Venue: Centre Broca
Victor Jouque
Teams: Energy balance and obesity
Daniela cota
Neurocentre Magendie
Titre
Beyond satiety: deciphering the role of hypothalamic POMC neurons in the consumption of Hypercaloric food.
Résumé
Eating is a process essential for life. Therefore, powerful brain mechanisms have evolved to allow not only the matching of the organism’s energy needs with energy intake, but also the recognition of food rich in calories so as to guarantee survival under variable environmental food sources. In this context, neuronal circuits classically aiming at integrating information about the organism’s energy status must interact with networks regulating the rewarding aspect of food intake. Although exposure to calorie-rich diets is well known to promote overeating and consequent obesity in today’s modern societies, little is known about how such communication is set in place and the neuronal substrates underlying this phenomenon. Hypothalamic pro-opiomelanocortin (POMC) neurons are classically viewed as the mediators of satiety via the release of the neuropeptide a-MSH in response to metabolic and hormonal cues. However, recent evidence demonstrates that POMC neurons are highly heterogeneous, can become active before food consumption and stimulate feeding under specific conditions. In addition, POMC neurons release the u-opioid receptor (MOR) agonist β-endorphin, known to stimulate the intake of energy-dense food, therefore challenging the traditional view of their satietogenic function.
Objectives: The general aim of this thesis was to study the role of hypothalamic POMC neurons in the consumption of energy-dense palatable food. The specific objectives were the following:
(1) Define the mechanism engaged by POMC neurons in the hyperphagia toward hypercaloric food;
(2) Unravel the neuronal circuit implicated
By combining neuroanatomical, electrophysiological and in vivo calcium imaging approaches at single cell resolution, we demonstrate that POMC neurons are rapidly activated by consumption of high-fat diet (HFD) through orosensory processes.
Activation of hypothalamic POMC neurons is specific to HFD exposure and it drives hyperphagia in both sexes, as chemogenetic inhibition of POMC neurons reduces HFD intake. These effects seem to require the synthesis and release of the POMC-derived peptide β-endorphin, as its levels increase in POMC terminals upon HFD exposure, while HFD-driven hyperphagia can be selectively inhibited by MOR antagonism. Single nucleus RNA sequencing (SnRNAseq) data further show that POMC neurons activated in response to HFD have increased expression of molecular mechanisms controlling the synthesis, addressing and release of β-endorphin.
Using anterograde tracing of POMC neuronal projections, we then reveal that POMC neurons project to several structures implicated in food reward, especially the lateral septum. Using patch clamp recording coupled with optogenetics, we demonstrate that POMC neurons are electrically connected with LS neurons through an inhibitory neurocircuit. Pharmacological inhibition of MOR activity specifically in the LS, but not in other brain structures receiving POMC neuron projections, recapitulates the hypophagic effects induced by general MOR blockade. Finally, in vivo optogenetic inhibition of the POMC-LS neurocircuit reduces HFD intake, demonstrating that the lateral septum acts as a downstream brain region mediating HFD-driven hyperphagia by integrating POMC-derived β-endorphin.
Our work suggests that, contrary to established dogma, certain POMC neurons subpopulations drive the intake of hypercaloric and palatable food through a previously uncharacterized neurocircuit involving the release of b-endorphin in the lateral septum. These set of findings, altogether provide novel information on the complex role played by hypothalamic POMC neurons in the regulation of feeding beyond satiety.
– Keywords : POMC neurons, feeding behavior, Hypothalamus, Neuronal circuits
– Mes publications :
López-Gambero AJ, Jouque V, Cota D. A sympathetic brake on gut GLP-1 release. Neuron. 2024 Mar 20. Doi : 10.1016/j.neuron.2024.02.015. PMID :38513615
Jouque V, Miralpeix C, López-Gambero AJ, Nicolas JC, Quarta C, Cota D. Beyond satiety: unraveling the complex roles of POMC neurons in behavior and metabolism. Rev Endocr Metab Disord. 2025 Sep 19. Doi: 10.1007/s11154-025-09993-2. PMID: 40971005
Jury
Amandine Gautier-Stein, DR
Gangarossa Guiseppe, Pr
Serge Luquet, DR
Rovere Carole, CR