CREG1 heterozygous mice are susceptible to high fat diet-induced obesity and insulin resistance.

Xiaoxiang Tian,Chenghui Yan,Quanyu Zhang,Yanxia Liu,Yaling Han,Meili Liu,Dan Liu,Shaohua Li,Xin-Liang Ma

doi:10.1371/journal.pone.0176873

Abstract

Cellular repressor of E1A-stimulated genes 1 (CREG1) is a small glycoprotein whose physiological function is unknown. In cell culture studies, CREG1 promotes cellular differentiation and maturation. To elucidate its physiological functions, we deleted the Creg1 gene in mice and found that loss of CREG1 leads to early embryonic death, suggesting that it is essential for early development. In the analysis of Creg1 heterozygous mice, we unexpectedly observed that they developed obesity as they get older. In this study, we further studied this phenotype by feeding wild type (WT) and Creg1 heterozygote (Creg1+/-) mice a high fat diet (HFD) for 16 weeks. Our data showed that Creg1+/- mice exhibited a more prominent obesity phenotype with no change in food intake compared with WT controls when challenged with HFD. Creg1 haploinsufficiency also exacerbated HFD-induced liver steatosis, dyslipidemia and insulin resistance. In addition, HFD markedly increased pro-inflammatory cytokines in plasma and epididymal adipose tissue in Creg1+/- mice as compared with WT controls. The activation level of NF-κB, a major regulator of inflammatory response, in epididymal adipose tissue was also elevated in parallel with the cytokines in Creg1+/- mice. These pro-inflammatory responses elicited by CREG1 reduction were confirmed in 3T3-L1-derived adipocytes with CREG1 depletion by siRNA transfection. Given that adipose tissue inflammation has been shown to play a key role in obesity-induced insulin resistance and metabolic syndrome, our results suggest that Creg1 haploinsufficiency confers increased susceptibility of adipose tissue to inflammation, leading to aggravated obesity and insulin resistance when challenged with HFD. This study uncovered a novel function of CREG1 in metabolic disorders.

Highlights

Obesity is a growing epidemic with tremendously increased prevalence over the last 30 years worldwide [1]
Our genetic analysis revealed that global knockout of Creg1 gene leads to early embryonic death around E7.5, so Creg1+/- mice were used in this study
There was no difference in the average weight of daily food intake between wild type (WT) and Creg1+/- mice no matter which diet was fed (Fig 2C), demonstrating that calorie intake was similar in WT and Creg1+/- mice fed with either normal diet (ND) (3.85 Kcal/g chow) or high fat diet (HFD) (5.24 Kcal/g chow)

Summary

Introduction

Obesity is a growing epidemic with tremendously increased prevalence over the last 30 years worldwide [1]. Previous studies have demonstrated that a state of chronic, low-grade inflammation characterized by abnormal cytokine production and activation of inflammatory signaling pathways in adipose tissue is an initial event during pathogenesis in obesity [6,7,8]. The nuclear factor-κB (NF-κB) pathway and autophagy seem to mediate these anti-inflammatory effects [19, 23] Based on these findings, we tested the hypothesis that CREG1 might suppress development of obesity and insulin resistance by inhibiting inflammatory responses. HFD triggered systemic and adipose tissue inflammation in Creg1+/- mice, possibly through activation of the NF-κB pathway. To the best of our knowledge, this is the first demonstration that CREG1 negatively regulates the pathogenesis of obesity and related metabolic dysfunctions. These results provide new insights into the function of CREG1 and help us to better understand the molecular mechanisms of obesity

Methods

Results

Conclusion