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Disruption of Epithelial HDAC3 in Intestine Prevents Diet-Induced Obesity in
Whitt J, Woo V, Lee P, Moncivaiz J, Haberman Y, Denson L, Tso P, Alenghat T
Submitted Externally on 8/20/2018
Volume : Pages
155 : 501 - 513
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., Adult C57BL/6 (control) mice
and mice with constitutive or inducible IEC-specific disruption of Hdac3
(HDAC3?IEC 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., Control mice fed an HFD
gained weight, became obese, and had reduced glucose tolerance with increased
serum insulin, whereas HFD-fed HDAC3?IEC mice did not develop obesity. Serum
levels of triglycerides were reduced in HDAC3?IEC mice, and these mice had less
liver fat and smaller adipocytes, compared with HFD-fed control mice. HDAC3?IEC
mice had similar food intake and activity as control mice, but higher energy
expenditure because of increased catabolism. IECs from HDAC3?IEC 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
HDAC3?IEC 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., 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
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