Absence of Tissue Inhibitor of Metalloproteinase-4 (TIMP4) ameliorates high fat diet-induced obesity in mice due to defective lipid absorption

Siva S V P Sakamuri,Wesam Bahitham,Russell Watts,Zamaneh Kassiri,Xiuhua Wang,Abhijit Takawale,Richard Lehner,Samuel Hernandez-Anzaldo,Carlos Fernandez-Patron

doi:10.1038/s41598-017-05951-4

Siva S V P Sakamuri, Wesam Bahitham + Show 7 more

Open Access

https://doi.org/10.1038/s41598-017-05951-4

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Journal: Scientific Reports	Publication Date: Jul 24, 2017
Citations: 29	License type: open-access

Affiliation: University of Alberta

Abstract

Tissue inhibitor of metalloproteases (TIMPs) are inhibitors of matrix metalloproteinases (MMPs) that regulate tissue extracellular matrix (ECM) turnover. TIMP4 is highly expressed in adipose tissue, its levels are further elevated following high-fat diet, but its role in obesity is unknown. Eight-week old wild-type (WT) and Timp4-knockout (Timp4−/−) mice received chow or high fat diet (HFD) for twelve weeks. Timp4−/− mice exhibited a higher food intake but lower body fat gain. Adipose tissue of Timp4−/–-HFD mice showed reduced hypertrophy and fibrosis compared to WT-HFD mice. Timp4−/–-HFD mice were also protected from HFD-induced liver and skeletal muscle triglyceride accumulation and dyslipidemia. Timp4−/−-HFD mice exhibited reduced basic metabolic rate and energy expenditure, but increased respiratory exchange ratio. Increased free fatty acid excretion was detected in Timp4−/−-HFD compared to WT-HFD mice. CD36 protein, the major fatty acid transporter in the small intestine, increased with HFD in WT but not in Timp4−/− mice, despite a similar rise in Cd36 mRNA in both genotypes. Consistently, HFD increased enterocyte lipid content only in WT but not in Timp4−/− mice. Our study reveals that absence of TIMP4 can impair lipid absorption and the high fat diet-induced obesity in mice possibly by regulating the proteolytic processing of CD36 protein in the intestinal enterocytes.

Highlights

IntroductionCD36 protein, the major fatty acid transporter in the small intestine, increased with high fat diet (HFD) in WT but not in Timp4−/− mice, despite a similar rise in Cd36 mRNA in both genotypes
Consistent with the leaner appearance of Timp4−/−-high fat diet (HFD) mice (Fig. 2B), the size of the visceral fat pads were significantly reduced in these mice compared to WT-HFD (Fig. 2C,D), but no difference was observed in retroperitoneal (Fig. 2E) or inguinal fat pad size (Fig. 2F, Supplementary Figure 3) between the two HFD groups
HFD-fed Timp4−/− mice exhibited a significantly lower body fat content (Fig. 2Gi) which comprised a lower percentage of total body weight (Fig. 2Gii), but a higher lean mass content (Fig. 2Hi) that comprised a higher percentage of the total body weight (Fig. 2Hii) compared to parallel WT groups (Fig. 2G)

Summary

Introduction

CD36 protein, the major fatty acid transporter in the small intestine, increased with HFD in WT but not in Timp4−/− mice, despite a similar rise in Cd36 mRNA in both genotypes. Obesity is a pathophysiological state involving excess accumulation of triglycerides in the adipose tissue, thereby increasing the risk of developing fatty liver, dyslipidemia, insulin resistance and hypertension[1,2,3,4]. Visceral obesity associated with these complications constitute metabolic syndrome which in turn increases the risk of type II diabetes and cardiovascular diseases[5]. Excess storage of TG in adipose tissue during obesity alters its metabolic and secretive functions leading to development of obesity-associated comorbidities[7]. Provides structural support for the tissues as well as regulating cell functions by activating various signaling mechanisms directly or indirectly by sequestering signaling molecules[9]

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