Overexpressing human GPR109A leads to pronounced reduction in plasma triglyceride levels in BAC transgenic rats

Abstract Background and aims Nicotinic acid administration causes plasma non-esterified fatty acid (NEFA) reduction and plasma lipid changes, including reduced triglyceride levels. GPR109A, which is expressed mainly in adipose tissue and has anti-lipolytic activity, was reported to be a molecular target for nicotinic acid. However, recent clinical reports have shown that most GPR109A agonists failed to induce clinically meaningful plasma lipid changes. In addition, a recent study has shown that the TG lowering effect of nicotinic acid was not diminished in Gpr109a deficient mice, which is different from the original finding. Therefore, whether GPR109A activation can lead to plasma lipid changes is unclear. Methods We created a bacterial artificial chromosome (BAC) transgenic rat expressing human GPR109A (Tg rat) and examined the in vivo role of GPR109A. Results Under fasted conditions, plasma NEFA and triglyceride levels in Tg rats were lower than those in non-Tg rats. In this condition, a positive correlation between plasma NEFA and triglyceride or β-hydroxybutyrate levels was observed. Furthermore, insulin levels in Tg rats were lower than those in non-Tg rats only when a reduction in NEFAs was observed, which is a phenomenon also reported for nicotinic acid. Interestingly, body weight gain in Tg rats was significantly lower than in non-Tg rats. Conclusions These results suggest that GPR109A signaling leads to a reduction in triglyceride and insulin levels, and that the triglyceride-lowering effect of nicotinic acid is at least partially mediated by GPR109A signaling.