👤 James C Fleet

Hypovitaminosis D is common in the obese population and patients suffering from obesity-associated disorders such as type 2 diabetes and fatty liver disease, resulting in suggestions for vitamin D supplementation as a potential therapeutic option. However, the pathomechanistic contribution of the vitamin D-vitamin D receptor (VDR) axis to metabolic disorders is largely unknown. We analyzed the pathophysiological role of global and intestinal VDR signaling in diet-induced obesity (DIO) using global Vdr-/- mice and mice re-expressing an intestine-specific human VDR transgene in the Vdr deficient background (Vdr-/- hTg). Vdr-/- mice were protected from DIO, hepatosteatosis and metabolic inflammation in adipose tissue and liver. Furthermore, Vdr-/- mice displayed a decreased adipose tissue lipoprotein lipase (LPL) activity and a reduced capacity to harvest triglycerides from the circulation. Intriguingly, all these phenotypes were partially reversed in Vdr-/- hTg animals. This clearly suggested an intestine-based VDR activity on systemic lipid homeostasis. Scrutinizing this hypothesis, we identified the potent LPL inhibitor angiopoietin-like 4 (Angptl4) as a novel transcriptional target of VDR. Our study suggests a VDR-mediated metabolic cross-talk between gut and adipose tissue, which significantly contributes to systemic lipid homeostasis. These results have important implications for use of the intestinal VDR as a therapeutic target for obesity and associated disorders. Show less

Low dietary calcium (Ca) intake during growth limits peak bone mass but physiological adaptation can prevent this adverse effect. To assess the genetic control on the physiologic response to dietary Ca restriction (RCR), we conducted a study in 51 BXD lines fed either 0.5% (basal) or 0.25% (low) Ca diets from ages 4 to 12 weeks (n = 8/line/diet). Ca absorption (CaAbs), femur bone mineral density (BMD), and bone mineral content (BMC) were examined. ANCOVA with body size as covariate was used to detect significant line and diet main effects, and line-by-diet interactions. Body size-corrected residuals were used for linkage mapping and to estimate heritability (h(2) ). Loci controlling the phenotypes were identified using composite interval mapping on each diet and for the RCR. h(2) of basal phenotypes (0.37-0.43) and their RCR (0.32-0.38) was moderate. For each phenotype, we identified multiple quantitative trait loci (QTL) on each diet and for the RCR. Several loci affected multiple traits: Chr 1 (88.3-90.6 cM, CaAbs, BMC), Chr 4 (45.8-49.2 cM, CaAbs, BMD, BMC), Chr 8 (28.6-31.6 cM, CaAbs, BMD, RCR), and Chr 15 (13.6-24 cM, BMD, BMC; 32.3-36 cM, CaAbs RCR, BMD). This suggests that gene clusters may regulate interdependent bone-related phenotypes. Using in silico expression QTL (eQTL) mapping and bioinformatic tools, we identified novel candidates for the regulation of bone under Ca stress (Ext1, Deptor), and for the first time, we report genes modulating Ca absorption (Inadl, Sc4mol, Sh3rf1, and Dennd3), and both Ca and bone metabolism (Tceanc2, Tll1, and Aadat). Our data reveal gene-by-diet interactions and the existence of novel relationships between bone and Ca metabolism during growth. © 2015 American Society for Bone and Mineral Research. Show less