Role of the POMC-ventral striatal neurocircuit in the development of diet-induced obesity – StriaPOM

Background: Due to the obesity epidemic, it is urgent to study diet-induced functional changes of neuronal circuits integrating the diverse components of feeding behavior (food hedonic and incentive salience, actual food intake) with the metabolic status of the organism, as those circuits may be relevant target for treatment. Hypothalamic pro-opiomelanocortin (POMC) neurons are typically recognized as the mediators of satiety in response to metabolic and hormonal cues, while medium spiny neurons (MSNs) of the nucleus accumbens (NAc) modulate food intake by decoding reward and motivation. Recent evidence demonstrates that POMC neurons are heterogeneous. Because of this heterogeneity, they may not only reduce, but also stimulate food intake, impacting motivational and hedonic responses that are typically under the control of MSNs.
Rationale and Objectives: Here we propose that a subpopulation of hypothalamic POMC neurons, which we will identify, play a critical role in driving the initial overconsumption of hypercaloric palatable food and ensuing weight gain through the modulation of NAc signaling.
Our objectives are: 1) to define the mechanisms engaged by POMC neurons in the initial hyperphagia to hypercaloric palatable food; 2) to establish the functional neuroanatomy of the POMC to NAc circuit and its changes in response to hypercaloric palatable food; 3) to establish the role of the POMC to NAc circuit in the development of diet-induced obesity.
Methods: We will use state-of-the-art neuroscience methodological approaches, spanning from the use of patch-clamp and in vitro optogenetics for electrophysiology to in vivo calcium imaging of neurons of interest and in vivo chemo-genetics approaches for in depth analysis of circuit-dependent changes of feeding behavior. These approaches will be combined with the use of specific genetic models, which will undergo behavioral and metabolic characterization.
Originality: Here we put forward the original hypothesis that POMC neurons, thanks to their heterogeneity, may not only inhibit, but also stimulate feeding, especially for hypercaloric, palatable food, and that they do so by modulating the NAc. No study has so far investigated the role of the POMC to NAc circuit in the adaptive response to caloric overload, or the specific function of this circuit in the modulation of food intake and development of diet-induced obesity. The objectives that we therefore aim at reaching through the StriaPOM project are both novel and original, while sitting on published and unpublished observations that overall support the hypothesis proposed and its logic.
Expected results and potential benefits: In a world where the prevalence of obesity keeps increasing, how what we eat impacts feeding behavior and metabolism is a fundamental question for which answers are urgently needed. By using a multidisciplinary approach involving original genetic models and neuroanatomical, electrophysiological, behavioral and metabolic studies, StriaPOM aims at providing some of these long-awaited answers. We anticipate that the obtained results will help clarify the actual link among exposure to excessive caloric sources, change in brain function and obesity pathophysiology, generating information on further roles played by POMC neurons and on a new circuit that may be target for the development of novel anti-obesity drugs. Therefore, we expect that this new knowledge will advance the fields of Physiology, Neuroscience and Metabolism, by providing critical information on how nutrient-related information is integrated by specific neuronal types and circuits so to modulate different constituents of feeding behavior as well as metabolic responses at the organism level.