Abstract 1035: C/EBPα Has Depot-specific Roles In White Adipose Tissue Development And Function.

Obesity, defined as excess white adipose tissue (WAT), associates with a higher risk of metabolic disease and comorbidities, and continues to be on the rise in the developed world. However, different WAT depots associate with differing levels of cardiometabolic risk. Expansion of visceral WAT (vWAT) correlates with increased risk for cardiovascular disease and type 2 diabetes, while expansion of subcutaneous WAT (sWAT) does not. These observations suggest mechanistic differences between the two depots, and elucidating these mechanisms may provide insights into promoting cardiometabolic health in humans. Human GWAS have shown that SNPs near the gene CEBPA associate with waist-to-hip ratio, a metric of vWAT mass in humans, suggesting CEBPA plays a specific role in vWAT. CEBPA encodes the transcription factor C/EBPα, a known regulator of adipogenesis. We established adipocyte-specific Cebpa knockout (Cebpa_ASKO) mice and found they lack gonadal WAT (gWAT), the largest vWAT depot in mice. Conversely, sWAT is still present in Cebpa_ASKO mice, although with reduced mass (-23%, p<0.05) and larger adipocytes. Additionally, Cebpa_ASKO mice have reduced lipolysis (-26% NEFAs, p<0.05), plasma adiponectin (-89%, p<0.0001) and leptin (-82%, p<0.05), suggesting the remaining sWAT is dysfunctional. Together, these data suggest that C/EBPα has WAT depot-specific roles, being required for vWAT development, but only for function in mature sWAT. Given the myriad roles for vWAT in metabolism and the absence of vWAT in Cebpa_ASKO mice, we investigated downstream metabolic consequences of this phenotype. Cebpa_ASKO mice have increased brown adipose tissue (BAT) mass (+118%, p<0.001) due to increased ectopic lipid deposition. Cebpa_ASKO mice also have increases in plasma cholesterol (+20%, p<0.05), liver mass (+24%, p<0.01), and hepatic fat content (+329%, p<0.01). Overall, these results demonstrate that adipocyte C/EBPα significantly influences whole body metabolism. Ongoing studies center on delineating the different mechanisms through which C/EBPα functions in vWAT and sWAT. Understanding the depot-specific mechanisms of C/EBPα could have practical implications for new clinical targets of obesity and metabolic disease.