Niacin stimulates adiponectin secretion through the GPR109A receptor

Abstract

Niacin (nicotinic acid) has recently been shown to increase serum adiponectin concentrations in men with the metabolic syndrome. However, little is known about the mechanism(s) by which niacin regulates the intracellular trafficking and secretion of adiponectin. Since niacin appears to exert its effects on lipolysis through receptor (GPR109A)-dependent and -independent pathways, the purpose of this investigation was to examine the role of the recently identified GPR109A receptor in adiponectin secretion. Initial in vivo studies in rats demonstrated that niacin (30 mg/kg po) acutely increases serum adiponectin concentrations, whereas it decreases NEFAs. Further in vitro studies demonstrated an increase in adiponectin secretion and a decrease in lipolysis in primary adipocytes following treatment with niacin or ␤-hydroxybutyrate (an endogenous ligand of the GPR109A receptor), but these effects were blocked when adipocytes were pretreated with pertussis toxin. Niacin had no effect on adiponectin secretion or lipolysis in 3T3-L1 adipocytes, which have limited cell surface expression of the GPR109A receptor. To further substantiate these in vitro findings, wild-type and GPR109A receptor knockout mice were administered a single dose of niacin or placebo, and serum was obtained for the determination of adiponectin and NEFA concentrations. Serum adiponectin concentrations increased and serum NEFAs decreased in the wild-type mice within 10 min following niacin administration. However, niacin administration had no effect on adiponectin and NEFA concentrations in the GPR109A receptor knockout mice. These results demonstrate that the GPR109A receptor plays an important role in the dual regulation of adiponectin secretion and lipolysis. nicotinic acid; PUMA-G; HM74A; nonesterified fatty acids; lipolysis NIACIN (NICOTINIC ACID) HAS BEEN USED for more than 50 years as a pharmacological agent for the treatment of dyslipidemia and remains an effective strategy to decrease serum triglycerides and increase HDL cholesterol concentrations (6,19). In one of the first randomized clinical trials of heart disease prevention, niacin reduced serum triglyceride concentrations by 27% and nonfatal myocardial infarctions and cardiovascular disease (CVD) mortality by 27 and 26%, respectively (6a). More recent studies provide evidence that niacin is associated with a reduction in the number of angiographically documented vascular lesions and carotid artery intima-media thickness in patients with CVD (16, 31).The cardioprotective benefits of niacin have been attributed primarily to improvements in blood lipid and lipoprotein characteristics and reductions in vascular inflammation and thrombosis (18). However, recent studies have demonstrated that niacin significantly modulates serum adipokine concentrations. Westphal et al. (36) demonstrated that 6 wk of niacin treatment increased serum adiponectin concentrations by 54% in obese men with the metabolic syndrome. Investigations from our laboratory support these findings and further demonstrate th...

Lack of association between body mass index and plasma adiponectin levels in healthy adults

“…85,86 Although acute druginduced reduction of plasma free fatty acid in healthy human subjects was associated with a reduction of plasma adiponectin, 87 niacin treatment that decreased plasma free fatty acids led to a rapid increase in the plasma adiponectin concentration in healthy rats and mice likely through an increased secretion. 88 Studies on animal models provided additional information on the link between adiponectin and free fatty acids. Adiponectin appeared to be important for the metabolism of fatty acids as shown in mouse models.…”

Pharmacological effects of lipid-lowering drugs on circulating adipokines

“…The effects of niacin on circulating leptin concentrations are controversial. We observed that an acute dose of niacin (30 mg/kg) given to male Sprague-Dawley rats produced no change in serum leptin levels [39] . In addition, a chronic study in humans examined the effects of four and six weeks of extended-release niacin (1000 mg and 1500 mg respectively) on circulating leptin [40] .…”

“…Niacin increased serum low-and medium-molecular weight adiponectin, but preferentially increased the circulating concentrations of the HMW multimer in both studies. Additional studies from our group demonstrate that niacin increases adiponectin secretion in primary rat adipocytes and 3T3-L1 adipocytes stably expressing the niacin receptor in a receptor-dependent fashion [39] . We have also shown that a single dose of immediate-release niacin (30 mg/kg) acutely elevates serum adiponectin concentrations in rats and mice expressing the niacin receptor but not in mice with a genetic deletion of the receptor [39] .…”

“…Additional studies from our group demonstrate that niacin increases adiponectin secretion in primary rat adipocytes and 3T3-L1 adipocytes stably expressing the niacin receptor in a receptor-dependent fashion [39] . We have also shown that a single dose of immediate-release niacin (30 mg/kg) acutely elevates serum adiponectin concentrations in rats and mice expressing the niacin receptor but not in mice with a genetic deletion of the receptor [39] . Taken together, these studies suggest that both immediate and extended-release formulations of niacin increase serum total and HMW adiponectin concentrations and that these effects may occur rapidly following a single dose of niacin at least in rodents.…”

“…Each study that has examined the response of adiponectin to niacin administration has found that adiponectin increases as a result of niacin treatment (Table 3) [39,40,44,103,104] . Westphal and colleagues reported that serum total adiponectin concentrations increased by 54% in humans after four weeks of extended-release niacin (1000 mg/d) and by 94% after 6 wk (1500 mg/d) in patients with cardiovascular disease [40] .…”