While much is known about the role of agouti-regulated peptide/neuropeptide Y (AgRP/NPY) and pro-opiomelanocortin (POMC) neurons to regulate energy homeostasis, little is known about how forced energy expenditure, such as exercise, modulates these neurons and if these neurons are involved in post-exercise feeding behaviors. We utilized multiple mouse models to investigate the effects of acute, moderate-intensity exercise on food intake and neuronal activity in the arcuate nucleus (ARC) of the hypothalamus. NPY-GFP reporter mice were utilized for immunohistochemistry and patch-clamp electrophysiology experiments investigating neuronal activation immediately after acute treadmill exercise. Additionally, ARC AgRP/NPY neuron inhibition was performed using the Designer Receptors Exclusively Activated by Designer Drugs (DREADD) system in AgRP-Cre transgenic mice to investigate the importance of AgRP/NPY neurons in post-exercise feeding behaviors. Our experiments revealed that acute moderate-intensity exercise significantly increased food intake, ARC AgRP/NPY neuron activation, and PVN Sim1 neuron activation, while having no effect on ARC POMC neurons. Strikingly, this exercise-induced refeeding was completely abolished when ARC AgRP/NPY neuron activity was inhibited. While acute exercise also increased PVN Sim1 neuron activity, inhibition of ARC AgRP/NPY neurons had no effect on PVN Sim1 neuronal activation. Overall, our results reveal that ARC AgRP/NPY activation is required for acute exercise induced food intake in mice, thus providing insight into the critical role of ARC AgRP/NPY neurons in maintaining energy homeostasis in cases of exercise-mediated energy deficit.

α-Klotho, a known anti-aging protein, exerts diverse physiological effects including: maintenance of phosphate and calcium homeostasis, modulation of cell proliferation, and enhanced buffering of reactive oxygen species. However, the role of α-Klotho in the regulation of energy metabolism is complex and poorly understood. Here we investigated the effects of 5 weeks peripheral administration of α-Klotho in high fat diet induced obese mice. Food intake, blood glucose, and body weight were measured daily. Energy expenditure was determined with indirect calorimetry and body composition with magnetic resonance imaging. Liver and adipose tissue were collected for lipid content measurements and gene expression analysis. α-Klotho-treated mice experienced reduced adiposity, increased lean mass, and elevated energy expenditure, despite no changes in food intake, body weight, or fed blood glucose levels. Lipid accumulation in liver and adipose tissue was also reduced compared to controls. Furthermore, Real-time quantitative PCR showed reduced expression of key lipogenic genes in α-Klotho treated mice in these organs. Taken together, these data suggest encouraging therapeutic potential of α-Klotho and highlight a need for further research into the specific mechanisms explaining improved body composition, elevated energy expenditure, and reduced lipid content in both liver and adipose tissue in α-Klotho-treated mice.

a-Klotho is a circulating factor with well-documented antiaging properties. However, the central role of a-klotho in metabolism remains largely unexplored. The current study investigated the potential role of central a-klotho to modulate neuropeptide Y/agouti-related peptide (NPY/AgRP)-expressing neurons, energy balance, and glucose homeostasis. Intracerebroventricular administration of a-klotho suppressed food intake, improved glucose profiles, and reduced body weight in mouse models of type 1 and 2 diabetes. Furthermore, central a-klotho inhibition via an anti-a-klotho antibody impaired glucose tolerance. Ex vivo patch clamp electrophysiology and immunohistochemical analysis revealed that a-klotho suppresses NPY/AgRP neuron activity, at least in part, by enhancing miniature inhibitory postsynaptic currents. Experiments in hypothalamic GT1-7 cells observed that a-klotho induces phosphorylation of AKT ser473 , ERK thr202/tyr204 , and FOXO1 ser256 as well as blunts AgRP gene transcription. Mechanistically, fibroblast growth factor receptor 1 (FGFR1) inhibition abolished the downstream signaling of a-klotho, negated its ability to modulate NPY/AgRP neurons, and blunted its therapeutic effects. Phosphatidylinositol 3 kinase (PI3K) inhibition also abolished a-klotho's ability to suppress food intake and improve glucose clearance. These results indicate a prominent role of hypothalamic a-klotho/FGFR1/PI3K signaling in the modulation of NPY/ AgRP neuron activity and maintenance of energy homeostasis, thus providing new insight into the pathophysiology of metabolic disease.

High-intensity interval training has been reported to lower fasting blood glucose and improve insulin resistance of type 2 diabetes without clear underlying mechanisms. The purpose of this study was to investigate the effect of high-intensity interval training on the glycolipid metabolism and mitochondrial dynamics in skeletal muscle of high-fat diet (HFD) and one-time 100 mg/kg streptozocin intraperitoneal injection-induced type 2 diabetes mellitus (T2DM) mice. Our results confirmed that high-intensity interval training reduced the body weight, fat mass, fasting blood glucose, and serum insulin of the T2DM mice. High-intensity interval training also improved glucose tolerance and insulin tolerance of the T2DM mice. Moreover, we found that high-intensity interval training also decreased lipid accumulation and increased glycogen synthesis in skeletal muscle of the T2DM mice. Ultrastructural analysis of the mitochondria showed that mitochondrial morphology and quantity were improved after 8 weeks of high-intensity interval training. Western blot analysis showed that the expression of mitochondrial biosynthesis related proteins and mitochondrial dynamics related proteins in high-intensity interval trained mice in skeletal muscle were enhanced. Taken together, these data suggest high-intensity interval training improved fasting blood glucose and glucose homeostasis possibly by ameliorating glycolipid metabolism and mitochondrial dynamics in skeletal muscle of the T2DM mice.

Background and ObjectivesIntense exercise (IE) induced myocardial fibrosis (MF) showed contradictory findings in human studies, making the relationship between IE and the development of MF unclear. This study aims to demonstrate exercise induced MF is associated with cardiac damage, and inflammation is essential to the development of exercise induced MF.MethodsSprague-Dawley rats were submitted to daily 60-minutes treadmill exercise sessions at vigorous or moderate intensity, with 8-, 12-, and 16-week durations; time-matched sedentary rats served as controls. Enzyme-linked immunosorbent assay (ELISA) was used to measure serum cardiac troponin I (cTnI) concentration. After completion of the exercise protocol rats were euthanized. Biventricular morphology, ultrastructure, and collagen deposition were then examined. Protein expression of interleukin (IL)-1β and monocyte chemotactic protein (MCP)-1 was evaluated in both ventricles.ResultsAfter IE, right but not left ventricle (LV) MF occurred. Serum cTnI levels increased and right ventricular damage was observed at the ultrastructure level in rats that were subjected to long-term IE. Leukocyte infiltration into the right ventricle (RV) rather than LV was observed after long-term IE. Long-term IE also increased protein expression of pro-inflammation factors including IL-1β and MCP-1 in the RV.ConclusionsRight ventricular damage induced by long-term IE is pathological and the following inflammatory response is essential to the development of exercise induced MF.