La subpoblación de neuronas hipotalámicas GABAérgicas de proopiomelanocortina regulan el balance energético

TROTTA MILAGROS; BUMASCHNY VIVIANA; ALSINA RAMIRO

Congreso; Reunión Conjunta de Sociedades de Biociencias (LXII Reunión anual de la Sociedad Argentina de Investigación Clínica, SAIC); 2017

Obesity is an epidemic disease that affects 600 millionadult people worldwide, which is a consequence of alterationsin energy balance. The arcuate nucleus of thehypothalamus is a key area that integrates peripheralsignals of energy status and regulates energy homeostasisby projecting to second order neurons. Arcuateproopiomelanocortin (POMC) neurons inhibit food intakeand increase energy expenditure. Pomc mutanthumans and mice develop early onset severe obesity,what demonstrates that POMC neuropeptide is one ofthe main regulators of energy balance. Some studies revealthe existence of subpopulations of POMC neuronssecreting the antagonistic neurotransmitters glutamateor GABA, but their physiological roles and targets remainto be dissected. In order to elucidate the role of GABAergicPOMC neurons, we intercrossed a reversible Pomcknockout mouse line (in which Pomc expression can beconditionally reactivated), with another line bearing aGABA-specific Cre driver. These mice developed obesitybut, after the rescue of Pomc in GABAergic neurons,they normalized food intake and metabolic efficiency. Notably,females significantly decreased their body weightand reached an energy balance that matches that of leancontrol mice. Surprisingly, these physiological improvementswere achieved with the recovery of Pomc expressionin only 25% of total hypothalamic POMC neurons.Immunohistochemical analysis showed that GABAergicPOMC neurons preferentially project to the dorsomedialhypothalamus (DMH), a nucleus that induces food intakeby releasing NPY. In order to emphasize the role ofGABAergic subpopulation, by using another mouse lineexpressing a ubiquitous Cre, we found that the partialrescue of Pomc, unrestricted to any subpopulation, failedto improve body weight, food intake or metabolic efficiency.Altogether, these results show that GABAergic POMCneurons have a major role in the establishment of energybalance, probably, through an arcuate-DMH circuit.