Tissue inhibitor of matrix metalloproteinase 1 (TIMP1) controls adipogenesis in obesity in mice and in humans

• Published in: Diabetologia 2011-06, Vol.54 (6), p.1468-1479
• Main Authors: Meissburger, B., Stachorski, L., Röder, E., Rudofsky, G., Wolfrum, C.
• Format: Article
• Language: English
• Subjects: Adipocytes; Adipocytes - drug effects; Adipocytes - pathology; Adipogenesis - physiology; Animals; Biological and medical sciences; Body fat; Cell Differentiation - drug effects; Cells, Cultured; Diabetes. Impaired glucose tolerance; Dietary Fats - pharmacology; Disease Models, Animal; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Enzymes; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Extracellular matrix; Fatty Acids, Nonesterified - metabolism; Glucose; Human Physiology; Humans; Insulin resistance; Insulin Resistance - physiology; Internal Medicine; Lipid Metabolism - drug effects; Lipid Metabolism - physiology; Lipids; Male; Medical sciences; Medicine; Medicine & Public Health; Metabolic Diseases; Metabolism; Mice; Mice, Inbred C57BL; Obesity; Obesity - metabolism; Obesity - pathology; Obesity - physiopathology; Tissue Inhibitor of Metalloproteinase-1 - pharmacology; Tissue Inhibitor of Metalloproteinase-1 - physiology; Triglycerides - metabolism
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-011-2093-9

Aims/hypothesis Extracellular matrix reorganisation is a crucial step of adipocyte differentiation and is controlled by the matrix metalloproteinase–tissue inhibitor of matrix metalloproteinase (TIMP) enzyme system. We therefore sought to define the role of TIMP1 in adipogenesis and to elucidate whether upregulation of TIMP1 in obesity has direct effects on adipocyte formation. Methods TIMP1 protein levels and mRNA were measured in lean and obese mice with a focus on levels in adipose tissue. We also analysed the effect of recombinant murine TIMP1 on adipogenesis, adipocyte size and metabolic control in vitro and in vivo. Results TIMP1 levels were increased in the serum and adipose tissue of obese mouse models. Recombinant murine TIMP1 inhibited adipocyte differentiation in 3T3-L1 as well as in subcutaneous primary pre-adipocytes. Conversely, neutralising TIMP1 with a specific antibody enhanced adipocyte differentiation. In vivo, injection of recombinant TIMP1 in mice challenged with a high-fat diet led to enlarged adipocytes. TIMP1-treated mice developed an impaired metabolic profile with increased circulating NEFA levels, hepatic triacylglycerol accumulation and accelerated insulin resistance. Altered glucose clearance in TIMP1-injected mice was due to changes in adipose tissue glucose uptake, whereas muscle glucose clearance remained unaffected. Conclusions/interpretation TIMP1 is a negative regulator of adipogenesis. In vivo, TIMP1 leads to enlarged adipocytes in the state of overnutrition. This might contribute to the detrimental metabolic consequences seen in TIMP1-injected mice, such as systemic fatty acid overload, hepatic lipid accumulation and insulin resistance.