Search

Despite clear associations between vitamin D deficiency and obesity and/or type 2 diabetes, a causal relationship is not established. Vitamin D receptors (VDRs) are found within multiple tissues, including the brain. Given the importance of the brain in controlling both glucose levels and body weight, we hypothesized that activation of central VDR links vitamin D to the regulation of glucose and energy homeostasis. Indeed, we found that small doses of active vitamin D, 1α,25-dihydroxyvitamin D3 (1,25D3) (calcitriol), into the third ventricle of the brain improved glucose tolerance and markedly increased hepatic insulin sensitivity, an effect that is dependent upon VDR within the paraventricular nucleus of the hypothalamus. In addition, chronic central administration of 1,25D3 dramatically decreased body weight by lowering food intake in obese rodents. Our data indicate that 1,25D3-mediated changes in food intake occur through action within the arcuate nucleus. We found that VDR colocalized with and activated key appetite-regulating neurons in the arcuate, namely proopiomelanocortin neurons. Together, these findings define a novel pathway for vitamin D regulation of metabolism with unique and divergent roles for central nervous system VDR signaling. Specifically, our data suggest that vitamin D regulates glucose homeostasis via the paraventricular nuclei and energy homeostasis via the arcuate nuclei.

Glucagon receptor (GCGR) agonists cause hyperglycemia but also weight loss. However, GCG-like peptide 1 receptor (GLP1R)/GCGR mixed agonists do not exhibit the diabetogenic effects often attributed to GCGR activity. Thus, we sought to investigate the effect of glucagon agonism on insulin action and glucose homeostasis. Acute GCGR agonism induced immediate hyperglycemia, followed by improved glucose tolerance and enhanced glucose-stimulated insulin secretion. Moreover, acute GCGR agonism improved insulin tolerance in a dose-dependent manner in both lean and obese mice. Improved insulin tolerance was independent of GLP1R, FGF21, and hepatic glycogenolysis. Moreover, we observed increased glucose infusion rate, disposal, uptake, and suppressed endogenous glucose production during euglycemic clamps. Mice treated with insulin and GCGR agonist had enhanced phosphorylation of hepatic AKT at Ser473; this effect was reproduced in isolated mouse primary hepatocytes and resulted in increased AKT kinase activity. These data reveal that GCGR agonism enhances glucose tolerance, in part, by augmenting insulin action, with implications for the use of GCGR agonism in therapeutic strategies for diabetes. [ABSTRACT FROM AUTHOR]

Pharmacological activation of the hypothalamic glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) promotes weight loss and improves glucose tolerance. This demonstrates that the hypothalamic GLP-1R is sufficient but does not show whether it is necessary for the effects of exogenous GLP-1R agonists (GLP-1RA) or endogenous GLP-1 on these parameters. To address this, we crossed mice harboring floxed Glp1r alleles to mice expressing Nkx2.1-Cre to knock down Glp1r expression throughout the hypothalamus (GLP-1RKDDNkx2.1cre). We also generated mice lacking Glp1r expression specifically in two GLP-1RA-responsive hypothalamic feeding nuclei/cell types, the paraventricular nucleus (GLP-1RKDDSim1cre) and proopiomelanocortin neurons (GLP-1RKDDPOMCcre). Chow-fed GLP-1RKDDNkx2.1cre mice exhibited increased food intake and energy expenditure with no net effect on body weight. When fed a high-fat diet, these mice exhibited normal food intake but elevated energy expenditure, yielding reduced weight gain. None of these phenotypes were observed in GLP-1RKDDSim1cre and GLP-1RKDDPOMCcre mice. The acute anorectic and glucose tolerance effects of peripherally dosed GLP-1RA exendin-4 and liraglutide were preserved in all mouse lines. Chronic liraglutide treatment reduced body weight in chow-fed GLP-1RKDDNkx2.1cre mice, but this effect was attenuated with high-fat diet feeding. In sum, classic homeostatic control regions are sufficient but not individually necessary for the effects of GLP-1RA on nutrient homeostasis. [ABSTRACT FROM AUTHOR]

Previous studies in conscious rats have demonstrated that acute ethanol (OH) administration primarily blunts autonomic nervous system (ANS) counterregulatory responses during hypoglycemia by actions on the hindbrain. The specific aim of this study was to determine whether antecedent 4th Ventricle (4V) administration of OH can blunt ANS responses during next day hypoglycemia. Three groups of male conscious Sprague Dawley rats (n=27) were studied during three differing protocols. In one group (n=11) 5% OH was infused at 1µL/min into the 4V for 2 hours followed by a 2 hr hyperinsulinemic (5mU/kg/min) hypoglycemic clamp (50 mg/dl). The other groups consisted of two day studies with either (n=8) 2 hour morning and afternoon 4V OH infusion during hyperinsulinemic euglycemia followed by a day 2 hypoglycemic clamp or a control (n=8) of day 1 hyperinsulinemic euglycemia without OH and a identical day 2 hypoglycemia of 50mg/dl. Acute and previous day OH both produced reductions in epinephrine and norepinephrine responses during subsequent hypoglycemia. However previous day 4V OH produced greater blunting of epinephrine and corticosterone during hypoglycemia as compare to acute 4V. (See Table 1) In summary these results demonstrate that previous day administration of OH into the hindbrain (4V) can result in substantial blunting of hypothalamo-pituitary-adrenal and ANS counterregulatory responses during subsequent hypoglycemia in conscious rats. Our data suggest that alcohol maybe considered as an additional factor causing hypoglycemia associated autonomic failure. [ABSTRACT FROM AUTHOR]