeutics. P.E. Scherer: None.
• Arriaga, Y. E., Gupta, A., Verma, U., Karri, S., Syed, S. K., Khosama, L., Mansour, J. C., Beg, M. S., Stern, J. H., & Scherer, P. E. (2017). The effects of pioglitazone treatment on pancreatic cancer-related insulin resistance.. Journal of Clinical Oncology, 35(4_suppl), 329-329. doi:10.1200/jco.2017.35.4_suppl.329
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  329Background: Insulin resistance (IR) in pancreatic cancer (PC) patients is associated with cachexia and poor outcome. Pioglitazone (PIO) improves insulin sensitivity via activation of peroxisome proliferator-activated receptor (PPAR gamma). Effects of PIO on insulin sensitivity, glucose homeostasis, and circulating adipokine levels in PC have not been examined. Methods: Patients with metastatic PC were administered PIO 45mg/day orally for 8 weeks concurrent with chemotherapy. Patients with known DM at enrollment were identified Fasting plasma was collected at baseline, weeks 2, 4, 6, 8 of pioglitazone treatment and at 2 weeks-post treatment. The primary objective was to describe changes in indicators of IR, including glucoregulatory hormone levels, glucose tolerance, and inflammatory cytokines. Results: Fourteen patients (age 64y), with a mean BMI of 28 were enrolled. Mean adiponectin increased from baseline to week 8 of treatment (14.2± 3.3 and 46.9±11.4µg/ml, respectively, P ≤ 0.01), and returned to b...
• Nelson, M. D., Szczepaniak, L. S., Wei, J., Szczepaniak, E., Sánchez, F. J., Vilain, E., Stern, J. H., Bergman, R. N., Bairey Merz, C. N., & Clegg, D. J. (2016). Transwomen and the Metabolic Syndrome: Is Orchiectomy Protective?. Transgender health, 1(1), 165-171.
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  Male-to-female transsexual women or who undergo cross-sex hormone treatments experience increased health-related risks (e.g., increased rates of cardiovascular disease and premature death). Yet, the exact mechanism by which altering biochemistry leads to metabolic impairment remains unclear. While much attention has been paid to cross-sex hormone therapy, little is known about the metabolic risk associated with orchiectomy. To address the above limitation, we prospectively enrolled 12 transwomen: 4 who had undergone bi-lateral orchiectomy and 8 who had not. Both groups were using cross-sex hormones. Glucose tolerance was assessed using a standard 75g oral glucose tolerance test. Hepatic steatosis was assessed by H magnetic resonance spectroscopy. The amount of subcutaneous and visceral abdominal fat was determined from a single abdominal axial image at the level between the vertebral L2 and L3 bodies. Baseline venous fasting blood sampling was performed for measurement of hemoglobin A1c, glucose, insulin, sex hormones, and sex hormone binding globulin. The major novel findings were: (1) orchiectomy and cross-sex hormone therapy is associated with less hepatic steatosis and insulin resistance; (2) orchiectomy may be metabolically protective, and (3) circulating concentrations of sex hormones may be a major determinant of metabolic health in transwomen. To our knowledge, this is the first study to suggest an independent and protective role of orchiectomy on the metabolic health of transwomen.
• Stern, J. H., Rutkowski, J. M., & Scherer, P. E. (2016). Adiponectin, Leptin, and Fatty Acids in the Maintenance of Metabolic Homeostasis through Adipose Tissue Crosstalk. Cell metabolism, 23(5), 770-84.
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  Metabolism research has made tremendous progress over the last several decades in establishing the adipocyte as a central rheostat in the regulation of systemic nutrient and energy homeostasis. Operating at multiple levels of control, the adipocyte communicates with organ systems to adjust gene expression, glucoregulatory hormone exocytosis, enzymatic reactions, and nutrient flux to equilibrate the metabolic demands of a positive or negative energy balance. The identification of these mechanisms has great potential to identify novel targets for the treatment of diabetes and related metabolic disorders. Herein, we review the central role of the adipocyte in the maintenance of metabolic homeostasis, highlighting three critical mediators: adiponectin, leptin, and fatty acids.
• Rutkowski, J. M., Stern, J. H., & Scherer, P. E. (2015). The cell biology of fat expansion. The Journal of cell biology, 208(5), 501-12.
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  Adipose tissue is a complex, multicellular organ that profoundly influences the function of nearly all other organ systems through its diverse metabolite and adipokine secretome. Adipocytes are the primary cell type of adipose tissue and play a key role in maintaining energy homeostasis. The efficiency with which adipose tissue responds to whole-body energetic demands reflects the ability of adipocytes to adapt to an altered nutrient environment, and has profound systemic implications. Deciphering adipocyte cell biology is an important component of understanding how the aberrant physiology of expanding adipose tissue contributes to the metabolic dysregulation associated with obesity.
• Stern, J. H., & Scherer, P. E. (2015). Adipose tissue biology in 2014: Advances in our understanding of adipose tissue homeostasis. Nature reviews. Endocrinology, 11(2), 71-2.
• , ., , ., & , . (2014).

