Adipose expression of CREB3L3 modulates body weight during obesity

Maximilian A Mccann,Chong Wee Liew,Stephen Duncan,Yanliang Li,Marcos Muñoz,Jose Cordoba-Chacon,Matthias Blüher,Victoria Gil,Guifen Qiang

doi:10.1038/s41598-021-98627-z

Abstract

We found the hepatic transcription factor Cyclic-AMP Responsive Element Binding Protein 3-like-3 (CREB3L3) to be expressed in adipose tissue, and selectively downregulated in the more metabolically protective subcutaneous adipose tissue in obese mice and humans. We sought to elucidate the specific role of this factor in adipose biology. CREB3L3 fat-specific knockout mice were fed a high-fat diet to induce obesity and metabolic dysfunction. Additionally, we injected a flip-excision adeno-associated virus directly into the subcutaneous inguinal adipose tissue of Adiponectin-Cre mice to create a depot-specific overexpression model for further assessment. Fat-specific ablation of CREB3L3 enhanced weight gain and insulin resistance following high-fat feeding, as fat-specific knockout mice expended less energy and possessed more inflammatory adipose tissue. Conversely, inguinal fat CREB3L3 overexpression deterred diet-induced obesity and ameliorated metabolic dysfunction. Together, this study highlights the relevance of CREB3L3 in obese adipose tissue and demonstrates its role as a powerful body weight modulator.

Highlights

We found the hepatic transcription factor Cyclic-AMP Responsive Element Binding Protein 3-like-3 (CREB3L3) to be expressed in adipose tissue, and selectively downregulated in the more metabolically protective subcutaneous adipose tissue in obese mice and humans
As part of the data mining process for these studies, we identified the endoplasmic reticulum (ER)-bound transcription factor cyclic-AMP Responsive Element Binding Protein 3-like-3 (CREB3L3) as a protein that is differentially regulated in obese iWAT and epididymal white adipose tissue (eWAT)
The mice at UIC and the Joslin Diabetes Center had been bred for several generations, meaning their microbiomes differed from the mice housed at Jackson Labs

Summary

Introduction

We found the hepatic transcription factor Cyclic-AMP Responsive Element Binding Protein 3-like-3 (CREB3L3) to be expressed in adipose tissue, and selectively downregulated in the more metabolically protective subcutaneous adipose tissue in obese mice and humans. Obese adipose tissue undergoes changes in lipid metabolism, inflammation, and adipokine secretion This leads to increased release of free fatty acids and pro-inflammatory cytokines, in addition to shifting the secretion of adipokines. These shifts in the adipose secretome drive lipotoxicity, inflammation, and eventual insulin resistance in other metabolic organs, culminating in the development of metabolic s yndrome[1,2,3,4,5]. Among the white adipose tissues, visceral fat enlargement strongly correlates with the development of metabolic syndrome[6] This is believed to be due to the more inflammatory nature of this tissue[7] and its enhanced ability to mobilize fatty acids via lipolysis[8].

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