Glucose Stimulates Glial Cell Line-Derived Neurotrophic Factor Gene Expression in Microglia through a GLUT5-Independent Mechanism.

Feeding-regulating neurotrophic factors are expressed in both neurons and glial cells. However, nutritional regulation of anorexigenic glial cell line-derived neurotrophic factor (GDNF) and orexigenic mesencephalic astrocyte-derived neurotrophic factor (MANF) expression in specific cell types remains poorly understood. Hypothalamic glucose sensing plays a critical role in the regulation of food intake. It has been theorized that local glucose concentration modulates microglial activity partially via glucose transporter 5 (GLUT5). We hypothesized that an increased local glucose concentration stimulates GDNF expression while inhibiting MANF expression in the hypothalamus and microglia via GLUT5. The present study investigated the effect of glucose on Gdnf and Manf mRNA expression in the mouse hypothalamus and murine microglial cell line SIM-A9. Intracerebroventricular glucose treatment significantly increased Gdnf mRNA levels in the hypothalamus without altering Manf mRNA levels. Exposure to high glucose caused a significant increase in Gdnf mRNA expression and a time-dependent change in Manf mRNA expression in SIM-A9 cells. GLUT5 inhibitor treatment did not block glucose-induced Gdnf mRNA expression in these cells. These findings suggest that microglia are responsive to changes in the local glucose concentration and increased local glucose availability stimulates the expression of microglial GNDF through a GLUT5-independent mechanism, contributing to glucose-induced feeding suppression.

Central melanocortin receptor agonist reduces hepatic lipogenic gene expression in streptozotocin-induced diabetic mice.

AIMS: The central melanocortin system regulates a variety of metabolic functions including lipid metabolism and hepatic lipogenic gene expression. The objective of the present study was to determine whether central melanocortin regulates hepatic lipogenic gene expression under insulin insufficient condition. MAIN METHODS: We examined the effect of intracerebroventricular (i.c.v.) injection of MTII, a melanocortin agonist, on hepatic gene expression in a mouse model of the insulin-deficient diabetes. Diabetes was induced in male C57BL/6J mice by intraperitoneal injections of streptozotocin (STZ). Diabetic mice received daily i.c.v. injections of MTII (3 nmol) for 11 days. Hepatic expression levels of lipogenic genes and their transcription factors were measured. KEY FINDINGS: MTII treatment significantly reduced hepatic expression levels of genes encoding lipid biosynthetic enzymes, stearoyl-CoA desaturase 1 (SCD1), glycerol-3-phosphate acyltransferase 1 (GPAT1), acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1), and DGAT2 mRNA without significant changes in serum insulin levels, homeostasis model-assessment of insulin resistance (HOMA-IR) and glucose tolerance in STZ-induced diabetic mice. MTII treatment also reduced fatty acid synthase (FAS) and SCD1 protein levels in the liver of diabetic mice. Expression levels of genes encoding transcription factors of these lipogenic genes, sterol regulatory element-binding protein 1c (SREBP-1c) and peroxisome proliferator-activated receptor γ2 (PPARγ2) were also significantly reduced by MTII treatment. SIGNIFICANCE: These data suggest that the insulin-independent mechanism is involved in the regulation of hepatic lipogenic gene expression. Enhanced central melanocortin signaling may be effective in improving abnormal lipid metabolism associated with insulin-deficiency or insulin-insufficiency.

Treatment with a melanocortin agonist improves abnormal lipid metabolism in streptozotocin-induced diabetic mice.

Impairments in leptin-melanocortin signaling are associated with insulin-deficient diabetes and leptin treatment has been shown to be effective in reversing hyperglycemia in animal models of type 1 diabetes. Therefore, we hypothesized that enhanced central melanocortin signaling reverses the metabolic impairments associated with type 1 diabetes. To address this hypothesis, streptozotocin (STZ)-induced diabetic mice were treated with daily intracerebroventricular injection of MTII, a melanocortin agonist, for 11days. STZ-induced hyperglycemia and glucose intolerance were not improved by MTII treatment. MTII treatment did not alter expression levels of genes encoding gluconeogenic enzymes including glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK), in the liver of diabetic mice. Skeletal muscle and white adipose tissue glucose transporter 4 (GLUT4) mRNA levels were not altered by MTII treatment in diabetic mice. In contrast, serum nonesterified fatty acid (NEFA) levels were significantly increased in STZ-induced diabetic mice compared to non-diabetic control mice and MTII treatment significantly reduced serum NEFA levels in diabetic mice. MTII treatment also significantly reduced expression levels of hormone sensitive lipase (HSL) and adipose triglyceride lipase (ATGL) mRNA in white adipose tissue of diabetic mice without a significant change in serum insulin levels. Expression levels of lipoprotein lipase (LPL) and fatty acid translocase (FAT/CD36) mRNA in white adipose tissue and skeletal muscle were not changed by MTII treatment. These data suggest that central melanocortin signaling regulates lipid metabolism and that enhancing central melanocortin signaling is effective in reversing abnormal lipid metabolism, but not carbohydrate metabolism, at least partly by reducing lipolysis in type 1 diabetes.

Relationship between blood glucose levels and hepatic Fto mRNA expression in mice.

Common variants in the fat mass and obesity associated (FTO) gene are associated with obesity and type 2 diabetes. Fto-deficient mice develop hepatic insulin resistance, leading to the hypothesis that hepatic Fto plays a role in the regulation of glucose metabolism and that hepatic Fto expression is regulated by metabolic states. We found that hepatic Fto mRNA levels were increased by fasting in mice. Intraperitoneal glucose injection reduced hepatic Fto mRNA levels without significant changes in body weight in fasted mice. The inverse correlation between Fto mRNA and glucose remained significant after adjusting for body weight. There were positive correlations between hepatic Fto mRNA expression and gluconeogenic gene expression. These data support the hypothesis that hepatic Fto expression changes in response to metabolic states and glucose reduces hepatic Fto mRNA expression independently of body weight. Hepatic Fto may participate in the feedback regulation of glucose metabolism via gluconeogenesis.

Regulation of hepatic PPARgamma2 and lipogenic gene expression by melanocortin.

The central melanocortin system regulates hepatic lipid metabolism. Hepatic lipogenic gene expression is regulated by transcription factors including sterol regulatory element-binding protein 1c (SREBP-1c), carbohydrate responsive element-binding protein (ChREBP), and peroxisome proliferator-activated receptor gamma2 (PPARgamma2). However, it is unclear if central melanocortin signaling regulates hepatic lipogenic gene expression through the activation of these transcription factors. To delineate the molecular mechanisms by which the melanocortin system regulates hepatic lipid metabolism, we examined the effect of intracerebroventricular injection of SHU9119, a melanocortin receptor antagonist, on hepatic expression levels of genes involved in lipid metabolism in mice. SHU9119 treatment increased hepatic triglyceride content and mRNA levels of lipogenic genes, SREBP-1c, and PPARgamma2, whereas it did not cause any changes in hepatic ChREBP mRNA levels. These findings suggest that reduced central melanocortin signaling increases hepatic lipid deposition by stimulating hepatic lipogenic gene expression at least partly through the activation of SREBP-1c and PPARgamma2.