C/EBP α is Essential for Gonadal but Not Inguinal White Adipose Tissue Formation in Mice

The distribution of excess white adipose tissue (WAT) in obesity correlates with risk for comorbidities. Thus, understanding depot-specific WAT developmental mechanisms is translationally relevant. SNPs near the gene CEBPA associate with waist to hip ratio, and while C/EBPα is a recognized regulator of adipogenesis, there is no previously known role for C/EBPα in regulating adipose distribution.

We crossed Cebpa floxed mice to the AdipoQ-Cre transgenic mouse strain, generating mice with adipocyte-specific knockout of Cebpa (Cebpa_ASKO). Mice were phenotyped on a chow diet and after prolonged high-fat diet (HFD) feeding.

Cebpa_ASKO mice almost entirely lack gonadal WAT (gWAT), while inguinal WAT (iWAT) is present in near normal amounts. Despite developing, Cebpa_ASKO iWAT contains fewer and larger adipocytes, fails to expand under HFD challenge, and is dysfunctional as evidenced by transcriptomics and functional studies. Finally, Cebpa_ASKO mice have lipid-laden brown adipose tissue (BAT), increased hepatic triglycerides, and increased plasma cholesterol, all of which worsen with prolonged HFD feeding.

These results highlight a previously unrecognized difference in the essentiality of C/EBPα for gWAT and iWAT development and highlight novel interorgan relationships between WAT and other metabolic tissues. Further studies of these specific mechanisms could have clinical relevance for targeting visceral adiposity in humans.