Crtc1 Deficiency Causes Obesity Potentially via Regulating PPARγ Pathway in White Adipose.

Yimeng Hu,Yuan He,Mingxia Fan,Qiang Luo,Zhihua Wang,Yu Fang,Jian Lv,Lili Li

doi:10.3389/fcell.2021.602529

Abstract

Obesity is characterized by excessive fat accumulation and associated with glucose and lipid metabolism disorders. Crtc1, a transcription cofactor regulating CREB activity, has been involved in the pathogenesis of metabolic syndrome; however, the underlying mechanism remains under debate. Here we generated a Crtc1–/– mouse line using the CRISPR/Cas9 system. Under normal feeding conditions, Crtc1–/– mice exhibited an obese phenotype resultant from the abnormal expansion of the white adipocytes. The development of obesity in Crtc1–/– mice is independent of alterations in food intake or energy expenditure. Moreover, Crtc1–/– mice were more prone to insulin resistance and dyslipidemia, as evidenced by higher levels of plasma glucose, insulin and FABP4 than wildtype mice. Transcriptome analysis in liver and epididymal white adipose tissue (eWAT) showed that the fat accumulation caused by Crtc1 deletion was mainly related to lipid metabolism in adipose tissue, but not in liver. GSEA and KEGG analysis identified PPAR pathway to be of the highest impact on lipid metabolism in eWAT. This regulation was independent of a direct interaction between CRTC1 and PPARγ. Our findings demonstrate a crucial role of Crtc1 in regulating lipid metabolism in adipose during development, and provide novel insights into obesity prevention and therapeutics.

Highlights

Obesity is associated with risks of numerous co-morbidities including insulin resistance, dyslipidaemia, hypertension, cardiovascular disease and cancer (Emerging Risk Factors et al, 2011; Seravalle and Grassi, 2017; Malden et al, 2020).During the development of obesity, expansion of white adipose tissue (WAT) may be derived from an increase in the size and/or in the number of adipocytes, causing compromised capacity of WAT to sense nutrients and further result in ectopic lipid deposition (Jo et al, 2009; Sun et al, 2011)
CREB regulated transcription coactivator 1 (Crtc1)−/− mice were larger and heavier than Crtc1+/+ mice at the age of 8 months (Figures 2A,B). This increase was obviously contributed by the increased weights of fats including epididymal white adipose tissue (eWAT), subcutaneous white adipose tissue (sWAT) and brown adipose tissues (BAT) (Figure 2D)
The results of Gene Set Enrichment Analysis (GSEA) (Table 2) and Gene ontology (GO) enrichment analysis (Figure 6F) of different expression genes (DEGs) in eWAT showed that biological processes affected by Crtc1 deletion were closely related to fatty acid metabolism and adipocyte differentiation

Summary

INTRODUCTION

Obesity is associated with risks of numerous co-morbidities including insulin resistance, dyslipidaemia, hypertension, cardiovascular disease and cancer (Emerging Risk Factors et al, 2011; Seravalle and Grassi, 2017; Malden et al, 2020).During the development of obesity, expansion of white adipose tissue (WAT) may be derived from an increase in the size (hypertrophy) and/or in the number of adipocytes (hyperplasia), causing compromised capacity of WAT to sense nutrients and further result in ectopic lipid deposition (Jo et al, 2009; Sun et al, 2011). Previous studies have reported Crtc mediates the central effects of leptin on satiety and reproduction (Altarejos et al, 2008), and participates in the regulation of circadian clock (Jagannath et al, 2013), peripheral glucose metabolism (Kim et al, 2015), cardiac function and growth (Morhenn et al, 2019), and memory formation (Uchida et al, 2017). Peroxisome proliferator activated receptor γ (Pparγ) belongs to a family of nuclear receptors possessing transcriptional activity and regulating variety of genes (Surgucheva and Surguchov, 2008). It is a master regulator of whole-body lipid metabolism, adipogenesis, and insulin sensitivity (Ahmadian et al, 2013). Our findings shed a light on the lipogenesis during development and provide novel molecular targets to achieve weight loss

MATERIALS AND METHODS

RESULTS

DISCUSSION

ETHICS STATEMENT