Premium
Control of Resting Metabolism by Regulator of G Protein Signaling‐2 (Rgs2) in AgRP Neurons
Author(s) -
Deng Guorui,
Morselli Lisa L,
Sapouckey Sarah A,
Sebag Julien A,
Rahmouni Kamal,
GibsonCorley Katherine N,
Sigmund Curt D,
Cui Huxing,
Paradee William J,
Grobe Justin L
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.867.5
Subject(s) - regulator of g protein signaling , rgs2 , biology , medicine , endocrinology , g protein , heterotrimeric g protein , arc (geometry) , regulator , microbiology and biotechnology , receptor , neuropeptide y receptor , signal transduction , neuropeptide , gtpase activating protein , genetics , gene , geometry , mathematics
Resting metabolic rate (RMR) normally accounts for ~70% of total energy expenditure, and obesity is associated with and maintained via suppression of RMR. We recently demonstrated that the angiotensin II (ANG) type 1 receptor (Agtr1a) in cells expressing Agouti‐related peptide (AgRP) within the arcuate nucleus of the hypothalamus (ARC) is required for RMR responses to various stimuli, including leptin, high‐fat diet, and deoxycorticosterone acetate (DOCA)‐salt. Agtr1a activation by ANG results in downstream G‐protein signaling that is negatively modulated by endogenous terminators, such as Regulator of G protein Signaling‐2 (Rgs2). Rgs2 terminates Agtr1a second‐messenger signaling by promoting reassembly of the heterotrimeric G protein. Interestingly, mice with whole‐body disruption of Rgs2 exhibit altered thermoregulation. Rgs2 is known to inhibit Agtr1a signaling in other tissues, and thus we hypothesize that Rgs2 within AgRP neurons modifies RMR control. First, Rgs2 expression in the various subsets of AgRP neurons of the ARC from wildtype C57BL/6J mice was confirmed by in silico reanalysis of a published single‐cell RNAseq dataset (GSE74672), and by RNAscope in situ hybridization. Second, using CRISPR we generated a new mouse model expressing a conditional allele for Rgs2 (Rgs2 flox ) in which exons 2–4 are flanked by LoxP sites. Third, these animals were iteratively bred with mice expressing Cre‐recombinase via the AgRP locus (Jax 012899) to eliminate Rgs2 from cells expressing AgRP. Preliminary assessments of these Rgs2 AgRP‐KO animals under baseline, chow‐fed conditions indicate that the animals are viable and born in expected ratios. Fed standard chow (Teklad 7013), Rgs2 AgRP‐KO mice of both sexes exhibit normal body mass, but may consume less food relative to control littermates (at 10 weeks of age, 8.0±1.9 n=8 vs 9.3±1.4 n=19 kcal/hr, p=0.06). Interestingly, Rgs2 AgRP‐KO mice may exhibit a shift in body composition, with greater body fat by NMR (10.5±1.2 n=8 vs 7.3±.5 n=22 % total mass, p<0.05). Preliminary tests of RMR indicate that during chow‐fed conditions, RMR is normal in Rgs2 AgRP‐KO mice after correction for body mass and sex by generalized linear modeling (0.134±0.006 n=8 vs 0.132±0.005 n=8 kcal/hr, p=0.78). Such findings are expected, as our previous studies of animals lacking Agtr1a in AgRP cells indicate that Agtr1a signaling in these cells is required for RMR responses to various stimuli but not baseline control. Tests of RMR responses of Rgs2 AgRP‐KO mice to various stimuli are ongoing, and we anticipate that responses to leptin and ANG will be potentiated. In conclusion, we have demonstrated that Rgs2 is expressed in AgRP cells of the ARC, and we have developed a novel model to study its role in cardiometabolic control. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .