Reduced α-MSH Underlies Hypothalamic ER-Stress-Induced Hepatic Gluconeogenesis.

Alterations in ER homeostasis have been implicated in the pathophysiology of obesity and type-2 diabetes (T2D). Acute ER stress induction in the hypothalamus produces glucose metabolism perturbations. However, the neurobiological basis linking hypothalamic ER stress with abnormal glucose metabolism remains unknown. Here, we report that genetic and induced models of hypothalamic ER stress are associated with alterations in systemic glucose homeostasis due to increased gluconeogenesis (GNG) independent of body weight changes. Defective alpha melanocyte-stimulating hormone (α-MSH) production underlies this metabolic phenotype, as pharmacological strategies aimed at rescuing hypothalamic α-MSH content reversed this phenotype at metabolic and molecular level. Collectively, our results posit defective α-MSH processing as a fundamental mediator of enhanced GNG in the context of hypothalamic ER stress and establish α-MSH deficiency in proopiomelanocortin (POMC) neurons as a potential contributor to the pathophysiology of T2D.

Hypothalamic and brainstem neuronal circuits controlling homeostatic energy balance.

Alterations in adequate energy balance maintenance result in serious metabolic disturbances such as obesity. In mammals, this complex process is orchestrated by multiple and distributed neuronal circuits. Hypothalamic and brainstem neuronal circuits are critically involved in the sensing of circulating and local factors conveying information about the energy status of the organism. The integration of these signals culminates in the generation of specific and coordinated physiological responses aimed at regulating energy balance through the modulation of appetite and energy expenditure. In this article, we review current knowledge on the homeostatic regulation of energy balance, emphasizing recent advances in mouse genetics, electrophysiology, and optogenetic techniques that have greatly contributed to improving our understanding of this central process.

Mitofusin 2 in POMC neurons connects ER stress with leptin resistance and energy imbalance.

Mitofusin 2 (MFN2) plays critical roles in both mitochondrial fusion and the establishment of mitochondria-endoplasmic reticulum (ER) interactions. Hypothalamic ER stress has emerged as a causative factor for the development of leptin resistance, but the underlying mechanisms are largely unknown. Here, we show that mitochondria-ER contacts in anorexigenic pro-opiomelanocortin (POMC) neurons in the hypothalamus are decreased in diet-induced obesity. POMC-specific ablation of Mfn2 resulted in loss of mitochondria-ER contacts, defective POMC processing, ER stress-induced leptin resistance, hyperphagia, reduced energy expenditure, and obesity. Pharmacological relieve of hypothalamic ER stress reversed these metabolic alterations. Our data establish MFN2 in POMC neurons as an essential regulator of systemic energy balance by fine-tuning the mitochondrial-ER axis homeostasis and function. This previously unrecognized role for MFN2 argues for a crucial involvement in mediating ER stress-induced leptin resistance.