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Intestinal MYC modulates obesity-related metabolic dysfunction
Yuhong Luo1, Shoumei Yang1, Xuan Wu2,3
1Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Nature Metabolism
|July 2, 2021
Summary
Intestinal MYC (myelocytomatosis oncogene) drives obesity and metabolic dysfunction. Reducing intestinal MYC improves obesity, insulin resistance, and fatty liver disease by increasing GLP-1 and lowering ceramides.
Area of Science:
- Metabolic regulation
- Molecular biology
- Obesity research
Background:
- MYC (myelocytomatosis oncogene) is a key regulator of cell proliferation.
- Its role in systemic metabolism, particularly in the intestine, is not fully understood.
- Obesity and associated metabolic disorders are significant global health concerns.
Purpose of the Study:
- To investigate the role of intestinal MYC in regulating systemic metabolism.
- To explore MYC as a potential therapeutic target for metabolic diseases.
- To elucidate the molecular mechanisms linking intestinal MYC to metabolic dysfunction.
Main Methods:
- Analysis of human ileum biopsies for MYC expression in relation to body mass index.
- Generation of intestine-specific MYC-deficient mice to study effects on diet-induced obesity and metabolic parameters.
- Measurement of glucagon-like peptide-1 (GLP-1) production and secretion.
- Identification of MYC target genes using molecular biology techniques.
- Administration of a MYC inhibitor (10058-F4) in mouse models of metabolic disease.
Main Results:
- Increased MYC expression in ileum biopsies from individuals with obesity, correlating positively with body mass index.
- Intestine-specific MYC reduction in mice ameliorated high-fat-diet-induced obesity, insulin resistance, hepatic steatosis, and steatohepatitis.
- Reduced intestinal MYC expression led to increased GLP-1 production and secretion.
- Ceramide synthase 4 (Cers4) was identified as a direct MYC target gene.
- MYC inhibition with 10058-F4 improved metabolic disorders, increasing GLP-1 and decreasing serum ceramide levels.
Conclusions:
- Intestinal MYC plays a critical role in regulating systemic metabolism and promoting obesity and related disorders.
- Targeting intestinal MYC, for example, through pharmacological inhibition, offers a promising therapeutic strategy for metabolic diseases.
- The mechanisms involve modulation of GLP-1 secretion and regulation of ceramide synthesis via Cers4.
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