2. Academic Validation
  3. Intestinal MYC modulates obesity-related metabolic dysfunction

Intestinal MYC modulates obesity-related metabolic dysfunction

  • Nat Metab. 2021 Jul;3(7):923-939. doi: 10.1038/s42255-021-00421-8.
Yuhong Luo 1,  Shoumei Yang 1,  Xuan Wu 2 3,  Shogo Takahashi 1 4,  Lulu Sun 1,  Jie Cai 1,  Kristopher W Krausz 1,  Xiaozhen Guo 5,  Henrique B Dias 1,  Oksana Gavrilova 6,  Cen Xie 1 5,  Changtao Jiang 7,  Weiwei Liu 8 9,  Frank J Gonzalez 10
Affiliations

Affiliations

  • 1 Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • 2 Department of Laboratory Medicine and Central Laboratory, Shanghai Tenth People's Hospital, Tongji University, Shanghai, P.R. China.
  • 3 Department of Laboratory Medicine, Shanghai Skin Disease Hospital, Tongji University, Shanghai, P.R. China.
  • 4 Department of Biochemistry and Molecular & Cellular Biology, Georgetown University, Washington, DC, USA.
  • 5 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P.R. China.
  • 6 Mouse Metabolism Core Laboratory, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
  • 7 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, P.R. China.
  • 8 Department of Laboratory Medicine and Central Laboratory, Shanghai Tenth People's Hospital, Tongji University, Shanghai, P.R. China. [email protected].
  • 9 Department of Laboratory Medicine, Shanghai Skin Disease Hospital, Tongji University, Shanghai, P.R. China. [email protected].
  • 10 Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. [email protected].
PMID: 34211180 DOI: 10.1038/s42255-021-00421-8
Abstract

MYC is a transcription factor with broad biological functions, notably in the control of cell proliferation. Here, we show that intestinal MYC regulates systemic metabolism. We find that MYC expression is increased in ileum biopsies from individuals with obesity and positively correlates with body mass index. Intestine-specific reduction of MYC in mice improves high-fat-diet-induced obesity, Insulin resistance, hepatic steatosis and steatohepatitis. Mechanistically, reduced expression of MYC in the intestine promotes glucagon-like peptide-1 (GLP-1) production and secretion. Moreover, we identify Cers4, encoding ceramide synthase 4, catalysing de novo ceramide synthesis, as a MYC target gene. Finally, we show that administration of the MYC inhibitor 10058-F4 has beneficial effects on high-fat-diet-induced metabolic disorders, and is accompanied by increased GLP-1 and reduced ceramide levels in serum. This study positions intestinal MYC as a putative drug target against metabolic diseases, including non-alcoholic fatty liver disease and non-alcoholic steatohepatitis.

Figures
Products