Ablation of Adipose CREB3L3 Protects Mice from Obesity-Induced Metabolic Dysfunction

Metabolically healthy obesity (MHO) is a subtype of obesity where individuals lack the metabolic symptoms associated with obesity, despite being obese. Our lab has found that the fat-specific ablation of cyclic-AMP Responsive Element Binding Protein 3-like-3 (CREB3L3) creates a phenotype mimicking MHO in mice fed a high-fat diet (HFD). CREB3L3 is an ER-bound transcription factor that we have discovered to not only be expressed in adipose tissue, but selectively downregulated in obese subcutaneous fat from both mice and human patients. Subcutaneous fat is considered the more “metabolically-protective” subtype of white adipose tissue in obesity, so we hypothesized that this downregulation of CREB3L3 could contribute to the healthier phenotype of obese subcutaneous fat, and the ablation of this protein specifically in adipose tissue could be metabolically beneficial. We found that the fat-specific knockout (KO) of CREB3L3 significantly increased body weight and the mass of both the subcutaneous inguinal (iWAT) and visceral epididymal (eWAT) fat depots on HFD, as compared to wild type controls. However, the KO mice do not exhibit the insulin resistance or glucose intolerance expected with their more obese phenotype, likely due to enhanced lipid storage in adipose tissue, which sequesters lipids away from the circulation and liver. Indeed, the KO mice do not exhibit dyslipidemia and have reduced hepatic triglyceride content. The enhanced adipose lipid storage is achieved via the enlargement of the iWAT and eWAT in the KO mice. Morphometric analysis shows that both of these tissues have more adipocytes, and the eWAT has more large adipocytes. While adipocyte hypertrophy typically contributes to metabolic dysfunction, the KO eWAT, along with the iWAT, actually exhibit a reduction in inflammatory marker expression. This ability to reduce adipose inflammation while enhancing lipid storage capacity allows the CREB3L3 KO mice to gain more weight on HFD, yet maintain a healthy metabolic profile. Disclosure M.A. McCann: None. G. Qiang: None. V. Gil: None. H. Whang Kong: None. K. Zhang: None. C. LIew: None.