  Advances in our understanding of adipose tissue homeostasis

  . Nature Reviews Endocrinology. doi:10.1038/nrendo.2014.219
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  In 2014, numerous noteworthy papers focusing on adipose tissue physiology were published. Many of these articles showed the promise of adipose-tissue-targeted approaches for therapeutic intervention in obesity and type 2 diabetes mellitus. Here, we highlight advances in the development and maintenance of brown and/or beige adipocytes and the metabolic implications of inflammation in adipose tissues.
• Brennan, K. M., Thomson, C. A., Stern, J. H., Grant, A. S., Tinker, L., Hale, L., Woods, N. F., & Chen, Z. (2014). Short sleep duration is associated with decreased serum leptin, increased energy intake and decreased diet quality in postmenopausal women: Short Sleep Duration in Postmenopausal Women. Obesity, 22(5), E55-E61. doi:10.1002/oby.20683
• Stern, J. H. (2014).

  Biomarker‐calibrated estimates of self‐reported energy intake and risk of weight gain in postmenopausal women (272.1)

  . The FASEB Journal. doi:10.1096/fasebj.28.1_supplement.272.1
• Stern, J. H., Grant, A. S., Thomson, C. A., Tinker, L., Hale, L., Brennan, K. M., Woods, N. F., & Chen, Z. (2014). Short sleep duration is associated with decreased serum leptin, increased energy intake and decreased diet quality in postmenopausal women. Obesity (Silver Spring, Md.), 22(5), E55-61.
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  Short sleep duration induces hormonal perturbations contributing to hyperphagia, insulin resistance, and obesity. The majority of these studies are conducted in young adults. This analysis in a large (n = 769) sample of postmenopausal women (median age 63 years) sought to (a) confirm that sleep duration and sleep quality are negatively correlated with circulating leptin concentrations and (b) to examine the relationship between self-reported sleep, dietary energy intake, and diet quality, as well as, investigate the role of leptin in these associations.
• Stern, J. H., Kim, K., & Ramsey, J. J. (2014). The Influence of Shc Proteins on the Whole Body Energetic Response to Calorie Restriction Initiated in 3-Month-Old Mice. ISRN Nutrition, 2014, 1-10. doi:10.1155/2014/562075
• Stern, J. H., Kim, K., & Ramsey, J. J. (2014). The influence of shc proteins on the whole body energetic response to calorie restriction initiated in 3-month-old mice. ISRN nutrition, 2014, 562075.
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  There is increasing evidence that Shc proteins play a role in energy metabolism, and we have previously reported that knockdown of Shc proteins influences the energetic response to acute (3 days) calorie restriction (CR) in 18-month-old mice. Whether Shc proteins play a role in the metabolic response to CR in younger mice has yet to be elucidated. Hence, we sought to determine the impact of 3 days and longer term (2 months) CR on energy expenditure (EE) and respiratory quotient (RQ) in 3 month-old Shc knockout (ShcKO) and wild-type (WT) mice. ShcKO mice decreased (P < 0.001) EE normalized for body weight (EEBW) by 3 days of CR, while no such change was observed in WT animals. However, both ShcKO and WT mice decreased (P < 0.001) EEBW at 2 months of CR and there were no differences in body weight between the ShcKO and WT mice at either 3 days or 2 months of CR. Consistent with increased fatty acid oxidation, only ShcKO mice maintained decreased (P < 0.001) 24 h RQ through 2 months of CR, suggesting that they were able to maintain increased fatty acid oxidation for a longer period of time than WT mice. These results indicate that Shc proteins may contribute to some of the acute energetic responses to CR.
• Stern, J. H. (2012).

