Adipocyte ANGPTL8 Regulates Insulin Sensitivity and Thermogenic Programing

ANGPTL8 (A8), expressed mainly in the liver and adipocytes, regulates lipoprotein lipase (LPL) and lipid metabolism. Hepatic A8 and ANGPTL3 form a complex that inhibits LPL. However, the precise intracellular role of A8 in adipocytes is yet to be explored. We observed that RNAi-knockdown of A8 in mouse primary subcutaneous (SC) pre-adipocytes reduces adipocyte differentiation, glycerol, and fatty acid release at day 7 post-differentiation. RNAseq analysis of A8 siRNA or control siRNA transfected SC pre-adipocytes on days 0, 2, 4 and 7 of differentiation showed that A8 silencing impeded adipogenic and oxidative phosphorylation pathways and reduced expression of insulin signaling pathway genes IRS1, IRS2, PPARG, mTOR, early during differentiation, suggesting a role for A8 in the regulation of insulin sensitivity. Next, we investigated the functional role of adipose A8 by generating conditional adipocyte-specific A8 Knockout (AT-A8-KO) mice. AT-A8-KO mice on 45% high fat diet (HFD) with 30% fructose for 20 weeks showed a decrease in body weight gain, glycemia, brown fat mass, plasma TG and smaller cell size of SC adipocytes, while increased rectal temperature compared to controls. Interestingly, OGTT revealed AT-A8-KO mice in control diet or in HFD have significantly lower insulinemia. ITT results confirmed significant improvement of insulin sensitivity of AT-A8-KO mice on HFD. In addition, upon exposure to 6°C for 24h, AT-A8-KO mice exhibited elevated body temperature and energy expenditure compared to control mice, indicating that adipose tissue A8 negatively modulates cold-induced thermogenesis. Our results reveal that A8 regulates in vitro adipocyte differentiation, probably by modulating insulin signaling and mitochondrial respiration, and that deletion of adipocyte A8 in mice enhances insulin sensitivity, cold induced body temperature and energy expenditure. Therefore, targeting adipose specific A8 may be beneficial in promoting insulin sensitivity and preventing obesity. Disclosure A.Ghosh: None. I.Al-khairi: None. J.Abubaker: None. F.Al-mulla: None. M.Abu-farha: None. M.Prentki: None. Y.H.Leung: None. J.C.Y.Yu: None. R.M.Sladek: None. I.Chenier: None. A.Oppong: None. M.Peyot: None. M.Madiraju: None. Funding Dasman Diabetes Institute (731)