Angiotensin (Ang)-(1-7), a protective hormone of the renin-angiotensin system, has emerged as a novel target to improve cardiovascular and metabolic functions in animal models. In addition to blood pressure lowering effects, recent studies from our laboratory and others have shown that Ang-(1-7) can promote insulin sensitization and weight loss in obese rodents. Our recent preliminary findings suggest these effects are centrally-mediated, with Ang-(1-7) mas receptors (MasR) widely distributed to the arcuate nucleus of the hypothalamus. In particular, we found that MasR are highly colocalized with proopiomelanocortin (POMC)-containing neurons in this brain region, neurons which when activated reduce food intake and increase energy expenditure to promote weight loss as well as improve insulin sensitivity. The importance of MasR localized to POMC neurons in metabolic functions, however, is currently unknown. In this study, we tested the hypothesis MasR expressed in POMC neurons are important for normal control of energy balance and glucose homeostasis. To test this, mice containing conditional knockout alleles of the Ang-(1-7) MasR were crossed with POMC-Cre mice to specifically delete MasR from POMC neurons (POMCMasR-KO). Body mass and composition, insulin sensitivity, and glucose tolerance were measured in male and female POMCMasR-KO mice and wild-type littermates (n=6-11/group) at 8 weeks of age on a standard chow diet. Despite similar fasting glucose and insulin levels, male POMCMasR-KO mice had worsened insulin sensitivity compared with wild-type littermates (area under the curve for decrease in glucose from baseline in response to intraperitoneal insulin: -2134±1071 vs. -6531±1507, respectively; p=0.029), with no differences in body mass, adiposity, lean mass, or glucose tolerance. In female mice, there was no effect of POMC MasR deletion on any of the metabolic outcomes tested. These findings suggest that MasR localized to POMC neurons provide tonic and sex-specific modulation of insulin sensitivity in mice. Additional studies are needed to determine if altered MasR signaling in POMC neurons could contribute to insulin resistance in disease states such as obesity and type II diabetes.
https://doi.org/10.1096/fasebj.2022.36.S1.0R781