Abstract
BackgroundPlasma levels of tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) are elevated in obesity and obesity-related disorders, such as steatosis, but the metabolic role of TIMP-1 is unclear. Here we investigated how the presence or absence of TIMP-1 affected the development of diet-induced glucose intolerance and hepatic steatosis using the Timp1 null mice.Methods Timp1 knockout (TKO) and wild type (TWT) mice were fed chow, high-fat diet (HFD) or intermediate fat and sucrose diet (IFSD). We determined body weight, body composition, lipid content of the liver, energy intake, energy expenditure, oral glucose tolerance, as well as insulin tolerance. In addition, the histology of liver and adipose tissues was examined and expression of selected genes involved in lipid metabolism and inflammation in liver and adipose tissues was determined by RT-qPCR.ResultsTKO mice gained less weight and had lower energy efficiency than TWT mice when fed HFD, but not when fed chow or IFSD. Importantly, TKO mice were protected from development of HFD- as well as IFSD-induced glucose intolerance, hepatic steatosis, and altered expression of genes involved in hepatic lipid metabolism and inflammation.ConclusionCollectively, our results indicate that TIMP-1 contributes to the development of diet-induced hepatic steatosis and glucose intolerance and may be a potential therapeutic target.
Highlights
Obesity is associated with low-grade inflammation and increases the risk of chronic diseases such as type 2 diabetes, coronary heart disease, hypertension, dyslipidemia and non-alcoholic steatohepatitis (NASH) predisposing to premature death
Timp1 knockout (TKO) mice were protected from development of high-fat diet (HFD)- as well as intermediate fat and sucrose diet (IFSD)-induced glucose intolerance, hepatic steatosis, and altered expression of genes involved in hepatic lipid metabolism and inflammation
Our results indicate that tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) contributes to the development of diet-induced hepatic steatosis and glucose intolerance and may be a potential therapeutic target
Summary
Obesity is associated with low-grade inflammation and increases the risk of chronic diseases such as type 2 diabetes, coronary heart disease, hypertension, dyslipidemia and non-alcoholic steatohepatitis (NASH) predisposing to premature death. TIMP-1 deficiency has been reported to increase body weight (BW) and fat mass in female mice fed a low fat chow diet [16]. This was suggested to be caused by hyperphagia elicited via hypothalamic pathways and reduced thermogenesis, but peripheral actions promoting adipogenesis may contribute. This may be gender specific, since male TIMP-1 deficient mice fed a highfat diet (HFD) were reported to have decreased BW and fat mass [17]. We investigated how the presence or absence of TIMP-1 affected the development of diet-induced glucose intolerance and hepatic steatosis using the Timp null mice
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