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

TL;DR

This study shows that C/EBPα is crucial for the development of gonadal fat in mice but not for inguinal fat, leading to metabolic issues when it's missing.

Contribution

The study reveals a depot-specific role of C/EBPα in white adipose tissue development and uncovers new interorgan metabolic relationships.

Findings

Cebpa_ASKO mice lack gonadal WAT but have near-normal inguinal WAT.

Inguinal WAT in Cebpa_ASKO mice is dysfunctional and fails to expand on a high-fat diet.

The knockout mice show lipid accumulation in brown fat, increased liver triglycerides, and elevated cholesterol.

Abstract

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.

What is already known?○The transcription factor C/EBPα is a critical regulator of adipogenesis.○The genomic locus containing the gene CEBPA is associated with visceral adiposity in humans.
What does this study add?○Adipocyte‐specific Cebpa knockout mice fail to develop gonadal white adipose tissue (WAT) due to stalled development in the perinatal period.○All other WAT depots develop normally but are dysfunctional, leading to numerous metabolic phenotypes in the knockout mice.
How might these results change the direction of research?○Given the clinical relevance of visceral adipose, further elucidation of the depot‐specific mechanisms of C/EBPα may unveil novel avenues for therapeutic intervention.○The metabolic phenotypes present in our mice suggest novel relationships between WAT function and other metabolic organs worthy of further research.

What is already known?○The transcription factor C/EBPα is a critical regulator of adipogenesis.○The genomic locus containing the gene CEBPA is associated with visceral adiposity in humans.

The transcription factor C/EBPα is a critical regulator of adipogenesis.

The genomic locus containing the gene CEBPA is associated with visceral adiposity in humans.

What does this study add?○Adipocyte‐specific Cebpa knockout mice fail to develop gonadal white adipose tissue (WAT) due to stalled development in the perinatal period.○All other WAT depots develop normally but are dysfunctional, leading to numerous metabolic phenotypes in the knockout mice.

Adipocyte‐specific Cebpa knockout mice fail to develop gonadal white adipose tissue (WAT) due to stalled development in the perinatal period.

All other WAT depots develop normally but are dysfunctional, leading to numerous metabolic phenotypes in the knockout mice.

How might these results change the direction of research?○Given the clinical relevance of visceral adipose, further elucidation of the depot‐specific mechanisms of C/EBPα may unveil novel avenues for therapeutic intervention.○The metabolic phenotypes present in our mice suggest novel relationships between WAT function and other metabolic organs worthy of further research.

Given the clinical relevance of visceral adipose, further elucidation of the depot‐specific mechanisms of C/EBPα may unveil novel avenues for therapeutic intervention.

The metabolic phenotypes present in our mice suggest novel relationships between WAT function and other metabolic organs worthy of further research.

Human genetics has linked the gene CEBPA to waist to hip ratio and adipose distribution. We generated mice with AdipoQ‐Cre driven deletion of Cebpa and found these mice to have a specific reduction in gonadal white adipose tissue and myriad other metabolic phenotypes.

Figures