Reduced a-MSH underlies hypothalamic endoplasmic reticulum stress-induced hepatic gluconeogenesis

Alterations in endoplasmic reticulum (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 (a-MSH) production underlies this metabolic phenotype, as pharmacological strategies aimed at rescuing hypothalamic a-MSH content reversed this phenotype at metabolic and molecular level. Collectively, our results posit defective a-MSH processing as a fundamental mediator of enhanced GNG in the context of hypothalamic ER stress, and establish a-MSH deficiency in proopiomelanocortin (POMC) neurons as a potential contributor to the pathophysiology of T2D. Total RNA was extracted from whole-liver of 6-week old control (3 biological replicates) and POMCMfn2KO mice (5 biological replicates)内质网（endoplasmic reticulum, ER）稳态失衡与肥胖及2型糖尿病（type-2 diabetes, T2D）的病理生理过程密切相关。下丘脑急性内质网应激诱导可引发糖代谢紊乱。然而，连接下丘脑内质网应激与糖代谢异常的神经生物学机制仍未阐明。本研究发现，下丘脑内质网应激的遗传及诱导模型可引发系统性糖稳态失衡，该效应由糖异生（gluconeogenesis, GNG）增强介导，且不依赖于体重变化。下丘脑α-促黑素细胞激素（alpha melanocyte-stimulating hormone, α-MSH）生成缺陷是这一代谢表型的核心机制：通过药理学手段挽救下丘脑α-MSH含量，可在代谢与分子层面逆转该表型。综上，本研究结果证实，下丘脑内质网应激背景下，α-MSH加工缺陷是糖异生增强的关键介导因子，并明确促黑素皮质素原（proopiomelanocortin, POMC）神经元中α-MSH缺乏是2型糖尿病病理生理过程的潜在诱因。本研究从6周龄对照组（3份生物学重复）与POMCMfn2KO小鼠（5份生物学重复）的全肝组织中提取了总RNA。