THE SUBPOPULATION OF GABAERGIC PROOPIOMELANOCORTIN NEURONS OF THE HYPOTHALAMUS REGULATE ENERGY BALANCE

ALSINA, RAMIRO; BUMASCHNY, VIVIANA FLORENCIA; TROTTA, MILAGROS

CABA

Congreso; Reunión Conjunta de Sociedades de Biociencias 2017; 2017

Sociedad Argentina de Investigaciones Clínicas

Obesity is an epidemic disease that affects 600 million adult people worldwide, which is a consequence of alterations in energy balance. The arcuate nucleus of the hypothalamus is a key area that integrates peripheral signals of energy status and regulates energy homeostasis by projecting to second order neurons. Arcuate proopiomelanocortin (POMC) neurons inhibit food intake and increase energy expenditure. Pomc mutant humans and mice develop early onset severe obesity, what demonstrates that POMC neuropeptide is one of the main regulators of energy balance. Some studies reveal the existence of subpopulations of POMC neurons secreting the antagonistic neurotransmitters glutamate or GABA, but their physiological roles and targets remain to be dissected. In order to elucidate the role of GABAergic POMC neurons, we intercrossed a reversible Pomc knockout mouse line (in which Pomc expression can be conditionally reactivated), with another line bearing a GABA-specific Cre driver. These mice developed obesity but, after the rescue of Pomc in GABAergic neurons, they normalized food intake and metabolic efficiency. Notably, females significantly decreased their body weight and reached an energy balance that matches that of lean control mice. Surprisingly, these physiological improvements were achieved with the recovery of Pomc expression in only 25% of total hypothalamic POMC neurons. Immunohistochemical analysis showed that GABAergic POMC neurons preferentially project to the dorsomedial hypothalamus (DMH), a nucleus that induces food intake by releasing NPY. In order to emphasize the role of GABAergic subpopulation, by using another mouse line expressing a ubiquitous Cre, we found that the partial rescue of Pomc, unrestricted to any subpopulation, failed to improve body weight, food intake or metabolic efficiency. Altogether, these results show that GABAergic POMC neurons have a major role in the establishment of energy balance, probably, through an arcuate-DMH circuit.