Dataset Information

Intestine-targeted DGAT1 inhibition improves obesity and insulin resistance without skin aberrations in mice.

ABSTRACT:

Objective

Diacylglycerol O-acyltransferase 1 (DGAT1) catalyzes the final committed step in triglyceride biosynthesis. DGAT1 null mice are known to be resistant to diet-induced obesity, and more insulin sensitive relative to the wild-type; however, the mice exhibit abnormalities in the skin. This work determined whether the intestine-targeted DGAT1 inhibitor could improve obesity and insulin resistance without skin aberrations in mice.

Design and methods

We synthesized 2 DGAT1 inhibitors: Compound A, described in the patent application from the Japan Tobacco, and Compound B (A-922500), reported by Abbott Laboratories. Both compounds were evaluated for inhibitory activities against DGAT1 enzymes and effects on the skin in mice in vivo. Compound B was further investigated for effects on obesity and insulin resistance in diet-induced-obese (DIO) mice.

Results

The 2 compounds comparably inhibited the DGAT1 enzyme activity and the cellular triglyceride synthesis in vitro, while they showed different distribution patterns in mice in vivo. Compound A, which distributed systemically, caused skin aberrations, while Compound B, which preferentially distributed to the intestine, improved obesity and insulin resistance without skin aberrations in DIO mice.

Conclusions

Our results suggest that the intestine is the key tissue in which DGAT1 plays a role in promoting obesity and insulin resistance.

SUBMITTER: Tsuda N

PROVIDER: S-EPMC4236014 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Publications

Intestine-targeted DGAT1 inhibition improves obesity and insulin resistance without skin aberrations in mice.

Tsuda Naoto N Kumadaki Shin S Higashi Chika C Ozawa Makoto M Shinozaki Mikihiko M Kato Yutaka Y Hoshida Koutarou K Kikuchi Satomi S Nakano Yoshihisa Y Ogawa Yoshihiro Y Furusako Shoji S

PloS one 20141118 11

<h4>Objective</h4>Diacylglycerol O-acyltransferase 1 (DGAT1) catalyzes the final committed step in triglyceride biosynthesis. DGAT1 null mice are known to be resistant to diet-induced obesity, and more insulin sensitive relative to the wild-type; however, the mice exhibit abnormalities in the skin. This work determined whether the intestine-targeted DGAT1 inhibitor could improve obesity and insulin resistance without skin aberrations in mice.<h4>Design and methods</h4>We synthesized 2 DGAT1 inhi ...[more]

PMID: 25405858

Similar Datasets

Project description:Background and aimsAcyl-CoA:diacylglycerol acyltransferase 1 (DGAT1) is the rate-limiting enzyme catalyzing the final step of triglyceride synthesis by esterifying a diglyceride with a fatty acid. We have previously shown that apolipoprotein E-knockout (ApoE-/-) mice lacking Dgat1 have reduced intestinal cholesterol absorption and potentiated macrophage cholesterol efflux, and consequently, exhibit attenuated atherogenesis. However, hematopoietic Dgat1 deficiency lacked beneficial effects on atherosclerosis. Due to our recent results on the critical role of intestinal Dgat1 in murine cholesterol homeostasis, we delineated whether intestinal Dgat1 deficiency regulates atherogenesis in mice.MethodsWe generated intestine-specific Dgat1-/- mice on the ApoE-/- background (iDgat1-/-ApoE-/-) and determined cholesterol homeostasis and atherosclerosis development.ResultsWhen fed a Western-type diet, iDgat1-/-ApoE-/- mice exhibited a substantial decrease in fasting plasma cholesterol content in ApoB-containing lipoproteins. Although lipid absorption was delayed, iDgat1-/-ApoE-/- mice had reduced acute and fractional cholesterol absorption coupled with an elevated fecal caloric loss. In line, increased appearance of i.v. administered [³H]cholesterol in duodena and stool of iDgat1-/-ApoE-/- animals suggested potentiated cholesterol elimination. Atherosclerotic lesions were markedly smaller with beneficial alterations in plaque composition as evidenced by reduced macrophage infiltration and necrotic core size despite unaltered collagen content, indicating improved plaque stability.ConclusionsDisruption of Dgat1 activity solely in the small intestine of ApoE-/- mice strongly decreased plasma cholesterol levels by abrogating the assimilation of dietary cholesterol, partly by reduced absorption and increased excretion. Consequently, the reduced cholesterol burden significantly attenuated atherogenesis and improved the lesion phenotype in iDgat1-/-ApoE-/- mice.

Dataset Information

Intestine-targeted DGAT1 inhibition improves obesity and insulin resistance without skin aberrations in mice.

Objective

Design and methods

Results

Conclusions

Publications

Intestine-targeted DGAT1 inhibition improves obesity and insulin resistance without skin aberrations in mice.

Similar Datasets

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