Selective activation of β3-adrenoceptors by octopamine: comparative studies in mammalian fat cells

Abstract

Numerous synthetic agonists selectively stimulate beta3-adrenoceptors (ARs). The endogenous catecholamines, noradrenaline and adrenaline, however, stimulate all the beta-AR subtypes, and no selective physiological agonist for beta3-ARs has been described so far. The aim of this study was to investigate whether any naturally occurring amine can stimulate selectively beta3-ARs. Since activation of lipolysis is a well-known beta-adrenergic function, the efficacy and potency of various biogenic amines were compared with those of noradrenaline, isoprenaline, and beta3-AR agonists 4-(-{[2-hydroxy-(3-chlorophenyl)ethyl]-amino} propyl)phenoxyacetate (BRL 37,344) and (R,R)-5-(2-{[2-(3-chlorophenyl )-2-hydroxyethyl]-amino} propyl)-1,3-benzo-dioxole-2,2-dicarboxylate (CL 316,243) by testing their lipolytic action in white fat cells. Five mammalian species were studied: rat, hamster and dog, in which selective beta-AR agonists act as full lipolytic agents, and guinea-pigs and humans, in which beta3-AR agonists are less potent activators of lipolysis. Several biogenic amines were inefficient (e.g. dopamine, tyramine and beta-phenylethylamine) while others (synephrine, phenylethanolamine, epinine) were partially active in stimulating lipolysis in all species studied. Their actions were inhibited by all the beta-AR antagonists tested, including those selective for beta1- or beta2-ARs. Octopamine was the only amine fully stimulating lipolysis in rat, hamster and dog fat cells, while inefficient in guinea-pig or human fat cells, like the beta3-AR agonists. In rat white fat cells, beta-AR antagonists inhibited the lipolytic effect of octopamine with a relative order of potency very similar to that observed against CL 316,243. Competitive antagonism of octopamine effect resulted in the following apparent pA2 [-log(IC50), where IC50 is the antagonist concentration eliciting half-maximal inhibition] values: 7.77 (bupranolol), 6.48 [3-(2-ethyl-phenoxy)-1[(1 S)-1,2,3,4-tetrahydronaphth-1-ylaminol]-(2S)2-propanol oxalate, SR 59230A, a beta3-selective antagonist], 6.30[erythro-D,L-1(7-lethylindan-4-yloxy)-3-isopropylamino-+ ++butan-2-ol, ICI 118,551, a beta2-selective antagonist] and 4.71 [(+/-)-[2-(3-carbomyl-4-hydroxyphenoxy)-ethylamino]-3-[4-(1- methyl-4-trifluoromethyl-2-imidazolyl)-phenoxy]2-propanolmethane sulphonate, CGP 20712A, a beta1-selective antagonist]. Octopamine had other properties in common with beta3-AR agonists: stimulation of oxygen consumption in rat brown fat cells and very low affinity in displacing [3H]CGP 12,177 binding to [beta1- or beta2-ARs in dog and rat adipocyte membranes. In Chinese hamster ovary (CHO) cells expressing human beta3-ARs, octopamine inhibited [125I]ICYP binding with only twofold less affinity than noradrenaline while it exhibited an affinity around 200-fold lower than noradrenaline in CHO cells expressing human beta1- or beta2-ARs. These data suggest that, among the biogenic amines metabolically related to catecholamines, octopamine can be considered as the most selective for beta3-ARs.

Increased eating control and energy levels associated with consumption of bitter orange (<em>p</em>-synephrine) extract: a randomized placebo-controlled study

“…3,4,6,7 p-Synephrine has been shown to exhibit modest binding to β3-adrenergic receptors, [8][9][10] the activation of which is associated with enhanced lipolysis, glycemic control, thermogenesis, and appetite control.…”

The Action of &lt;i&gt;p&lt;/i&gt;-Synephrine on Lipid Metabolism in the Perfused Rat Liver

“…[1-14 C]oleic acid (56 mCi/mmol) and [1][2][3][4][5][6][7][8][9][10][11][12][13][14] C]octanoic acid (50 mCi/mmol).…”

“…The lipolytic activity of p-synephrine in adipocytes has been well characterized [1] [6] and it is possible that the compound exerts a similar effect in the liver. Furthermore, p-octopamine, an analogous amine that is also found in Citrus aurantium, though at a lesser concentration, has been demonstrated to exert lipolytic activity in adipocytes [1] [6]. In the perfused rat liver, the compound also increases fatty acid oxidation [11].…”

Lipolysis Induced by Segment Wall Extract from Satsuma Mandarin Orange (Citrus unshu Mark)

“…Other fruit juices such as peach and tomato also did not induce lipolysis (data not shown). It is well known that citrus fruits contain lipolytic amines such as synephrine ( 5 ). Synephrine concentration in the extracts from mar- keted fruit juices was determined using a HPLC system.…”