Alzheimer’s disease is a neurodegenerative disorder that affects the central nervous system. In this study, we characterized and examined the early metabolic changes in the triple transgenic mouse AD model (3xtg-AD), and their relationship with the hypothalamus, a key regulator of metabolism in the central nervous system. We observed that the 3xtg-AD model exhibited significantly higher oxygen consumption as well as food intake before reported amyloid plaque formation, indicating that metabolic abnormalities occurred at early onset in the 3xtg-AD model compared with their counterparts. Analysis of gene expression in the hypothalamus indicated increased mRNA expression of inflammation- and apoptosis-related genes, as well as decreased gene expression of Agouti-related protein (AgRP) and Melanocortin 4 receptor (MC4R) at 12 weeks of age. Immunofluorescence analysis revealed that pro-opiomelanocortin (POMC) and NPY-expressing neurons decreased at 24 weeks in the 3xtg-AD model. Four weeks of voluntary exercise were sufficient to reverse the gene expression of inflammation and apoptotic markers in the hypothalamus, six weeks of exercise improved glucose metabolism, moreover, 8 weeks of voluntary exercise training attenuated apoptosis and augmented POMC and NPY-expressing neuronal populations in the hypothalamus compared to the control group. Our results indicated that early onset of metabolic abnormalities may contribute to the pathology of AD, which is associated with increased inflammation as well as decreased neuronal population and key neuropeptides in the hypothalamus. Furthermore, early intervention by voluntary exercise normalized hypothalamic inflammation and neurodegeneration as well as glucose metabolism in the 3xtg-AD model. The data, taken as a whole, suggests a hypothalamic-mediated mechanism where exercise prevents the progression of dementia and of Alzheimer’s disease.

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.

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