Biology subjects

Stern, J. H.

Publications and source records attributed to Stern, J. H..

4 recordsLinked to original sources

bioRxiv2025

12 weeks of voluntary wheel running restores glucagon sensitivity in middle-aged mice

Aerobic exercise training is a potent intervention for the treatment and prevention of age-related metabolic disease, which is characterized by both insulin and glucagon resistance. While insulin resistance is a key driver of metabolic disease in aging, glucagon signaling is equally critical in maintaining both glucose and lipid homeostasis, particularly during exercise. Previous studies have established the glucagon sensitizing effects of exercise training in younger animals. Most studies in rodents employ rigorous and carefully dosed forced exercise protocols. This forced exercise is a stressful paradigm. We implemented a voluntary wheel running (VWR) intervention to assess the effects of aging and exercise training on glucagon sensitivity. We initiated 12-weeks of VWR in young adult (6-month-old) and middle-aged (12-month-old) C57BL/6NCrl male mice. Glucagon sensitivity, as assessed by glucagon stimulated hyperglycemia, was decreased in middle-aged compared to young adult sedentary mice (P=0.046). While VWR did not affect glucose clearance, circulating insulin, glucagon, or insulin sensitivity, regardless of age, VWR improved glucagon responsivity only in middle-aged mice (P=0.031). VWR increased hepatic glycogen content and increased glucagon-stimulated glycogen depletion, regardless of age (P<0.01). Results from these studies suggest that exercise training can enhance liver glucagon action in aging mice without otherwise altering glucose homeostasis. New and NoteworthyFew studies have examined the impact of aging on glucagon sensitivity. Here we show that glucagon sensitivity declines from young adulthood to middle age. Yet, 12 weeks of voluntary wheel running, an exercise intervention without the stress of forced treadmill running or swimming, restores glucagon sensitivity in middle-aged male mice without otherwise altering glucose homeostasis.

physiology↗

bioRxiv2025

Glucagon receptor signaling is indispensable for the healthspan effects of caloric restriction in aging male mice

Obesity and type 2 diabetes mellitus accelerate aging, shortening the duration of healthspan. Conversely, chronic calorie restriction (CR) extends healthspan. Research aimed at understanding the mechanism by which CR slows aging has focused heavily on insulin and downstream signaling cascades. Glucagon, a hormone that counter-regulates insulin, is commonly affected by these same interventions. To investigate the role of glucagon in aging we used dietary manipulation, global and liver-specific glucagon receptor knockout, and pharmacological glucagon receptor activation. We found that globally eliminating glucagon receptor signaling (Gcgr KO) decreases median lifespan by 35% in lean mice. These lifespan shortening effects are more robust in diet-induced obese mice (54%). Extending these findings to metabolic health, we found that glucagon receptor signaling is indispensable to the metabolic response to chronic CR in young and aged mice. While CR decreased liver fat, serum triglyceride, and serum cholesterol in WT mice, these metabolic benefits were absent in Gcgr KO mice. In line with these observations, we found that critical nutrient sensing pathways known to improve aging are dysregulated in mice lacking glucagon receptor signaling at the liver (Gcgrhep-/-). Liver-specific deletion of the glucagon receptor decreases hepatic AMP Kinase activation in aging mice, regardless of diet. Further, CR decreases hepatic mTOR activity in WT mice, but not in Gcgrhep-/- mice. Together, these findings propose that glucagon signaling plays a critical role in both normal aging and the lifespan and healthspan extension driven by caloric restriction.

physiology↗

bioRxiv2022

Identifying Biomarkers of Retinal Pigment Epithelial Cell Stem Cell-derived RPE Cell Heterogeneity and Transplantation Efficacy

Transplantation of retinal pigment epithelial (RPE) cells holds great promise for patients with retinal degenerative diseases such as age-related macular degeneration. In-depth characterization of RPE cell product identity and critical quality attributes are needed to enhance efficacy and safety of replacement therapy strategies. Here we characterized an adult RPE stem cell-derived (RPESC-RPE) cell product using bulk and single cell RNA sequencing (sc-RNA-seq), assessing functional cell integration in vitro into a mature RPE monolayer and in vivo efficacy by vision rescue in the Royal College of Surgeons rats. scRNA-seq revealed several distinct subpopulations in the RPESC-RPE product, some with progenitor markers. We identified RPE clusters expressing genes associated with in vivo efficacy and increased cell integration capability. Gene expression analysis revealed a lncRNA (TREX) as a predictive marker of in vivo efficacy. TREX knockdown decreased cell integration while overexpression increased integration in vitro and improved vision rescue in the RCS rats.

cell biology↗

bioRxiv2022

Glucagon Receptor Signaling at White Adipose Tissue Does Not Regulate Lipolysis

ObjectiveAlthough 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. MethodsWe assessed the effects of fasting and acute exogenous glucagon administration in wildtype C57BL/6J and Gcgr Adipocyte+/+ vs GcgrAdipocyte-/- mice. Using an ex vivo lipolysis protocol, we further examined the direct effects of glucagon on physiologically (fasted) and pharmacologically stimulated lipolysis. ResultsAdipocyte 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 GcgrAdipocyte-/- 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. ConclusionsWe 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.

physiology↗