The Role of CREB3L3 in Adipose Biology and Obesity

In this thesis, I investigated the role of cyclic-AMP Responsive Element Binding Protein 3-like-3 (CREB3L3) in adipose tissue. CREB3L3 is an ER-bound transcription factor that is an important regulator of lipid metabolism and has previously been described as liver specific. In the first chapter, we discovered 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 in response to ER stress, while expression is unchanged in the visceral fat. To investigate how this transcription factor contributes to adipose biology, we create a CREB3L3 fat-specific knockout (fKO) mouse in the second chapter. When challenged with high-fat diet, the fKO mice became 18% heavier than floxed controls and had significant expansion of their epididymal and inguinal adipose depots. 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 pro-inflammatory cytokines in the fKO tissue. This led to the fKO mice becoming more insulin resistant following high-fat feeding. In the third chapter we investigated the cause of the larger adipose tissues in the fKO mice. Indirect calorimetry experiments showed that a reduction in whole-body energy expenditure caused the enhanced adiposity of the fKO mice following high-fat feeding. In addition to having a shift in brown fat metabolism from fatty acid oxidation to lipid synthesis, fKO subcutaneous adipocytes were more resistant to browning upon treatment with the β3-adrenergic receptor agonist CL316,243. In the last chapter, we created a subcutaneous fat-specific overexpression model to address whether increased CREB3L3 expression in this tissue would prevent the development of obesity. I found that with only a modest increase in expression of CREB3L3 in subcutaneous fat, diet-induced obesity and insulin resistance is prevented. Taken together, our data show that this transcription factor is important for regulating body weight and inflammation during high-fat feeding. Our comprehensive phenotyping of our mouse models leads us to propose that the amount of CREB3L3 expression in adipose tissue is important for energy homeostasis and body weight regulation during obesity.