biostudies-literatureLuo YIntramural NIH HHS923-939https://www.ebi.ac.uk/biostudies/studies/S-EPMC9944847biostudies-literatureUnknown3(7)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-fNature metabolismIntestinal MYC modulates obesity-related metabolic dysfunction.PMC9944847Z01 BC005562ZIA BC005562Dias HBGuo XCai JKrausz KWGavrilova OLiu WSun LTakahashi SLuo YJiang CGonzalez FJYang SXie CWu XfalseIntestinal MYC modulates obesity-related metabolic dysfunction.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-f2021-01-01T00:00:00Z2021 Jul2025-04-04T19:00:36.414Z2025-04-04T19:00:36.414ZS-EPMC99448473421118010.1038/s42255-021-00421-8