The adverse effect of a hypercaloric high‐fat diet feeding on hypothalamic cellular energy homeostasis is attenuated by a hypoglycemiant

Obesity is a global public health challenge emerging from an energy homeostasis (EO) disruption. EO is primarily driven by neurons residing in the hypothalamus, whose function is critical to integrate neural and humoral signals that account for energy balance. Obesogenic diets induce a loss of function in the mechanism through which these neurons sense the energy status, leading to the systemic accumulation of excess energy. This could result from altered cellular EO involving mitochondria and molecular energy sensors, such as AMP-activated protein kinase (AMPK) and/or K_ATP channels. In this line, hyperglycemia induced by obesogenic diets alters the central regulation of energy balance in the hypothalamus, possibly due to the loss of sensing anorexigenic signals induced by hyperinsulinemia and hyperleptinemia, mediated by deficient energy control involving mitochondria, AMPK, and K_ATP channels. Therefore, reducing elevated glycemia in a mouse model of hypercaloric feeding could restore cellular energy sensing and normalize energy homeostasis. To test this hypothesis, this work aims to evaluate whether the loss of body energy balance induced by hypercaloric 45% high-fat diet (D45%) feeding is prevented by oral hypoglycemiant, metformin (MT), by restoring mitochondrial function, AMPK sensitivity, and K_ATP levels in the hypothalamus of mice. For this purpose, mice were fed a D45% and supplemented with MT for 12 weeks. Metabolic, physiological, and molecular parameters were assessed. The treatment with MT decreased food intake and body weight gain induced by D45% feeding; besides, MT increased horizontal locomotor activity and attenuated insulin resistance and glucose intolerance after 12 weeks of treatment. Regarding energy sensors, MT attenuated the increased phosphorylation of AMPK and reduced the expression of Kir6.2 induced by D45% feeding. These results show that reduced glycemia can partially reverse the decreased energy sensor function and the altered energy metabolism induced by feeding with a hypercaloric diet.