3,5-Dihydroxybenzoic Acid, a Specific Agonist for Hydroxycarboxylic Acid 1, Inhibits Lipolysis in Adipocytes

Abstract

Niacin raises high-density lipoprotein and lowers low-density lipoprotein through the activation of the ␤-hydroxybutyrate receptor hydroxycarboxylic acid 2 (HCA2) (aka GPR109a) but with an unwanted side effect of cutaneous flushing caused by vascular dilation because of the stimulation of HCA2 receptors in Langerhans cells in skin. HCA1 (aka GPR81), predominantly expressed in adipocytes, was recently identified as a receptor for lactate. Activation of HCA1 in adipocytes by lactate results in the inhibition of lipolysis, suggesting that agonists for HCA1 may be useful for the treatment of dyslipidemia. Lactate is a metabolite of glucose, suggesting that HCA1 may also be involved in the regulation of glucose metabolism. The low potency of lactate to activate HCA1, coupled with its fast turnover rate in vivo, render it an inadequate tool for studying the biological role of lactate/HCA1 in vivo. In this article, we demonstrate the identification of 3-hydroxybenzoic acid (3-HBA) as an agonist for both HCA2 and HCA1, whereas 3,5-dihydroxybenzoic acid (3,5-DHBA) is a specific agonist for only HCA1 (EC 50 ϳ150 M). 3,5-DHBA inhibits lipolysis in wild-type mouse adipocytes but not in HCA1-deficient adipocytes. Therefore, 3,5-DHBA is a useful tool for the in vivo study of HCA1 function and offers a base for further HCA1 agonist design. Because 3-HBA and 3,5-DHBA are polyphenolic acids found in many natural products, such as fruits, berries, and coffee, it is intriguing to speculate that other heretofore undiscovered natural substances may have therapeutic benefits.

Lactate Transport and Signaling in the Brain: Potential Therapeutic Targets and Roles in Body—Brain Interaction

“…Physical exercise is a low-cost, low-risk intervention, which has multiple beneficial effects on the body and the brain, including on impairment in normal aging and agerelated brain disease, such as cardiovascular and Alzheimer's disease, 128 and several mental disorders. 129 The fact that HCAR1 agonists, such as 3,5-DHBA, occur in fruits and berries 67 indicates the possibility for nutritional intervention, in addition to opportunity for development of new drugs acting via the lactate receptor.…”

Browning of White Adipose Cells by Intermediate Metabolites: An Adaptive Mechanism to Alleviate Redox Pressure

“…3B), as already described (36). To address the putative involvement of MCT in lactate-mediated increase in Ucp1 expression, we used two distinct MCT pharmacological inhibitors that have been shown to reduce lactate influx in several cell types (21,22,37).…”

Synthesis and Pharmacological Properties of Silicon‐Containing GPR81 and GPR109A Agonists

“…The crude product (2-bromo-4-(4-methoxyphenyl)-4-propyl-4-silacyclohexan-1-one;s ee ref. [5]) was dissolved in CH 3 CN (30 mL), followed by addition of Na 2 CO 3 (808 mg, 7.62 mmol) and thiourea (290 mg, 3.81 mmol) in single portions at 20 8C, and the reaction mixture was then stirred at 40 8Cf or 3h. After the mixture was cooled to 20 8C, CH 2 Cl 2 (30 mL) and asaturated aqueous NaHCO 3 solution (30 mL) were added sequentially,t he organic layer was separated, and the aqueous layer was extracted with CH 2 Cl 2 (3 20mL) and discarded.…”