Interleukin-1α deficiency reduces adiposity, glucose intolerance and hepatic de-novo lipogenesis in diet-induced obese mice.

While extensive research revealed that interleukin (IL)-1β contributes to insulin resistance (IR) development, the role of IL-1α in obesity and IR was scarcely studied. Using control, whole body IL-1α knockout (KO) or myeloid-cell-specific IL-1α-deficient mice, we tested the hypothesis that IL-1α deficiency would protect against high-fat diet (HFD)-induced obesity and its metabolic consequences. To induce obesity and IR, control and IL-1α KO mice were given either chow or HFD for 16 weeks. Glucose tolerance test was performed at 10 and 15 weeks, representing early and progressive stages of glucose intolerance, respectively. Liver and epididymal white adipose tissue (eWAT) samples were analyzed for general morphology and adipocyte size. Plasma levels of adiponectin, insulin, total cholesterol and triglyceride (TG), lipoprotein profile as well as hepatic lipids were analyzed. Expression of lipid and inflammation-related genes in liver and eWAT was analyzed. Primary mouse hepatocytes isolated from control mice were treated either with dimethyl sulfoxide (DMSO) (control) or 20 ng/mL recombinant IL-1α for 24 hours and subjected to gene expression analysis. Although total body weight gain was similar, IL-1α KO mice showed reduced adiposity and were completely protected from HFD-induced glucose intolerance. In addition, plasma total cholesterol and TG levels were lower and HFD-induced accumulation of liver TGs was completely inhibited in IL-1α KO compared with control mice. Expression of stearoyl-CoA desaturase1 (SCD1), fatty acid synthase (FASN), elongation of long-chain fatty acids family member 6 (ELOVL6), acetyl-CoA carboxylase (ACC), key enzymes that promote de-novo lipogenesis, was lower in livers of IL-1α KO mice. Treatment with recombinant IL-1α elevated the expression of ELOVL6 and FASN in mouse primary hepatocytes. Finally, mice with myeloid-cell-specific deletion of IL-1α did not show reduced adiposity and improved glucose tolerance. We demonstrate a novel role of IL-1α in promoting adiposity, obesity-induced glucose intolerance and liver TG accumulation and suggest that IL-1α blockade could be used for treatment of obesity and its metabolic consequences.

Almog T ，Kandel Kfir M ，Levkovich H ，Shlomai G ，Barshack I ，Stienstra R ，Lustig Y ，Leikin Frenkel A ，Harari A ，Bujanover Y ，Apte R ，Shaish A ，Harats D ，Kamari Y ... -  《BMJ Open Diabetes Research & Care》

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

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.

Aljohani A ，Khan MI ，Bonneville A ，Guo C ，Jeffery J ，O'Neill L ，Syed DN ，Lewis SA ，Burhans M ，Mukhtar H ，Ntambi JM ... -  《-》

Long-term exposure to a high-fat diet results in the development of glucose intolerance and insulin resistance in interleukin-1 receptor I-deficient mice.

McGillicuddy FC ，Reynolds CM ，Finucane O ，Coleman E ，Harford KA ，Grant C ，Sergi D ，Williams LM ，Mills KH ，Roche HM ... -  《-》

Proteoglycan 4 deficiency protects against glucose intolerance and fatty liver disease in diet-induced obese mice.

Proteoglycan 4 (Prg4) has emerged from human association studies as a possible factor contributing to weight gain, dyslipidemia and insulin resistance. In the current study, we investigated the causal role of Prg4 in controlling lipid and glucose metabolism in mice. Prg4 knockout (KO) mice and wild-type (WT) littermates were challenged with an obesogenic high-fat diet (45% of total calories as fat) for 16 weeks. To further stimulate the development of metabolic alterations, 10% fructose water was provided starting from week 13. Prg4 deficiency only tended to reduce diet-induced body weight gain, but significantly improved glucose handling (AUC: -29%; p < 0.05), which was also reflected by a tendency towards a reduced HOMA-IR score (-49%; p = 0.06 as compared to WT mice). This coincided with lower hepatic expression of glycolysis (Gck: -30%; p < 0.05) and lipogenesis (Acc: -21%; p < 0.05 and Scd1: -38%; p < 0.001) genes, which translated in significantly lower hepatic triglyceride levels (-56%; p < 0.001) in Prg4 KO mice as compared to WT mice. Prg4 KO mice likely had lower glucose utilization by skeletal muscle as compared to WT mice, judged by a significant reduction in the genes Glut4 (-29%; p < 0.01), Pfkm (-21%; p < 0.05) and Hk2 (-39%; p < 0.001). Moreover, Prg4 KO mice showed a favorable white adipose tissue phenotype with lower uptake of triglyceride-derived fatty acids (-46%; p < 0.05) and lower gene expression of inflammatory markers Cd68, Mcp1 and Tnfα (-65%, -81% and -63%, respectively; p < 0.01) than WT mice. Prg4 KO mice are protected from high-fat diet-induced glucose intolerance and fatty liver disease.

Nahon JE ，Hoekstra M ，van Harmelen V ，Rensen PCN ，Willems van Dijk K ，Kooijman S ，Van Eck M ... -  《-》

Methionine restriction prevents the progression of hepatic steatosis in leptin-deficient obese mice.

This study investigated the effects of dietary methionine restriction (MR) on the progression of established hepatic steatosis in the leptin-deficient ob/ob mouse. Ten-week-old ob/ob mice were fed diets containing 0.86% (control-fed; CF) or 0.12% methionine (MR) for 14 weeks. At 14 weeks, liver and fat were excised and blood was collected for analysis. In another study, blood was collected to determine in vivo triglyceride (TG) and very-low-density lipoprotein (VLDL) secretion rates. Liver histology was conducted to determine the severity of steatosis. Hepatic TG, free fatty acid levels, and fatty acid oxidation (FAO) were also measured. Gene expression was analyzed by quantitative PCR. MR reversed the severity of steatosis in the ob/ob mouse. This was accompanied by reduced body weight despite similar weight-specific food intake. Compared with the CF group, hepatic TG levels were significantly reduced in response to MR, but adipose tissue weight was not decreased. MR reduced insulin and HOMA ratios but increased total and high-molecular-weight adiponectin levels. Scd1 gene expression was significantly downregulated, while Acadvl, Hadha, and Hadhb were upregulated in MR, corresponding with increased β-hydroxybutyrate levels and a trend toward increased FAO. The VLDL secretion rate was also significantly increased in the MR mice, as were the mRNA levels of ApoB and Mttp. The expression of inflammatory markers, such as Tnf-α and Ccr2, was also downregulated by MR. Our data indicate that MR reverses steatosis in the ob/ob mouse liver by promoting FAO, increasing the export of lipids, and reducing obesity-related inflammatory responses.

Malloy VL ，Perrone CE ，Mattocks DA ，Ables GP ，Caliendo NS ，Orentreich DS ，Orentreich N ... -  《-》