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138-OR: Ablating Adipose CREB3l3 Preserves Metabolic Health during Obesity

During obesity, the adipose tissue becomes supersaturated with lipids, leading to inflammation, the release of free fatty acids into the bloodstream, and the development of metabolic syndrome. However, a small obese subpopulation does not develop metabolic syndrome and has been deemed to have “metabolically healthy” obesity (MHO). Our lab has created a mouse model that mimics MHO, via adipose-specific ablation of the ER-bound transcription factor cyclic-AMP Responsive Element Binding Protein 3-like-3 (CREB3L3). We have discovered that CREB3L3 is not only expressed in adipose tissue, but selectively downregulated in the “metabolically protective” subcutaneous fat in obese mice and human patients. We hypothesized that CREB3L3 downregulation could contribute to the healthier metabolic profile of subcutaneous fat during obesity, so we created a CREB3L3 fat-specific knockout (KO) mouse. CREB3L3 KO mice had enhanced diet-induced obesity following 12 weeks of high-fat diet feeding and significantly larger inguinal white adipose tissue (iWAT) and epididymal white adipose tissue (eWAT) compared to wild type controls. Unexpectedly, the KO mice do not exhibit the reduction in glucose tolerance or insulin sensitivity that would be expected with their more obese phenotype, which is likely due to the enlarged adipose tissues. The KO mice do not exhibit the expected dyslipidemia or hepatic steatosis, suggesting that the KO adipose tissue sequesters lipids away from these spaces. Additionally, the KO iWAT and eWAT have reduced inflammatory marker expression, suggesting that CREB3L3 plays a role in adipose inflammation. Indeed, we observed that obese mice overexpressing CREB3L3 via direct injection of a CREB3L3 adeno-associated virus into the iWAT and eWAT had marked upregulation of IL-1B and MCP1 in both of these tissues. Together, these data suggest that adipose ablation of CREB3L3 preserves metabolic health during obesity by allowing the adipose tissue to meet the body’s lipid storage demands via healthy expansion. Disclosure M.A. McCann: None. S. Li: None. Y. Li: None. V. Gil: None. C. LIew: None. Funding National Institutes of Health (R01DK109015)