α-Klotho is required for POMC-mediated regulation of energy homeostasis and leptin sensitivity

Obesity and diabetes are a major global epidemic which urgently requires a deeper understanding of its pathogenesis. A discrete set of hypothalamic neuronal and glial cell populations, including leptin-expressing cells in the arcuate nucleus, integrate multiple metabolic and sensory inputs to regulate appetite and energy balance(1), which become maladaptive in obesity. α-Klotho is a multifunctional membrane and secreted protein with well-studied effects on aging and mineral homeostasis; however, there is increasing evidence of its anti-diabetic and anti-obesogenic effects(2). Notably, central administration of α-Klotho suppresses Leptin-sensitive NPY/AgRP neuron activity, weight gain, and glucose intolerance in mouse models of obesity(3). We studied the role of endogenous klotho in POMC-expressing neurons and its effects on appetite and glucose homeostasis. We found hypothalamic expression of klotho protein localizes to the arcuate nucleus and transcriptomic datasets measure expression in both POMC and AgRP-expressing cells. We then studied the effects of klotho deletion in POMC expressing cells (using POMC-Cre klotho fl/fl mice) fed either a low or high fat diet. Unlike global klotho knockout(2), POMC-targeted knockout does not dramatically affect body weight or survivability up to 30 weeks. POMC Klotho knockout results in increased food intake and adiposity, impaired glucose tolerance, and increased serum Leptin levels compared to controls on a high fat diet, but no difference on a low fat diet. Despite altered glucose tolerance, serum insulin levels and insulin sensitivity were similar to controls within diets. Despite higher serum leptin levels in POMC Klotho KO mice, arcuate nucleus p-STAT3 abundance was decreased, demonstrating leptin resistance. Taken together, the present results underscore the role of α-Klotho in POMC neurons on energy balance and adiposity. 1.Timper K, Brüning JC. Hypothalamic circuits regulating appetite and energy homeostasis: pathways to obesity. Dis Model Mech. 2017;10(6):679-89. 2.Mori K, Yahata K, Mukoyama M, Suganami T, Makino H, Nagae T, et al. Disruption of klotho gene causes an abnormal energy homeostasis in mice. Biochem Biophys Res Commun. 2000;278(3):665-70. 3.Landry T, Laing BT, Li P, Bunner W, Rao Z, Prete A, et al. Central α-Klotho Suppresses NPY/AgRP Neuron Activity and Regulates Metabolism in Mice. Diabetes. 2020;69(7):1368-81. NIH/NIDDK (K08 DK114567) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.