Book Description
Increased prevalence of overweight and obesity represents a public health crisis, making people more susceptible for chronic metabolic diseases such as type 2 diabetes and non-alcoholic fatty liver disease. Increased consumption of carbohydrate promotes de novo lipogenesis and increases fat accumulation in adipose tissues. Stearoyl-CoA desaturase 1 (SCD1) is a critical regulator of lipogenesis, desaturating saturated fatty acids (SFA), mainly palmitate and stearate, into monounsaturated fatty acids (MUFA), palmitoleate and oleate, respectively. Studies using SCD1 deficient mouse models demonstrated a significant reduction of hepatic de novo lipogenesis, decreased body weight, enhanced glucose utilization in peripheral tissues and increased insulin sensitivity. The overall aim of the present work was to provide more insight into the contribution of liver derived MUFA in regulating systemic glucose metabolism. Our results reveal that hepatic SCD1 deficiency enhances glucose utilization in the liver and adipose tissue through upregulated GLUT1 and GLUT4, respectively. Increased glucose uptake correlated with induced hepatic expression and plasma levels of fibroblast growth factor 21 (FGF21). Feeding triolein, but not tristearin, supplemented HCD diet reduces elevated plasma FGF21 and restores blood glucose levels, suggesting that hepatic oleate regulates systemic glucose metabolism either directly or through modulating hepatic FGF21. In addition, our findings indicate that SCD1 deficiency induces ER stress through mTORC1 activation. Rapamycin treatment of LKO mice reduces HCD-induced expression of the co-transcription factor PGC-1[alpha] and reduces ER stress. Moreover, dietary or endogenously synthesized oleate suppresses mTORC1 activation and reduces ER stress in the liver of LKO and SCD1 GKO mice, respectively. It could be concluded from these results that active mTORC1 induces ER stress through increasing PGC-1[alpha] in response to SCD1 deficiency. Overall, this work contributes to our understanding of the role of hepatic oleate in regulation of systemic metabolism and hepatic signaling pathways such as mTORC1.