Hepatic stearoyl CoA desaturase 1 deficiency increases glucose uptake in adipose tissue partially through the PGC-1α-FGF21 axis in mice

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.

Keywords: adiponectin; carbohydrate metabolism; fibroblast growth factor (FGF); glucose metabolism; glucose transport; glucose transporters; heptokine-FGF21; insulin sensitivity; lipid metabolism; lipid signaling; liver; liver metabolism; liver–adipocyte cross-talk; monounsaturated fatty acids; obesity; stearoyl-CoA desaturase-1.

Figure 1.

Hepatic SCD1 deficiency enhances systemic glucose utilization. 10-week-old LOX and LKO male mice were fed an HCD for 10 days. Mice fasted 4 h before an oral gavage dose of 15 μCi/mouse of 2-[³H]deoxyglucose in 20% dextrose solution. Tissues were collected after 90 min, and radiolabel activity was measured by liquid scintillation counter. (n = 3/group). Values are mean ± S.E. *, p < 0.05; #, p = 0.068 versus LOX counterparts by Student's two-tailed t test.

Figure 2.

Hepatic SCD1 deficiency differentially regulates genes encoding glucose transporters in metabolic tissues. 12-week-old LOX and LKO male mice were fed an HCD for 10–14 days, and mice were fasted 4 h before collecting tissues for analysis. A and B, liver and WAT gene expression analysis for the indicated genes using qPCR. Values are mean ± S.E. (n = 6–9/group) expressed as arbitrary units (AU). C and D, Western blotting with the indicated antibodies performed on white and brown adipose tissues. Values are mean ± S.E. (n = 3–5/group). E and F, white and brown adipose tissue gene expression analysis for the indicated lipogenic genes using qPCR. Values are mean ± S.E. (n = 7–9/group). *, p < 0.05; ***, p < 0.001 versus LOX counterparts by Student's two-tailed t test.

Figure 3.

Hepatic SCD1 deficiency enhances glucose uptake through GLUT1-dependent and -independent mechanisms. 12-week-old LOX and LKO mice were fed an HCD for 10 days and fasted overnight prior to an intravenous injection of either vehicle or phloretin (10 mg/kg of body weight). One hour after phloretin treatment, mice received an intravenous injection of FDG 1 h before imaging. FDG uptake levels were quantified as the percent injected dose normalized by the mass of the tissue of interest. Values are mean ± S.E. (n = 4–6/group). *, p < 0.05 versus LOX counterparts by Student's two-tailed t test.

Figure 4.

Hepatic SCD1 deficiency induces FGF21 expression. 10-week-old LOX and LKO male mice were fed an HCD for 10 days, and mice were fasted 4 h before collecting tissues for analysis. A, relative FGF21 expression in liver and plasma. B, hepatic gene expression of KLB. C, relative FGF21 expression in white and brown adipose tissue. D, relative adiponectin expression in white adipose tissue and adiponectin plasma levels (n = 7–8/group). Values are mean ± S.E. *, p < 0.05; **, p < 0.01; ***, p < 0.001 versus LOX counterparts by Student's two-tailed t test. AU, arbitrary units.

Figure 5.

Oleate is a critical regulator of FGF21 expression. 12-week-old LOX and LKO mice were fed either an HCD, triolein, or tristearin for 10 days. Mice were euthanized after 4 h of fasting, and plasma samples were collected. A and B, relative FGF21 expression and plasma protein levels (A) and blood glucose levels (B) after 4 h of fasting. Values are mean ± S.E. (n = 3–5/group). *, p < 0.05 versus LOX counterparts by Student's two-tailed t test. C, FGF21 expression in primary hepatocytes treated with an SCD1 inhibitor (SCD Inh) or SCD1 inhibitor in combination with palmitate (16:0), palmitoleate (16:1), or oleate (18:1).

Figure 6.

Oleate regulates FGF21 partially through PGC-1α. A, relative PGC-1α expression in the liver of 10-week-old LOX and LKO male mice fed an HCD for 14 days. B, relative hepatic and plasma FGF21 expression of LKO and DLKO mice. C, relative GLUT4 expression in WAT of LKO and DLKO mice expressed as arbitrary units (AU). D, plasma glucose levels in 12-week-old LOX, LKO, and DLKO male mice fed an HCD. Values are mean ± S.E. (n = 8–10/group). *, p < 0.05; **, p < 0.01; ****, p < 0.0001 versus LOX counterparts by Student's two-tailed t test. E, summary. Hepatic SCD1 deficiency decreases oleate synthesis and increases FGF21 expression in the liver through PGC-1α. These changes are expected to increase glucose uptake in liver and adipose tissue either directly or indirectly.