Adipocyte C/EBPa is selectively required for gonadal white adipose tissue development

Obesity is associated with multiple metabolic comorbidities and continues to be prevalent in the developed world. It has been repeatedly shown that the distribution, not just amount, of excess white adipose tissue (WAT) in obesity correlates with a person’s risk for coronary artery disease and type 2 diabetes. Thus, understanding depot specific mechanisms of WAT development could shed light on mechanisms of metabolic disease. SNPs near the gene CEBPA, which encodes the transcription factor CCAAT/enhancer binding protein alpha (C/EBPa), have been associated by human genome-wide association studies with waist-to-hip ratio, suggesting CEBPA plays depot-specific roles in WAT. C/EBPa is a master regulator of adipocyte differentiation and metabolism, but its role in the development of specific WAT depots is not well understood. We generated mice with AdipoQ-Cre-driven adipocyte-specific Cebpa knockout (Cebpa_ASKO) and found that these mice have drastically reduced gonadal WAT (gWAT) mass. Meanwhile, inguinal WAT (iWAT) develops and is present in normal amounts. However, there are fewer and larger iWAT adipocytes and evidence of altered lipid metabolism, and Cebpa_ASKO mice fail to expand any of their white adipose depots when challenged with a high fat diet. Cebpa_ASKO mice also have multiple other metabolic phenotypes, including hypertrophic, lipid-laden BAT, increased hepatic triglycerides, and increased plasma cholesterol, and each phenotype worsens with prolonged high fat diet feeding. Taken together, these data point to C/EBPa playing depot-specific roles in adipose tissue development, as well as the importance of C/EBPa and visceral adipose tissue in maintaining metabolic homeostasis.