Abstract 1020: Hepatic Stearoyl-CoA Desaturase-1 Deficiency does not Protect Mice from Diet-Induced Obesity and Insulin Resistance
The metabolic syndrome comprises many pathologies including obesity, insulin resistance, and dyslipidemia, and also increases the risk for both type 2 diabetes and cardiovascular disease. A contributing factor to the metabolic syndrome is the accumulation of excess lipid in insulin-sensitive tissues such as liver, adipose, and muscle. Stearoyl-CoA desaturase 1 (SCD1) is a key regulator of lipogenesis, which catalyzes the synthesis of monounsaturated fatty acids from saturated fatty acid precursors. Mice with a global deletion of SCD1 (SCD1−/−) have previously been shown to be protected from high-fat diet-induced obesity, insulin resistance, and tissue lipid accumulation. Recently, antisense oligonucleotide inhibition of SCD1 has also been shown to protect mice from diet-induced obesity and hepatic steatosis. These metabolic outcomes are difficult to interpret due to potential effects of SCD1 deficiency in many tissues. To more explicitly elucidate the role of liver SCD1 in lipid metabolism, we generated mice with a liver-specific ablation of SCD1 (LSCD1) by crossing conditionally null SCD1flox/flox mice with albumin-Cre mice. LSCD1 mice are viable, fertile, and do not display the skin abnormalities observed in global SCD1−/− mice. Liver SCD protein and activity were decreased by greater than 99% in LSCD1 mice relative to wild type and SCD1flox/flox controls without affecting SCD activity in the adipose tissue, heart, or kidney. Unlike global SCD1−/− mice, LSCD1 mice fed a high-fat diet (Research Diets RD12492) developed obesity, increased fat pad mass, and hepatic steatosis comparable to SCD1flox/flox controls fed the high-fat diet. Glucose tolerance tests clearly indicate that both LSCD1 and SCD1flox/flox mice fed the high-fat diet developed whole body insulin resistance relative to chow-fed controls. Additionally, global SCD1−/− mice are lean despite severe hyperphagia relative to the obese LSCD1 mice. Together, these results indicate that hepatic SCD1 deficiency alone is insufficient to protect mice from high-fat diet-induced obesity and insulin resistance, suggesting that the metabolic changes in the global SCD1−/−mouse also involve loss of SCD activity in extrahepatic tissues.