The body contains two kinds of fat: white fat, which acts as an energy storage organ, and brown fat, which utilizes energy to generate heat. White fat consists of the subcutaneous and the visceral fat. Accumulation of visceral fat contributes more to metabolic dysfunction due to its increased rate of lipolysis, reduced ability to form brown-like adipocytes known as “beige” cells, and its more inflammatory nature. In this study, we investigated the role that cyclic-AMP Responsive Element Binding Protein 3-like-3 (CREB3L3) plays in adipose tissue. CREB3L3 is an ER-bound transcription factor that has previously been described as liver specific, and an important regulator of lipid metabolism. Upon discovering that CREB3L3 is not only expressed in adipose tissue, but selectively downregulated in the more “metabolically healthy” subcutaneous fat in both obese mice and humans, we investigated how ablating this transcription factor would affect adipose biology. To study this, we created a CREB3L3 fat-specific knockout (fKO) mouse. When challenged with high-fat diet, the fKO mice became 18% heavier than floxed controls. They had significant expansion of their epididymal and inguinal adipose depots, due to a reduction in whole-body energy expenditure and oxygen consumption as measured by indirect calorimetry. The fKO mice are also more resistant to browning during cold exposure and treatment with the β3-adrenergic receptor agonist CL316,243, suggesting impairment of adaptive thermogenesis in the subcutaneous fat. Expansion of the visceral epididymal fat caused the tissue to become more inflammatory as evidenced by an increase in the number of crown-like structures and expression of the macrophage marker F/480 in the fKO tissue. This led to the fKO mice becoming more insulin resistant following high-fat feeding. Together, ablation of CREB3L3 enhances adiposity and insulin resistance during obesity due to a reduction in browning potential and amplified visceral inflammation.
M.A. McCann: None. M.D. Munoz: None. V. Gil: None. K. Zhang: None. C. LIew: None.
National Institutes of Health (R01DK109015-01); American Heart Association (16PRE30190011)