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. 2016 Sep;65(9):2732-41.
doi: 10.2337/db16-0309. Epub 2016 May 23.

Hypothalamic Vitamin D Improves Glucose Homeostasis and Reduces Weight

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Free PMC article

Hypothalamic Vitamin D Improves Glucose Homeostasis and Reduces Weight

Stephanie R Sisley et al. Diabetes. .
Free PMC article

Abstract

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.

Figures

Figure 1
Figure 1
Hypothalamic 1,25D3 lowers plasma glucose by inhibition of hepatic glucose production. A: i3vt 1,25D3 improves glucose excursion after an intraperitoneal bolus of dextrose in DIO rats (n = 12 vs. 13). B: Insulin levels were lower in rats treated with i3vt 1,25D3 after a bolus of 0.5 g/kg i.v. dextrose (n = 7–8/group). CE: HFD-fed rats treated with 0.1 µg i3vt 1,25D3 at 120 and 180 min during a physiologic hyperinsulinemic-euglycemic clamp had increased glucose infusion rate (C) and during the last 30 min had decreased glucose production (D) with no change in glucose clearance compared with controls (E) (n = 4–5/group). F: At sacrifice, liver samples from rats treated with 1,25D3 during the clamp had no change in mRNA expression of g6pc3 but decreased pck1 compared with controls. *P < 0.05. AUC, area under the curve; Veh, vehicle.
Figure 2
Figure 2
Vitamin D receptors in PVN are important in regulating glucose. A: The VDR is present in the PVN of HFD-fed rats (×10 magnification). B and C: i3vt 1,25D3 increases c-fos in the PVN of DIO rats. This effect is diminished with pretreatment of a VDR antagonist, ZK159222 (×10 magnification). D and E: Intra-PVN 1,25D3 (0.1 µg) 60 min prior to glucose injection tends to improve glucose excursions in control virus–treated animals (D) but not in animals with VDR shRNA (E) (n = 4–6/group). F: PVN 1,25D3 causes a decrease in the area under the curve (AUC) in D but not in E. G and H: VDRf/f mice with bilateral PVN knockdown of VDR mediated through AAV-Cre delivery (VDRf/f/Cre) demonstrate increased glucose excursions after a bolus of 1.5 g/kg i.p. dextrose 16 weeks after AAV-Cre injection from 15–60 min (G) and in the area under the curve (H) (n = 7–8/group). Dashed lines outline the PVN. Scale bars = 100 μm. *P < 0.05 vs. vehicle or control; #P < 0.05 vs. antagonist/1,25D3.
Figure 3
Figure 3
Chronic hypothalamic 1,25D3 decreases body weight by decreasing food intake. A: Acute delivery of i3vt 1,25D3 (0.1 µg) did not alter food intake in HFD-fed rats (n = 10–11/group). B and C: Chronic delivery of i3vt 1,25D3 (0.01 µg/h, 0.26 µg/day) decreased body weight (B) and food intake (C) over 28 days (n = 3–4/group). D: After 28 days of chronic 1,25D3, fat mass, but not lean mass, was decreased. E: After 3 days (3d) of chronic 1,25D3 delivery, when the animals were still body weight matched, average energy expenditure was not different between the groups. F: No conditioned taste aversion occurred after 1,25D3 (0.1 µg) treatment. The positive control, lithium chloride (LiCl), produced a positive conditioned taste aversion. hr, hour. *P < 0.05 vs. vehicle treatment (BD) or water (F).
Figure 4
Figure 4
1,25D3 depolarizes POMC neurons. A: VDRs are present in the ARC (×10 magnification). B: POMC (green; first panel) and VDR (red; middle panel) neurons colocalize (yellow; third panel). C: 1,25D3 increases cyp24a1 levels in Neuro2A cells. The VDR antagonist ZK159222 attenuated the 1,25D3-induced expression of cyp24a1. D: Representative tracing of depolarization of a POMC neuron by 1,25D3. E: Change in membrane potential by 1,25D3 (n = 7) vs. vehicle (n = 11). Dashed lines outline the ARC. Scale bars = 100 μm. *P < 0.05 vs. vehicle; #P < 0.05 vs. ZK159222.

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