  The Influence of Shc Proteins and Aging on Whole Body Energy Expenditure and Substrate Utilization in Mice

  . Mechanisms of Aging and Development. doi:10.1016/j.mad.2012.05.001
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  While it has been proposed that Shc family of adaptor proteins may influence aging by regulating insulin signaling and energy metabolism, the overall impact of Shc proteins on whole body energy metabolism has yet to be elucidated. Thus, the purpose of this study was to determine the influence of Shc proteins and aging on whole body energy metabolism in a mouse model under ambient conditions (22°C) and acute cold exposure (12°C for 24 hours). Using indirect respiration calorimetry, we investigated the impact of Shc proteins and aging on EE and substrate utilization (RQ) in p66 Shc−/− (ShcKO) and wild-type (WT) mice. Calorimetry measurements were completed in 3, 15, and 27 mo mice at 22°C and 12°C. At both temperatures and when analyzed across all age groups, ShcKO mice demonstrated lower 24 h total EE values than that of WT mice when EE data was expressed as either kJ per mouse, or adjusted by body weight or crude organ mass (ORGAN) (P≤0.01 for all). The ShcKO mice also had higher (P
• Stern, J. H., Kim, K., & Ramsey, J. J. (2012). The influence of acute, late-life calorie restriction on whole body energy metabolism in p66Shc(-/-) mice. Mechanisms of ageing and development, 133(6), 414-20.
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  It has been proposed that Shc proteins may influence aging by regulating insulin signaling and energy metabolism. Evidence suggests that deletion of p66Shc could partially attenuate weight gain on a high fat diet by increasing energy expenditure. However, the impact of p66Shc on the metabolic response to calorie restriction (CR) has not been determined. Thus, we used indirect respiration calorimetry to determine the impact of CR on energy expenditure (EE) and substrate utilization (RQ) in 18mo p66Shc(-/-) and wild-type (WT) mice. Calorimetry measurements were completed at baseline and following 3d of 40% CR and 2 mo of 26% CR. There was no difference (P>0.10) in EE and RQ between gentoypes, regardless of how EE data was normalized. Both p66Shc(-/-) and WT mice showed decreases (P
• Stern, J. H., Kim, K., & Ramsey, J. J. (2012). The influence of shc proteins and aging on whole body energy expenditure and substrate utilization in mice. PloS one, 7(11), e48790.
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  While it has been proposed that Shc family of adaptor proteins may influence aging by regulating insulin signaling and energy metabolism, the overall impact of Shc proteins on whole body energy metabolism has yet to be elucidated. Thus, the purpose of this study was to determine the influence of Shc proteins and aging on whole body energy metabolism in a mouse model under ambient conditions (22°C) and acute cold exposure (12°C for 24 hours). Using indirect respiration calorimetry, we investigated the impact of Shc proteins and aging on EE and substrate utilization (RQ) in p66 Shc-/- (ShcKO) and wild-type (WT) mice. Calorimetry measurements were completed in 3, 15, and 27 mo mice at 22°C and 12°C. At both temperatures and when analyzed across all age groups, ShcKO mice demonstrated lower 24 h total EE values than that of WT mice when EE data was expressed as either kJ per mouse, or adjusted by body weight or crude organ mass (ORGAN) (P≤0.01 for all). The ShcKO mice also had higher (P
• Rossow, H. A., & Stern, J. H. (2011). Teaching comparative metabolism using a graphic computer model, Virtual Tissue. Advances in physiology education, 35(1), 99-102.
• Stern, J. H. (2010).

