Novel Pleiotropic Effects of Niacin
Type of Degreedissertation
Veterinary Anatomy, Physiology, and Pharmacology
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Introduction. Obesity is associated with a chronic low-grade inflammation of the adipose tissue that has been linked to obesity-related comorbidities, such as insulin resistance and cardiovascular disease. Niacin exerts anti-inflammatory effects in certain tissues, including the lung, kidney, and retina; however, to date there have been no studies examining the anti-inflammatory properties of niacin in adipose tissue. Objective. Therefore, our objective was to determine the effects of niacin on high-fat diet-induced adipose tissue inflammation and to characterize the role of the niacin receptor (GPR109A) and post-receptor intermediates involved. Methods. Male C57BL/6 mice were placed on a control diet or high-fat diet and were maintained on such diets for the duration of the study. After 6 weeks on the control or high-fat diets, vehicle or niacin treatments were begun. Half of the mice from each group received vehicle (water) and the other half received niacin (200 mg/kg/day in drinking water) for 4 weeks. Niacin concentrations were increased to 360 mg/kg/day for the fifth week of treatment. Identical studies were conducted concurrently in GPR109A-/- mice. Results. Niacin treatment attenuated high-fat diet-induced increases in adipose tissue expression of monocyte chemoattractant protein-1 (MCP-1) and IL-1 in the wild-type obese mice, indicating anti-inflammatory effects of niacin in the adipose tissue. MCP-1 is involved in the recruitment of pro-inflammatory macrophages to the adipose tissue in obesity. Niacin had no effect on total adipose tissue macrophage content, as evidenced by unchanged CD68 expression, but reduced the expression of the pro-inflammatory M1 macrophage marker CD11c in obese wild-type mice. Niacin had varying effects on markers of M2, or anti-inflammatory macrophages. Niacin increased serum concentrations of the anti-inflammatory adipokine, adiponectin by 21% in obese wild-type mice, but had no effect on lean wild-type or lean or obese GPR109A-/- mice. Niacin increased adiponectin gene and protein expression in the wild-type mice on the high-fat diet. This effect was lost in the GPR109A null mice. The increases in adiponectin serum concentrations, gene and protein expression occurred independently of changes in expression of PPAR, C/EBP, or SREBP-1c (key transcription factors known to positively regulate adiponectin gene transcription) in the adipose tissue. Further, niacin had no effect on adipose tissue expression of ERp44, Ero1-L, or DsbA-L (key ER chaperones involved in adiponectin production and secretion). In summary, short-term niacin treatment attenuates obesity-induced adipose tissue inflammation through reduced pro-inflammatory cytokine expression, increased anti-inflammatory cytokine expression and reduced M1 macrophage content in the adipose tissue in a niacin receptor-dependent manner. In additional studies, niacin decreased serum RBP4 (a protein elevated in obesity and causally related to insulin resistance) concentrations in obese wild-type mice by 22%. Niacin also tended to reduce serum RBP4 in the lean wild-type mice, although not significantly, by 16%. Interestingly, niacin significantly reduced serum RBP4 concentrations by 16% in the lean GPR109A-/- mice, but had no effect on obese GPR109A-/- mice. Adipose tissue and liver RBP4 gene and protein expression were unchanged in response to niacin treatment in any group. Since niacin was able to reduce serum RBP4 in wild-type and GPR109A null mice, but had no effect on RBP4 gene or protein expression in the liver or fat of any mice, niacin most likely reduces serum RBP4 concentrations in mice in a receptor-independent manner, possibly through increased clearance. Lastly, niacin attenuated high-fat diet-induced reductions in adipose tissue expression of GPR109A and GPR81, two members of a receptor subfamily involved in the metabolic sensing ability of the adipocyte. Conclusions. In summary, niacin produces novel pleiotropic actions on the adipose tissue including anti-inflammatory effects, decreased RBP4, and attenuation of high-fat diet-induced reduction in GPR109A and GPR81.