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.

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With advances in technology, the impact of natural antioxidants on vascular cell regeneration is attracting enormous attention as many current studies are now exploring the clinical potential of antioxidants in regenerative medicine. Natural antioxidants are an important step for improving future treatment and prevention of various diseases such as cardiovascular, cancer, neurodegenerative, and diabetes. The use of natural antioxidants which have effects on several types of stem cells with the potential to differentiate into functional endothelium and smooth muscle cells (known as vascular progenitors) for vascular regeneration might override pharmaceutical and surgical treatments. The natural antioxidant systems comprise of several components present in fruits, vegetables, legumes, medicinal plants, and other animal-derived products that interact with reactive free radicals such as oxygen and nitrogen species to neutralize their oxidative damaging effects on vascular cells. Neutralization by antioxidants involves the breaking down of the oxidative cascade chain reactions in the cell membranes in order to fine-tune the free radical levels. The effect of natural antioxidants on vascular regeneration includes restoration or establishment of new vascular structures and functions. In this review, we highlight the significant effects of natural antioxidants on modulating vascular cells to regenerate vessels, as well as possible mechanisms of action and the potential therapeutic benefits on health. The role of antioxidants in regenerating vessels may be critical for the future of regenerative medicine in terms of the maintenance of the normal functioning of vessels and the prevention of multiple vascular diseases.