LBSUN87 Human Cidec Transgene Improves Lipid Metabolism And Protects Against High Fat-diet Induced Glucose Intolerance In Mice

Abstract

Abstract CIDEC expression in adipose tissue positively correlates with insulin sensitivity in obese humans. Further, a single-nucleotide CIDEC variant (E186X) causes lipodystrophy, hypertriglyceridemia, and insulin resistance. To establish the unknown mechanistic link between CIDEC and maintenance of systemic glucose homeostasis, we generated transgenic mouse models expressing CIDEC (Ad-CIDECtg) and CIDEC E186X variant (Ad-CIDECmut) transgene specifically in the adipose tissue. Ad-CIDECtg but not Ad-CIDECmut mice were protected against high-fat diet (HFD)-induced glucose intolerance. Transcriptomics and lipidomics revealed the role of CIDEC in lipid metabolism. Serum triglycerides, cholesterol, and low-density lipoproteins were lower in HFD-fed Ad-CIDECtg mice compared to their littermate controls. Mechanistically, CIDEC regulates the enzymatic activity of ATGL via interacting with its activator, CGI-58, to reduce free fatty acid (FFA) release and lipotoxicity. We confirmed that CIDEC is indeed a vital regulator of lipolysis in adipose tissue of obese humans. Finally, treatment with recombinant CIDEC decreased triglyceride breakdown in visceral human adipose tissue. Our study unravels a central pathway whereby adipocyte-specific CIDEC plays a pivotal role in regulating adipose lipid-metabolism and whole-body glucose homeostasis. In sum, our findings identify human CIDEC as a potential 'drug' or a 'druggable' target to reverse obesity-induced lipotoxicity and glucose intolerance. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.