Disruption of Epithelial HDAC3 in Intestine Prevents Diet-Induced Obesity in Mice
Autor: | Patrick Tso, Theresa Alenghat, Patrick Lee, Vivienne Woo, Yael Haberman, Jessica Moncivaiz, Jordan Whitt, Lee A. Denson |
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Rok vydání: | 2018 |
Předmět: |
Male
0301 basic medicine medicine.medical_specialty Biopsy Transgene Mice Transgenic Butyrate Biology Diet High-Fat digestive system Histone Deacetylases Article Mice 03 medical and health sciences 0302 clinical medicine Insulin resistance Ileum Weight loss PCK1 Internal medicine medicine Animals Humans Obesity Intestinal Mucosa Child Hepatology Catabolism Body Weight Gastroenterology Epithelial Cells HDAC3 medicine.disease Small intestine Gastrointestinal Microbiome Mice Inbred C57BL Disease Models Animal 030104 developmental biology medicine.anatomical_structure Endocrinology 030220 oncology & carcinogenesis Female Insulin Resistance medicine.symptom Energy Metabolism |
Zdroj: | Gastroenterology. 155:501-513 |
ISSN: | 0016-5085 |
Popis: | 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. |
Databáze: | OpenAIRE |
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