POMC Expression in GABAergic Neurons Suppresses NPY Overexpression and Restores Food Intake in Obese Mice

ALSINA, RAMIRO; RUBINSTEIN, MARCELO; BELLO, ESTEFANÍA PILAR; FERRÁN, JOSÉ LUIS; TROTTA, MILAGROS; TAVELLA, MARÍA BELÉN; BUMASCHNY, VIVIANA FLORENCIA

Congreso; ENDO Online 2020; 2020

Endocrine Society

Hypothalamic arcuate proopiomelanocortin (Arc-POMC) neurons are involved in different physiological processes such as the regulation of energy balance, glucose homeostasis and stress induced analgesia. Since these neurons heterogeneously express different biological markers and project to many hypothalamic and extrahypothalamic areas, it is proposed that Arc-POMC neurons could be classified into different subpopulations having diverse physiological roles. The aim of the present study was to characterize the contribution of the subpopulation of Arc-POMC neurons co-secreting gamma-aminobutyric acid (GABA) neurotransmitter in the control of energy balance. Arc-Pomc expression restricted to GABAergic-POMC neurons was achieved by crossing a reversible Pomc-deficient mouse line (arcPomc-) with a tamoxifen-inducible Gad2-CreER transgenic line. Tamoxifen treatment of arcPomc-/-:Gad2-CreER mice at P60 resulted in Pomc expression in ~25 % of Arc-POMC neurons and ~23 % of Pomc mRNA levels, compared to Gad2-CreER control mice. Rescued mice normalized food intake, glycemia and fasting-induced hyperphagia, and significantly reduced body weight. Energy balance was also improved in arcPomc-/-:Gad2-CreER mice treated with tamoxifen at P25. Distribution analysis of rescued POMC immunoreactive fibers revealed that the DMH is a major target site of GABAergic-POMC neurons. Interestingly, the expression of the orexigenic neuropeptide Y (NPY) in the DMH was increased in arcPomc-/- obese mice but completely restored after Pomc rescue in arcPomc-/-:Gad2-CreER mice. Finally, we performed stereotactic intracerebral injections of fluorescent retrobeads into the DMH followed by in situ hybridization for Gad1 and found that ~75 % of Arc-POMC neurons projecting to the DMH are GABAergic. In conclusion, in the present study we show that the expression of Pomc in the subpopulation of Arc-GABAergic-POMC neurons is sufficient to maintain normal food intake. In addition, we found that DMH-NPY expression is negatively correlated with Pomc expression in GABAergic-POMC neurons, suggesting that food intake may be regulated by an Arc-GABAergic-POMC --> DMH-NPY pathway.