Indiana University-Purdue University Indianapolis (IUPUI) / Metabolic survival mechanisms that defend body weight and conserve energy are currently at odds with modernized society which has a food supply that is ubiquitous, calorie dense, and highly palatable. Chronic overnutrition leads to a metabolic syndrome of obesity, insulin resistance, inflammation, and cardiovascular diseases that is increasingly prevalent and threatens health on a global scale. The brain is both a victim and culprit of metabolic diseases, and prolonged metabolic dysfunction can exacerbate the pathological mechanisms underlying both metabolic and neurodegenerative diseases. Since neuroendocrine pathways comprise an essential feedback mechanism that detects circulating hormones and nutrients in order to regulate satiety, energy expenditure, and glucose homeostasis, our research goals were to characterize molecular mechanisms within neuroendocrine pathways that could be leveraged for treating obesity, diabetes, and Alzheimer’s disease. First, we identified the expression of a G protein-coupled receptor, Gpr17, in POMC neurons and discovered that it protects aged mice from high-fat diet (HFD)-induced metabolic derangements. We examined the electrophysiological properties of POMC neurons and found Gpr17 deficiency led to increased spontaneous action potentials. Moreover, Pomc-Cre-driven Gpr17 knockout (PGKO) mice, especially female knockouts, had increased POMC-derived alpha-melanocyte stimulating hormone and beta-endorphin despite a comparable level of prohormone POMC in their hypothalamic extracts. Second, we generated a highly insulin resistant mouse model with human GLUT4 promoter-driven insulin receptor knockout (GIRKO) in muscle, adipose, and GLUT4-expressing neuronal subpopulations. This genetic approach recapitulates the primary defect preceding type 2 diabetes (T2D) and revealed additional factors/mechanisms that drive the ultimate progression of overt diabetes. Third, we used 5xFAD mice as a model of Alzheimer’s disease and showed that they were more susceptible to HFD-induced metabolic dysregulation and expression of AD pathological markers in the hippocampus. Our results helped elucidate the molecular and cellular mechanisms responsible for increased AD pathology in high-fat diet-fed 5xFAD mice and suggest that metabolic dysfunctions are a therapeutic target to ameliorate AD pathology. In conclusion, metabolic diseases are pervasive and require nuanced approaches that target the neuroendocrine system in order to restore metabolic homeostasis and protect the brain from neurodegenerative processes that are associated with obesity and diabetes.

L’hypothalamus est une structure cérébrale ayant un rôle clé dans la régulation de la prise alimentaire. Parmi les différentes populations neuronales qui le composent, les neurones produisant la pro-opiomélanocortine (POMC) sont classiquement connus pour diminuer la prise alimentaire et le poids corporel via la libération de neuropeptides produits par le clivage de POMC. Notre étude, grâce à l’utilisation d’approches génétiques, pharmacologiques, électrophysiologiques et moléculaires, remet en question les notions classiques sur la fonction des neurones à POMC dans la balance énergétique, en démontrant qu’il existe deux sous-populations fonctionnellement distinctes de neurones à POMC, qui augmentent ou diminuent la prise alimentaire en fonction du neurotransmetteur qu’elles libèrent, l’acide γ-aminobutyrique (GABA) ou le glutamate. Une troisième population capable de produire aussi bien du GABA que du glutamate a également été identifiée. La régulation des neurones à POMC GABAergiques et glutamatergiques dépend de la voie de la cible de la rapamycine chez les mammifères (mTORC1), qui fonctionne comme un détecteur d’énergie cellulaire, et du système endocannabinoïde (ECS), qui régule la libération de neurotransmetteurs. De plus, nous avons également démontré, via l’utilisation de souris mutantes conditionnelles, l’importance de la protéine p62 ou séquestrome 1 (p62/SQSTM1), qui régule l’activité de mTORC1 et l’autophagie, dans les neurones à POMC dans la régulation de l’homéostasie énergétique. Nos données offrent un nouvel aperçu sur les mécanismes moléculaires impliqués dans la régulation de la balance énergétique. / The hypothalamus is a brain structure with a key role in the regulation of food intake. Among the different neuronal populations of which it is composed, pro-opiomelanocortin (POMC) neurons are classically known to decrease food intake and body weight through the release of neuropeptides produced by the cleavage of POMC. Our study, through the use of genetic, pharmacological, electrophysiological and molecular approaches, challenges conventional notions about POMC neuron function in energy balance by showing that there are two functionally distinct POMC neuronal sub-populations, which increase or decrease food intake depending on which neurotransmitter they release, γ-aminobutyric acid (GABA) or glutamate. A third population capable of producing both GABA and glutamate has also been identified. The regulation of POMC GABAergic and glutamatergic neurons depends on the mechanistic target of rapamycin complex 1 (mTORC1) pathway, which functions as a cellular energy sensor, and the endocannabinoid system (ECS), which regulates neurotransmitters release. In addition, we have also demonstrated through the use of a conditional knockout mice, the importance of the protein p62 or sequestrome 1 (p62/SQSTM1), which regulates mTORC1 activity and autophagy, in POMC neurons for the regulation of energy homeostasis. Our data provide new insights on the molecular mechanisms involved in the regulation of energy balance.