Decoding hypothalamic nutrient sensing and food intake regulation via mTORC1, melanocortin and endocannabinoid interactions. – NeuroNutriSens

In order to appropriately address the aims of the project, the partners will use a multidisciplinary approach comprising the generation and characterization of novel transgenic animal models, the analysis of feeding behavior and electrophysiological, neuroanatomical and molecular studies. More specifically, in order to determine the exact implication of the mTORC1 pathway and of the endocannabinoid system in the regulation of melanocortin circuits, the partners will use optogenetics and the pharmacogenetic approach called DREADD (Designer Receptors Exclusively Activated by Designer Drugs).These methodological approaches will allow a very precise manipulation of the neuronal circuits of interest.

The project is currently ongoing. It will take advantage of two recently established international collaborations, respectively with Dr. Jorge Moscat, Sanford-Burnham Medical Research Institute, and with Dr. Tibor Harkany, University of Wien, Austria.

The final goal of the project is to provide new knowledge about the central mechanisms controlling food intake and body weight, in order to pave the way towards the identification of novel pharmacological therapeutic approaches against obesity and other eating-related disorders.

A review article has been published in Mol Cell Endocrinol in 2014 in which we illustrate the critical role played by the mTOR pathway in integrating information concerning nutrients and hormones in the hypothalamus. Anotehr review article has been published in Trends Endocrinol Metab in 2015 and describes the pivotal orchestrator role of the endocannabinoid system in the regulation of energy balance. An original article has been published in Endocrinology in 2015 in which we investigate the function of the cannabinoid type 1 (CB1) receptor signaling in the hypothalamic paraventricular nucleus. Finally, another original article has been published in Dis Model Mech in 2016 and it describes the interaction between mTOR and endocannabinoid system in the regulation of glucose metabolism.

Adequate food intake is necessary for the survival of the individual and the species and healthy eating is essential for health and well being. Despite the apparent logic of such a statement, nutrition-related diseases are currently on the rise. Among these, obesity represents a major health problem worldwide. Nevertheless, knowledge about how feeding behavior and energy balance are finely regulated within the central nervous system (CNS) is still limited. Within the CNS, the hypothalamus is a major center of convergence and integration of nutrient and hormonal signals, using this information to adjust food intake and peripheral metabolism in response to the energy needs of the organism. While substantial information is available concerning how hypothalamic neurons and their circuits contribute to the regulation of energy homeostasis, relatively little is known as to how specific pathways and neurotransmitter systems interact to regulate the activity of these circuits and ultimately food intake. Notably, the hypothalamic melanocortin system is in the unique position of easily detecting nutrient and hormonal signals, which in turn regulate food intake by engaging intracellular signaling cascades regulating cellular responses to fuel availability. The mammalian target of rapamycin complex 1 (mTORC1) pathway is a key fuel sensing mechanism implicated in the regulation of food intake, whereas both endocannabinoid and melanocortin neurotransmitter signaling have critical roles in the hypothalamic control of energy balance. Each of these elements might represent target for therapy of nutrition-related diseases. However, so far no studies have identified the exact cascade of events linking the mTORC1 pathway with the modulation of the activity of specific neurotransmitter systems and the consequent control of food intake. Remarkably, melanocortin actions in vivo are best observed upon refeeding after a prolonged fast, a condition known to activate POMC neurons in the hypothalamic arcuate nucleus, but also able to affect mTORC1 and endocannabinoid system functions. Based on a solid series of unpublished data, here we hypothesize that the hypothalamic neuronal melanocortin network senses fuel-related signals by engaging mTORC1 and endocannabinoid-dependent mechanisms to regulate food intake. Thus, our project will aim at: 1) establishing the signal(s) causing refeeding-induced POMC neurons activity and the role of the mTORC1 pathway in their decoding at neuronal level; 2) determining the role of the mTORC1 pathway in modulating refeeding-induced POMC neurons activity and; 3) establishing how changes in mTORC1 and melanocortin signaling impact the endocannabinoid system and, ultimately, food intake. To reach our goals we will combine genetic (including the generation of novel transgenic mouse models), pharmacological, behavioral, biochemical, electrophysiological, optogenetic, neuroanatomical and molecular approaches. The interdisciplinary nature of our work will allow obtaining a detailed characterization of the molecular and neuronal mechanisms underlying the complex link among neuronal nutrient sensing, associated changes in molecular, cellular and electrophysiological functions, and actual behavior. By providing essential clues linking nutritional status to molecular, neuroanatomical and behavioral changes, we expect that our studies will increase our understanding of the CNS mechanisms regulating food intake, possibly leading to the identification of new molecular targets for the treatment of pathological conditions characterized by an altered energy balance, including obesity and other eating-related disorders.