  The effect of p66Shc on energy expenditure in mice

  . The FASEB Journal. doi:10.1096/fasebj.24.1_supplement.888.7
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  Previous investigations have shown that the p66Shc protein has a significant effect on life span. While the mechanism underlying the impact that p66Shc has on life span remains to be elucidated, it has been proposed that p66Shc may interact with the IGF-1/insulin signaling pathway to modulate metabolism, and possibly energy expenditure, under conditions of stress. As a first step in testing this possibility, oxygen consumption and carbon dioxide production were measured in 3-month-old male p66Shc knockout (p66Shc−/−) and wild type C57BL/6 mice for 24h at 23oC and for 5h at 12–13oC. Average 24h energy expenditure (EE) at 23oC did not differ (P > 0.10) between the p66Shc−/− and C57BL/6 groups. Dark vs. light phase EE (12h dark: 12h light) was greater in both groups, but did not differ among p66Shc−/− and C57BL/6 mice. Cold-exposed EE also did not differ between the groups. RQ measured at 23oC was higher in the p66Shc−/− compared to C57BL/6 mice and this difference was most pronounced during the dark cycle. Cold-exposed RQ was also greater in the p66Shc−/− vs. C57BL/6 mice (p66Shc−/−, 0.85 ± 0.004; C57BL/6, 0.83 ± 0.005). These preliminary data suggest that while EE does not differ in p66Shc−/− vs. C57BL/6 mice, the mix of substrate used for energy metabolism may be influenced by the p66Shc protein. The influence of the p66Shc protein on substrate utilization observed here is consistent with a role for this protein in the IGF-1/insulin-dependent intracellular signally pathway. (Supported by NIH PO1 AG025532)

Proceedings Publications

• Stern, J., Safayan, L., & Marx, T. (2021). Moderate Calorie Restriction Enhances Hepatic Glucagon Sensitivity in Aged Mice. In The Gerontological Society of America Annual Scientific Meeting, 5, 681-681.
• Stern, J. H. (2007, April).

  Vitamin C status is inversely related to body mass and fat mass in lean, physically fit adults

  . In Experimental Biology 2007.

Presentations

• Martin, P., Ngu, E., Zappia, I., Peters, E. C., Ghimire, S., Matthew, G., Marx, T. J., & Stern, J. H. (2023, March). Glucagon receptor signaling is indispensable for the metabolic and lifespan response to lifelong caloric restriction. University of Arizona College of Medicine Research Day. Selected short talk.. Tucson, AZ: University of Arizona COM-T.
• Matthew, G., Ngu, E., Zappia, I., Martin, P., & Stern, J. H. (2023, March). Glucagon Receptor Reactivation in Aging and Healthspan. University of Arizona College of Medicine Research Day. Poster Presentation.. Tucson, AZ: University of Arizona COM-T.
• 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.
• Stern, J. H. (2023, March). Glucagon Signaling in Aging and Type 2 Diabetes. University of Arizona College of Medicine Research Day. Invited Faculty Short Talk. Tucson, AZ: University of Arizona COM-T.
• Zappia, I., Martin, P., Ngu, E., Matthew, G., & Stern, J. H. (2023, March). Glucagon Receptor Signaling Regulates Critical Nutrient Signaling Pathways to Affect Aging. . University of Arizona College of Medicine Research Day. Selected short talk.. Tucson, AZ: University of Arizona COM-T.
• Stern, J. H. (2020, January). Aberrant Glucagon Signaling in Obesity and a Potential Role in Aging. Endocrine Grand Rounds. University of Arizona College of Medicine, Division of Endocrinology: University of Arizona College of Medicine.
• Stern, J. H. (2019, April). Glucagon Signaling and the Adaptation to Exercise and Aging. Endocrine Works in Progress. University of Arizona College of Medicine, Division of Endocrinology: University of Arizona.
• Stern, J. H. (2019, April). Glucagon Signaling in the Metabolic Adaptation to Fasting and Obesity. University of Arizona Department of Physiology Seminar Series. University of Arizona Department of Physiology: University of Arizona.
• Stern, J. H. (2019, September). Aberrant Glucagon Signaling in Obesity and a Potential Role in Aging. School of Animal & Comparative Biomedical Sciences Seminar Series. University of Arizona School of Animal & Comparative Biomedical Sciences: University of Arizona.

Poster Presentations

• Stern, J. H., Vasileva, A., & Marx, T. (2019, October). Glucagon Signaling in Obesity and Aging. Third Annual Innovations and Inventions Research Showcase. University of Arizona, Tucson, AZ: University of Arizona.