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. 2024 May 11;25(10):5227.
doi: 10.3390/ijms25105227.

Differential Modulation of Catecholamine and Adipokine Secretion by the Short Chain Fatty Acid Receptor FFAR3 and α2-Adrenergic Receptors in PC12 Cells

Deepika Nagliya  1 , Teresa Baggio Lopez  1 , Giselle Del Calvo  1 , Renee A Stoicovy  1 , Jordana I Borges  1 , Malka S Suster  1 , Anastasios Lymperopoulos  1
Affiliations

Differential Modulation of Catecholamine and Adipokine Secretion by the Short Chain Fatty Acid Receptor FFAR3 and α2-Adrenergic Receptors in PC12 Cells

Deepika Nagliya et al. Int J Mol Sci. .

Abstract

Sympathetic nervous system (SNS) hyperactivity is mediated by elevated catecholamine (CA) secretion from the adrenal medulla, as well as enhanced norepinephrine (NE) release from peripheral sympathetic nerve terminals. Adrenal CA production from chromaffin cells is tightly regulated by sympatho-inhibitory α2-adrenergic (auto)receptors (ARs), which inhibit both epinephrine (Epi) and NE secretion via coupling to Gi/o proteins. α2-AR function is, in turn, regulated by G protein-coupled receptor (GPCR)-kinases (GRKs), especially GRK2, which phosphorylate and desensitize them, i.e., uncouple them from G proteins. On the other hand, the short-chain free fatty acid (SCFA) receptor (FFAR)-3, also known as GPR41, promotes NE release from sympathetic neurons via the Gi/o-derived free Gβγ-activated phospholipase C (PLC)-β/Ca2+ signaling pathway. However, whether it exerts a similar effect in adrenal chromaffin cells is not known at present. In the present study, we examined the interplay of the sympatho-inhibitory α2A-AR and the sympatho-stimulatory FFAR3 in the regulation of CA secretion from rat adrenal chromaffin (pheochromocytoma) PC12 cells. We show that FFAR3 promotes CA secretion, similarly to what GRK2-dependent α2A-AR desensitization does. In addition, FFAR3 activation enhances the effect of the physiologic stimulus (acetylcholine) on CA secretion. Importantly, GRK2 blockade to restore α2A-AR function or the ketone body beta-hydroxybutyrate (BHB or 3-hydroxybutyrate), via FFAR3 antagonism, partially suppress CA production, when applied individually. When combined, however, CA secretion from PC12 cells is profoundly suppressed. Finally, propionate-activated FFAR3 induces leptin and adiponectin secretion from PC12 cells, two important adipokines known to be involved in tissue inflammation, and this effect of FFAR3 is fully blocked by the ketone BHB. In conclusion, SCFAs can promote CA and adipokine secretion from adrenal chromaffin cells via FFAR3 activation, but the metabolite/ketone body BHB can effectively inhibit this action.

Keywords: G protein-coupled receptor kinase-2; adipokine; adrenal chromaffin cell; beta-hydroxybutyrate; catecholamine; free fatty acid receptor-3; short chain free fatty acid; signal transduction; α2-adrenergic receptor.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Figures

Figure 1
Figure 1
FFAR3 and CA production in PC12 cells. (A,B) In vitro Epi (A) and NE (B) secretion from cultured PC12 cells treated with 1 mM propionate (Prop) or 1 mM BHB (or both) for 20 min. Responses are shown as % of the response of the cells to a 50 μM nicotine challenge (nicotine-induced). (C) TH mRNA levels in the same cells treated with the same concentrations of the same drugs but after 12 h of treatment. For all panels: *, p < 0.05; n = 5 independent experiments per condition.
Figure 2
Figure 2
GRK2 and α2AAR regulation of CA production in PC12 cells. (A,B) In vitro Epi (A) and NE (B) secretion from cultured PC12 cells pretreated with 10 μM brimonidine (Brimo) or 50 μM Cmpd101 (Cmpd) (or both), prior to a 50 μM nicotine (Nic) challenge for 20 min. Responses are shown as % of the response of the cells to a 50 μM nicotine challenge post-vehicle (0.5% DMSO) pretreatment (nicotine-induced, “Nic” alone). (C) TH mRNA levels in the same cells treated with the same concentrations of the same drugs but after 12 h of nicotine exposure. For all panels: *, p < 0.05; n = 5 independent experiments per condition.
Figure 3
Figure 3
FFAR3 and α2AAR crosstalk in the regulation of CA secretion from PC12 cells. In vitro Epi (A) and NE (B) secretion from cultured PC12 cells pretreated with 1 mM propionic acid (Prop), 10 μM brimonidine (Brimo), 1 mM BHB or combinations thereof, prior to a 50 μM nicotine (Nic) challenge for 20 min. Responses are shown as % of the response of the cells to a 50 μM nicotine challenge alone (i.e., post-vehicle (0.5% DMSO) pretreatment: “nicotine-induced” or “Nic” alone). *, p < 0.05; vs. “Nic” alone; #, p < 0.05; vs. any other condition; ^, p < 0.05; vs. “Nic+Brimo” or “Nic+Prop+Brimo” or “Nic+Prop+BHB”; n = 5 independent experiments per condition.
Figure 4
Figure 4
FFAR3 and adipokine production in PC12 cells. In vitro leptin (A) and adiponectin (B) secretion from cultured PC12 cells treated with 1 mM propionate (Prop) or 1 mM BHB (or both). Responses are shown as fold of the vehicle (Veh, 0.5% DMSO) response. *, p < 0.05; n = 5 independent experiments per condition.
Figure 5
Figure 5
Opposing roles of α2AR and FFAR3 in CA secretion and BHB-suppressed FFAR3-dependent adipokine secretion in chromaffin cells. αi: Inhibitory G protein alpha subunit. αi/o: Inhibitory/other G protein alpha subunit. GTP: Guanosine triphosphate. GDP: Guanosine diphosphate. SCFA: Short-chain fatty acid (e.g., propionate). BHB: Beta-hydroxy (or 3-hydroxy) butyric acid. See text for details and for all other molecular acronym descriptions.
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