Abstract
Increased carbohydrate consumption increases hepatic de novo lipogenesis, which has been linked to the development of chronic metabolic diseases, including obesity, hepatic steatosis, and insulin resistance. Stearoyl CoA desaturase 1 (SCD1) is a critical lipogenic enzyme that catalyzes the synthesis of two monounsaturated fatty acids, oleate and palmitoleate, from the saturated fatty acids stearate and palmitate, respectively. SCD1-deficient mouse models are protected against diet-induced adiposity, hepatic steatosis, and hyperglycemia. However, the mechanism of this protection by SCD1 deficiency is unclear. Using liver-specific SCD1 knockout (LKO) mice fed a high-carbohydrate, low-fat diet, we show that hepatic SCD1 deficiency increases systemic glucose uptake. Hepatic SCD1 deficiency enhanced glucose transporter type 1 (GLUT1) expression in the liver and also up-regulated GLUT4 and adiponectin expression in adipose tissue. The enhanced glucose uptake correlated with increased liver expression and elevated plasma levels of fibroblast growth factor 21 (FGF21), a hepatokine known to increase systemic insulin sensitivity and regulate whole-body lipid metabolism. Feeding LKO mice a triolein-supplemented but not tristearin-supplemented high-carbohydrate, low-fat diet reduced FGF21 expression and plasma levels. Consistently, SCD1 inhibition in primary hepatocytes induced FGF21 expression, which was repressed by treatment with oleate but not palmitoleate. Moreover, deletion of the transcriptional coactivator PPARγ coactivator 1α (PGC-1α) reduced hepatic and plasma FGF21 and white adipocyte tissue-specific GLUT4 expression and raised plasma glucose levels in LKO mice. These results suggest that hepatic oleate regulates glucose uptake in adipose tissue either directly or partially by modulating the hepatic PGC-1α-FGF21 axis.
Highlights
Increased carbohydrate consumption increases hepatic de novo lipogenesis, which has been linked to the development of chronic metabolic diseases, including obesity, hepatic steatosis, and insulin resistance
We have shown previously that global Stearoyl CoA desaturase 1 (SCD1) deficiency protects against diet-induced adiposity and improves glucose metabolism
Given that SCD1 is deleted from all tissue, using global knockout (GKO) mice alone was not sufficient to determine the individual contribution of SCD1 from different tissues to these phenotypes
Summary
We have shown previously that global SCD1 deficiency protects against diet-induced adiposity and improves glucose metabolism. Spleen, WAT, and BAT of LKO mice showed increased glucose uptake relative to the corresponding tissues of LOX control mice (Fig. 1). To determine how hepatic SCD1 deficiency enhances glucose uptake in metabolic tissues, we measured the expression of glucose transporter genes in the liver, WAT and BAT. Consistent with the 2-[3H]deoxyglucose uptake study, livers of LKO mice showed increased glucose uptake compared with livers of control LOX mice This induction of glucose uptake was reduced to control levels upon phloretin treatment, which suggests that SCD1 deficiency induces glucose uptake in the liver through recruitment of GLUT1 (Fig. 3, S1). The data indicate that hepatic SCD1 deficiency decreases oleate synthesis and increases FGF21 expression in the liver, at least in part through PGC-1␣ These changes are expected to increase glucose uptake in adipose tissue either directly or indirectly (Fig. 6E)
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