Abstract
Vertical sleeve gastrectomy (VSG) produces sustainable weight loss, remission of type 2 diabetes (T2D), and improvement of nonalcoholic fatty liver disease (NAFLD). However, the molecular mechanisms underlying the metabolic benefits of VSG have remained elusive. According to our previous results, diet-induced obesity induces epigenetic modifications to chromatin in mouse liver. We demonstrate here that VSG in C57BL/6J wild-type male mice can reverse these chromatin modifications and thereby impact the expression of key metabolic genes. Genes involved in lipid metabolism, especially omega-6 fatty acid metabolism, are up-regulated in livers of mice after VSG while genes in inflammatory pathways are down-regulated after VSG. Consistent with gene expression changes, regulatory regions near genes involved in inflammatory response displayed decreased chromatin accessibility after VSG. Our results indicate that VSG induces global regulatory changes that impact hepatic inflammatory and lipid metabolic pathways, providing new insight into the mechanisms underlying the beneficial metabolic effects induced by VSG.
Highlights
A dramatic increase in the prevalence of obesity over the last few decades has led to a worldwide epidemic
To investigate the molecular mechanisms underlying the beneficial metabolic effects induced by Vertical sleeve gastrectomy (VSG), we performed genome-wide profiling of chromatin accessibility and gene expression in C57BL/6J wild-type male mice after VSG surgery and compared these profiles to mice with a sham surgery
Though the overall weight of VSG mice was greater than Control mice, lipid accumulation and triglyceride levels in liver were reversed by VSG
Summary
A dramatic increase in the prevalence of obesity over the last few decades has led to a worldwide epidemic. We demonstrate that diet-induced changes in gene expression and chromatin accessibility can be reversed by VSG. To understand the regulatory changes induced by VSG, we profiled genome-wide chromatin accessibility in livers of mice that underwent VSG or Sham procedures, as well as Control mice (Fig. 1A).
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