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

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.

Extracellular Matrix Remodeling of Adipose Tissue in Obesity and Metabolic Diseases

“…Specifically, a TIMP-3 deletion in mice has pointed to cause hepatic steatosis and WAT inflammation [78] while an overexpression seemed to protect from them [79]. Relating to TIMP-4, recent studies have evidenced the pathogenic effect of TIMP-4 deregulation in IR in different rodent models [80,81].…”

Le Carbone prevents liver damage in non-alcoholic steatohepatitis-hepatocellular carcinoma mouse model via AMPKα-SIRT1 signaling pathway activation

“…There are some reports that heterozygous PPARγ-deficient mice are protected from HFD, aging-induced adipocyte hypertrophy, obesity, and insulin resistance [ 42 , 43 ]. Deletion of TIMP4 improves the obesity in HFD-induced experimental mice through impairment of lipid absorption [ 44 ]. Interestingly, our present study showed that the hepatic protein expression of PPARγ, ADRP, and TIMP4, were markedly elevated in the NASH mice group, but significantly reduced in the livers of LC treated mice ( Fig.…”

Association of TIMP4 gene variants with steroid-induced osteonecrosis of the femoral head in the population of northern China

“…(2017) reported the association of TIMP4 rs3755724 with predictors of ≥5% weight loss. Furthermore, in a study of obesity, TIMP4 was associated with high fat diet-induced obesity and may act through the regulation of lipid absorption (Sakamuri et al., 2017). There is a growing awareness that steroid hormones may cause ONFH through disruptions to lipid metabolism.…”