The Durk Pearson & Sandy Shaw®
Life Extension NewsTM
Volume 12 No.
3 • June 2009
Could the French Paradox and the Benefits of the Mediterranean Diet Be Partly Due to Activation of the Niacin Receptor?
It possibly could. Let us explain. GPR109A is the nicotinic acid receptor (also called HM74a/PUMA-G), which is activated by nicotinic acid (niacin), resulting in the suppression of lipolysis (release of fatty acids) by adipocytes (fat cells). Niacin is an extremely effective antilipolytic agent, which is the basis for its beneficial effects in reducing LDL cholesterol and triglycerides. Niacin also increases HDL and acts as an anti-inflammatory agent.
In a recent study, researchers hypothesized that many phenolic acids might bind and activate GPR109A, the receptor for the antidyslipidemic effects of niacin. They noted that consumption of products rich in phenolic acids, such as wine and the “Mediterranean Diet” correlates with a reduced risk of cardiovascular disease. They explain that “both phenolic acids and nicotinic acid are small carboxylic acids with close structural similarity. We also note that application of certain phenolic acids, such as benzoic acid, also induces a flushing response and prostaglandin D2 release in a manner similar to that of nicotinic acid treatment. We thus asked whether phenolic acids could act as GPR109A agonists [activators].”
They, indeed, found that phenolic acids could activate GPR109A, with a potency (in the cinnamic acid class) in the order of trans-cinnamic acid > p-coumaric acid >
0-coumaric acid > sinapic acid > ferulic acid > caffeic acid. In the benzoic acid class, the order of potency was benzoic acid > protocatechuic acid > salicylic acid > p-hydroxybenzene acid.
Part of this study used membranes from Chinese Hamster Ovary cells stably expressing GPR109A, GPR109B, GPR81, or PUMA-G to assess the binding of the test phenolic acids. Human adipocytes were used to test for the anti-lipolytic effect of the tested compounds. Also, mice with knockouts of the PUMA-G receptor were generated to study the effect of the phenolic acids on epididymal fat pad lipolysis.
The IC50 (concentration that inhibited human adipocyte lipolysis by 50%) was, for nicotinic acid, 0.2 μm. The IC50 for trans-cinnamic acid was 160 μm for
o-Coumaric acid was 470 μm and for p-Coumaric acid was 130 μm. As the authors note: “Interestingly, the apparent potency of caffeic, gallic and protocatechuic acids observed from the adipocyte lipolysis assay appeared much higher than that found in the 35S-GTPgammaS [*] binding assay, suggesting that a mechanism independent of GPR109A may contribute to an antilipolytic activity of these phenolic compounds as well.” Importantly, the authors noted synergistic antilipolytic effects of a combination of trans-cinnamic acid, p-coumaric acid, or benzoic acid, which alone suppressed lipolysis by 17, 26, and 3%, respectively. A combination of the three at the same concentrations, however, resulted in a reduction of lipolysis by 53%. “These data suggest that while individually an antilipolytic effect of these phenolic compounds may be weak, together they could potentially achieve a functional significance.”
Within 15 minutes of oral administration of 0.15 mg of cinnamic acid per mouse, there was a significant reduction of plasma free fatty acids in the wild-type mice, but not in the PUMA-G (niacin receptor) knockout mice.
So, the next time somebody asks you whether you think that GPR109A (or HM74A/PUMA-G) could be an important factor in the French Paradox or the benefits of the Mediterranean Diet, you will know what to tell them. On the other hand, if nobody asks you this rather unlikely question, you will still have this very useful knowledge to help guide your own and your family and friends’ eating and drinking. Live long & prosper!
We recommend both eating diets enriched in phenolic acids and taking supplemental niacin (such as our Niacin Easy™). Some people (like ourselves) actually like the niacin flush. Durk always takes it just before sex so that he is flushing during orgasm.
- Ren et al. Phenolic acids suppress adipocyte lipolysis via activation of the nicotinic acid receptor GPR109A (HM74a/PUMA- G). J Lipid Res 50:908-14 (2009).