Insulin Sensitizing Effects of Vitamin D Mediated through Reduced Adipose Tissue Inflammation and Fibrosis

Abstract

Adipose tissue inflammation and fibrosis appear to be mediated by adipocytes and contribute to insulin resistance. Since vitamin D (25(OH)D) has anti-inflammatory and anti-fibrotic effects, expression of its receptor in adipocytes and macrophages suggests that 25(OH)D signaling could mediate paracrine effects within adipose tissue and improve insulin resistance. We performed a randomized, double-blinded placebo-controlled trial to examine the effects of repleting vitamin D in 25(OH)D-deficient (<20 ng/ml), insulin resistant, overweight-to-obese humans (n=19). 25(OH)D repletion to >30 ng/ml was associated with reductions in adipose tissue expression of inflammatory (0.6-0.7-fold decreased expression of TNF-α, IL-6, iNOS and PAI-1) and pro-fibrotic (0.4-0.8-fold decreased expression of TGF-β1, HiF1α, Collagen I, V, VI and MMP7) genes, decreased collagen VI immunofluorescence (19% reduction, p=0.02) and improved hepatic insulin sensitivity, assessed as suppression of endogenous glucose production (EGP) during hyperinsulinemic clamp studies (1.28 ± 0.20 vs. 0.88 ± 0.18 mg/kg/min, p=0.03). To determine whether vitamin D’s effects are mediated through adipocytes, we studied an adipocyte-specific vitamin D receptor knockout mouse model (Adiponectin-Cre+VDR+/ fl) after 12 weeks on high fat diet. Despite no differences in body weight or adiposity, VDR KO mice exhibited increased adipose tissue expression of several pro-inflammatory (Tnf-α, iNos, Pai-1, Mcp-1 and F4/80; 4-10 fold) and pro-fibrotic genes (Tgf-β1, Collagen VI, and Tsp1; 2-4 fold), in concert with hepatic insulin resistance during 2h hyperinsulinemic (4 mU/kg/min)-euglycemic clamps (EGP 10 ± 3 vs. 3 ± 2 mg/kg/min in WT, p = 0.021). These human and rodent studies establish a beneficial role of vitamin D in restraining adipose tissue inflammation and fibrosis as well as hepatic insulin resistance, and suggest that normalizing 25(OH)D levels could have metabolic benefits in targeted individuals. Disclosure E. Lontchi-Yimagou: None. S. Kang: None. K. Zhang: None. A. Goyal: None. J. You: None. P. Kishore: None. E. Rosen: None. M. Hawkins: None.