Inhibiting menin attenuates high-fat diet–induced weight gain by limiting intestinal lipid absorption in mice
Xiaoru Cao, Pingping Zhou, Haiyue Meng, Zhitao Guo, Yan Cao, Chenghao Wang, Lulu Liu, Yinghao Guo, Yue Wang, Guoshun Xin, Dabin Liu, Feng Geng, Jian Ma
Xiaoru Cao, Pingping Zhou, Haiyue Meng, Zhitao Guo, Yan Cao, Chenghao Wang, Lulu Liu, Yinghao Guo, Yue Wang, Guoshun Xin, Dabin Liu, Feng Geng, Jian Ma
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Research Article Gastroenterology Metabolism

Inhibiting menin attenuates high-fat diet–induced weight gain by limiting intestinal lipid absorption in mice

Abstract

Intestinal lipid metabolism is essential for systemic energy homeostasis, and its modulation is emerging as a therapeutic strategy for obesity. Menin, encoded by the MEN1 gene, is a scaffold protein that regulates chromatin remodeling and gene expression and is abundantly expressed in intestinal epithelial cells (IECs), but its metabolic role remains underexplored. Here, we generated IEC-specific Men1-knockout mice and found that Men1 deficiency protected against high-fat diet–induced obesity, accompanied by elevated carboxylesterase 1 (CES1) expression in IECs. Increased CES1 promoted triglyceride (TG) hydrolysis and reduced intracellular TG storage, thereby limiting the lipid substrate pool required for ApoB48-dependent chylomicron assembly. Although lipid hydrolysis was enhanced, steady-state free fatty acid levels were not increased; instead, Men1 deficiency activated fatty acid β-oxidation programs and increased etomoxir-sensitive fatty acid–dependent mitochondrial respiration, supporting enhanced fatty acid catabolism. Mechanistically, menin recruited histone deacetylase 1 and interacted with the nuclear receptor liver X receptor-β to suppress Ces1g transcription, thereby sustaining efficient intestinal lipid absorption. Pharmacological inhibition of menin with MI-463 recapitulated the metabolic effects of inducible Men1 deletion. In a human gut organoid-on-chip system, MI-463 dose-dependently increased CES1 expression and markedly reduced lipid accumulation. Collectively, our findings identify menin as a regulator of intestinal lipid metabolism and suggest menin inhibition as a potential therapeutic strategy for obesity-related metabolic disorders.

Authors

Xiaoru Cao, Pingping Zhou, Haiyue Meng, Zhitao Guo, Yan Cao, Chenghao Wang, Lulu Liu, Yinghao Guo, Yue Wang, Guoshun Xin, Dabin Liu, Feng Geng, Jian Ma

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Figure 4

Men1 deficiency enhances FAO capacity in IECs.

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Men1 deficiency enhances FAO capacity in IECs. (A) Gene set enrichment ...
(A) Gene set enrichment analysis (GSEA) of IEC transcriptomes from Men1fl/fl and Men1ΔIEC mice, showing enrichment of mitochondrial FAO, PPARα-regulated lipid metabolism, and peroxisomal lipid metabolism pathways. (B) RT-qPCR analysis of FAO-related genes in IECs isolated from Men1fl/fl and Men1ΔIEC mice. (C) WB analysis of menin and CPT1A protein expression in IECs from Men1fl/fl and Men1ΔIEC mice. (D) Oxygen consumption rate (OCR) in primary IECs. (E) FAO activity in primary IECs. (F) CS activity in primary IECs. (G and H) RT-qPCR analysis of Ces1g (G) and Cpt1a (H) mRNA levels in MODE-K cells transduced with control vector or 2 independent Men1 shRNAs under BSA control or oleic acid treatment conditions. (I and J) Seahorse XF palmitate oxidation stress assay in control MODE-K cells treated with BSA or palmitate in the presence or absence of etomoxir (I), and quantification of basal and maximal OCR (J). FCCP, carbonyl cyanide p-trifluoromethoxyphenylhydrazone. (K and L) Seahorse XF palmitate oxidation stress assay in vector control and Men1-knockdown MODE-K cells supplied with palmitate in the presence or absence of etomoxir (K) and quantification of basal and maximal OCR (L). For B and C, n = 3 mice per group; for D–F, n = 6 mice per group; for G–L, n = 3. All data are presented as mean ± SD. Statistical significance was assessed by 2-way ANOVA for panels B, G, H, J, and L and by unpaired 2-tailed Student’s t test for panels D–F. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.