(d)-β-Hydroxybutyrate Inhibits Adipocyte Lipolysis via the Nicotinic Acid Receptor PUMA-G*

By Andrew K. P. Taggart, J. Kero, X. Gan, T. Cai, K. Cheng, M. Ippolito, N. Ren, Rebecca Kaplan, Kenneth K. Wu, Tsuei-ju Wu and 8 more. Journal of Biological Chemistry, 2005

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As a treatment for dyslipidemia, oral doses of 1–3 grams of nicotinic acid per day lower serum triglycerides, raise high density lipoprotein cholesterol, and reduce mortality from coronary heart disease (Tavintharan, S., and Kashyap, M. L. (2001) Curr. Atheroscler. Rep. 3, 74–82). These benefits likely result from the ability of nicotinic acid to inhibit lipolysis in adipocytes and thereby reduce serum non-esterified fatty acid levels (Carlson, L. A. (1963) Acta Med. Scand. 173, 719–722). In mice, nicotinic acid inhibits lipolysis via PUMA-G, a Gi/o-coupled seven-transmembrane receptor expressed in adipocytes and activated macrophages (Tunaru, S., Kero, J., Schaub, A., Wufka, C., Blaukat, A., Pfeffer, K., and Offermanns, S. (2003) Nat. Med. 9, 352–355). The human ortholog HM74a is also a nicotinic acid receptor and likely has a similar role in anti-lipolysis. Endogenous levels of nicotinic acid are too low to significantly impact receptor activity, hence the natural ligands(s) of HM74a/PUMA-G remain to be elucidated. Here we show that the fatty acid-derived ketone body (d)-β-hydroxybutyrate ((d)-β-OHB) specifically activates PUMA-G/HM74a at concentrations observed in serum during fasting. Like nicotinic acid, (d)-β-OHB inhibits mouse adipocyte lipolysis in a PUMA-G-dependent manner and is thus the first endogenous ligand described for this orphan receptor. These findings suggests a homeostatic mechanism for surviving starvation in which (d)-β-OHB negatively regulates its own production, thereby preventing ketoacidosis and promoting efficient use of fat stores.

Subfields: Biochemistry, Epidemiology, Physiology

View Paper: https://www.semanticscholar.org/paper/278e3dd0705e96144662fc38b9d6535faf7c0480

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Citations in the corpus

From Dietary Fiber to Host Physiology: Short-Chain Fatty Acids as Key Bacterial Metabolites. (2016, unknown): “6 mM, respectively (Taggart et al., 2005).”
Progress and challenges in translating the biology of atherosclerosis (2011, background): “The recognition of G-protein-coupled receptors for nicotinic acid, and of β-hydroxybutyrate as an endogenous ligand of one such receptor, has not yet led to a therapeutic approac”
Metabolic Regulation of Gene Expression by Histone Lysine β-hydroxybutyrylation (2016, unknown): “At the cellular level, β-hydroxybutyrate has been reported to modulate sperm motility, receptor signaling pathways, and autophagy (Taggart et al., 2005, Finn and Dice, 2005), as well as global gene expression profiles associated with cancer cell “stemness” (MartinezOutschoorn et al., 2011).”
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The microbial metabolite butyrate regulates intestinal macrophage function via histone deacetylase inhibition (2014, background): “Several GPCRs, including Gpr109a (HCA2), Gpr41 (FFA3), and Gpr43 (FFA2), have been shown to be activated by SCFA such as n-butyrate (27, 28).”
Multi-dimensional roles of ketone bodies in fuel metabolism, signaling, and therapeutics (2017, background): “…creates a negative feedback loop in which ketosis places a modulatory brake on ketogenesis by diminishing the release of nonesterified fatty acids from adipocytes (Ahmed et al., 2009; Taggart et al., 2005), an effect that can be counterbalanced by the sympathetic drive that stimulates lipolysis.”
GPR109A is a G-protein-coupled receptor for the bacterial fermentation product butyrate and functions as a tumor suppressor in colon (2009, background): “Recently, Taggart and colleagues (28) showed that the ketone body h-D-hydroxybutyrate is a ligand”
Gut Microbiota-Derived Short-Chain Fatty Acids, T Cells, and Inflammation (2014, background): “cAMP regulation, suppression of adipocyte lipolysis, HDL metabolism, DC trafficking, antitumor activity, and HDL metabolism (48, 122-126)”
Activation of the receptor (Gpr109a) for niacin and the commensal metabolite butyrate suppresses colonic inflammation and carcinogenesis (2014, unknown): “Although GPR43 is activated by all three SCFAs, GPR109A (encoded by Niacr1) is activated only by butyrate (Blad et al., 2012; Taggart et al., 2005).”