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Deletion of intestinal Hdac3 remodels the lipidome of enterocytes and protects mice from diet-induced obesity.

ABSTRACT: Histone deacetylase 3 (Hdac3) regulates the expression of lipid metabolism genes in multiple tissues, however its role in regulating lipid metabolism in the intestinal epithelium is unknown. Here we demonstrate that intestine-specific deletion of Hdac3 (Hdac3^IKO) protects mice from diet induced obesity. Intestinal epithelial cells (IECs) from Hdac3^IKO mice display co-ordinate induction of genes and proteins involved in mitochondrial and peroxisomal β-oxidation, have an increased rate of fatty acid oxidation, and undergo marked remodelling of their lipidome, particularly a reduction in long chain triglycerides. Many HDAC3-regulated fatty oxidation genes are transcriptional targets of the PPAR family of nuclear receptors, Hdac3 deletion enhances their induction by PPAR-agonists, and pharmacological HDAC3 inhibition induces their expression in enterocytes. These findings establish a central role for HDAC3 in co-ordinating PPAR-regulated lipid oxidation in the intestinal epithelium, and identify intestinal HDAC3 as a potential therapeutic target for preventing obesity and related diseases.

SUBMITTER: Davalos-Salas M

PROVIDER: S-EPMC6876593 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Deletion of intestinal Hdac3 remodels the lipidome of enterocytes and protects mice from diet-induced obesity.

Dávalos-Salas Mercedes M Montgomery Magdalene K MK Reehorst Camilla M CM Nightingale Rebecca R Ng Irvin I Anderton Holly H Al-Obaidi Sheren S Lesmana Analia A Scott Cameron M CM Ioannidis Paul P Kalra Hina H Keerthikumar Shivakumar S Tögel Lars L Rigopoulos Angela A Gong Sylvia J SJ Williams David S DS Yoganantharaja Prusoth P Bell-Anderson Kim K Mathivanan Suresh S Gibert Yann Y Hiebert Scott S Scott Andrew M AM Watt Matthew J MJ Mariadason John M JM

Nature communications 20191122 1

Histone deacetylase 3 (Hdac3) regulates the expression of lipid metabolism genes in multiple tissues, however its role in regulating lipid metabolism in the intestinal epithelium is unknown. Here we demonstrate that intestine-specific deletion of Hdac3 (Hdac3<sup>IKO</sup>) protects mice from diet induced obesity. Intestinal epithelial cells (IECs) from Hdac3<sup>IKO</sup> mice display co-ordinate induction of genes and proteins involved in mitochondrial and peroxisomal β-oxidation, have an incr ...[more]

PMID: 31757939

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Project description:BACKGROUND & AIMS:Intestinal microbiota modulate metabolism and associate closely with epithelial cells in the intestine. In intestinal epithelial cells (IECs), histone deacetylase 3 (HDAC3) integrates microbiota-derived signals to control intestinal homeostasis. We investigated whether HDAC3 in IECs regulates metabolism and the development of obesity in mice. METHODS:Adult C57BL/6 (control) mice and mice with constitutive or inducible IEC-specific disruption of Hdac3 (HDAC3ΔIEC mice) were placed on a standard chow or high-fat diet (HFD, 60% kcal from fat). We measured body composition, weight, glucose tolerance, and energy expenditure. IECs were isolated from small intestine and gene expression, and lipid levels were analyzed. HDAC3 levels were determined in 43 pediatric patient ileal biopsy samples and compared with body weight. RESULTS:Control mice fed an HFD gained weight, became obese, and had reduced glucose tolerance with increased serum insulin, whereas HFD-fed HDAC3ΔIEC mice did not develop obesity. Serum levels of triglycerides were reduced in HDAC3ΔIEC mice, and these mice had less liver fat and smaller adipocytes, compared with HFD-fed control mice. HDAC3ΔIEC mice had similar food intake and activity as control mice, but higher energy expenditure because of increased catabolism. IECs from HDAC3ΔIEC mice had altered expression levels of genes that regulate metabolism in response to the microbiota (such as Chka, Mttp, Apoa1, and Pck1) and accumulated triglycerides compared with IECs from control mice. The microbiota-derived short-chain fatty acid butyrate was decreased in obese mice. Butyrate significantly reduced the activity of HDAC3 and increased Pck1 expression in only control IECs. Administration of butyrate to control mice with diet-induced obesity, but not HDAC3ΔIEC mice, led to significant weight loss. Disruption of HDAC3 in IECs of mice after they became obese led to weight loss and improved metabolic profile. Levels of HDAC3 in intestinal biopsy samples correlated with patient weight. CONCLUSIONS:We found that epithelial HDAC3 promotes development of diet-induced obesity in studies of mice and that butyrate reduces activity of HDAC3 in IECs to prevent diet-induced obesity. This pathway might be manipulated to prevent or reduce obesity-associated disease.

Dataset Information

Deletion of intestinal Hdac3 remodels the lipidome of enterocytes and protects mice from diet-induced obesity.

Publications

Deletion of intestinal Hdac3 remodels the lipidome of enterocytes and protects mice from diet-induced obesity.

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