Characterization of β-adrenergic receptors in bovine intramuscular and subcutaneous adipose tissue: comparison of lubabegron fumarate with β-adrenergic receptor agonists and antagonists

Abstract

Chinese hamster ovary cell constructs expressing either the β 1-, β 2- or β 3-adrenergic receptor (AR) were used to determine whether a novel β-AR modulator, lubabegron fumarate (LUB; Experior, Elanco Animal Health) might exert greater potency for a specific β-AR subtype. EC50 values calculated based on cAMP accumulation in dose response curves indicate that LUB is highly selective for the β 3-AR subtype, with an EC50 of 6 × 10–9 M, with no detectible agonistic activity at the β 2-AR. We hypothesized that the accumulation of lipolytic markers would reflect the agonist activity at each of the β-receptor subtypes of the specific ligand; additionally, there would be differences in receptor subtype expression in subcutaneous (s.c.) and intrmuscular (i.m.) adipose tissues. Total RNA was extracted from adipose tissue samples and relative mRNA levels for β 1-, β2-, and β 3-AR were measured using real-time quantitative polymerase chain reaction. Fresh s.c. and i.m. adipose tissue explants were incubated with isoproterenol hydrochloride (ISO; β-AR pan-agonist), dobutamine hydrochloride (DOB; specific β 1-AA), salbutamol sulfate (SAL; specific β 2-AA), ractopamine hydrochloride (RAC), zilpaterol hydrochloride (ZIL), BRL-37344 (specific β 3-agonist), or LUB for 30 min following preincubation with theophylline (inhibitor of phosphodiesterase). Relative mRNA amounts for β 1-, β 2-, and β 3-AR were greater (P < 0.05) in s.c. than in i.m. adipose tissue. The most abundant β-AR mRNA in both adipose tissues was the β 2-AR (P < 0.05), with the β 1- and β 3-AR subtypes being minimally expressed in i.m. adipose tissue. ISO, RH, and ZH stimulated the release of glycerol and nonesterified fatty acid (NEFA) from s.c. adipose tissue, but these β-AR ligands did not alter concentrations of these lipolytic markers in i.m. adipose tissue. LUB did not affect glycerol or NEFA concentrations in s.c. or i.m. adipose tissue, but attenuated (P < 0.05) the accumulation of cAMP mediated by the β 1- and β 2-AR ligands DOB and SAL in s.c. adipose tissue. Collectively, these data indicate that bovine i.m. adipose tissue is less responsive than s.c. adipose tissue to β-adrenergic ligands, especially those that are agonists at the β 1- and β3-receptor subtypes. The minimal mRNA expression of the β 1- and β 3 subtypes in i.m. adipose tissue likely limits the response potential to agonists for these β-AR subtypes.

Effects of feeding lubabegron on gas emissions, growth performance, and carcass characteristics of beef cattle housed in small-pen environmentally monitored enclosures during the last 3 mo of the finishing period

“…There was minimal mRNA expression for the β 1 and β 3 receptors in intramuscular fat, and the authors concluded this could likely limit the response to agonists of these receptor subtypes. Results from Hwang et al (2021) suggest the decrease in marbling score observed in the current study was likely not due to lipolysis. To fully elucidate how marbling score was reduced by LUB, evaluation of chemical composition and adipose cellularity would be needed, but the dilution of intramuscular fat by LM hypertrophy has been offered as a mechanism by which marbling score is reduced by other biotechnologies that increase LM area ( Duckett et al, 1999 ; Gonzales et al, 2020 ).…”

“…Routine measurements of carcass fat showed no change to adjusted fat thickness, a decrease in KPH at only the highest LUB dose, and a reduction in marbling score for all doses of LUB. Minimal data from LUB-treated cattle are available for comparison, but Hwang et al (2021) characterized β-adrenergic receptors in bovine intramuscular and subcutaneous adipose tissue, and those results provide relevant information regarding the mechanism by which adipose tissue may be affected by the β 3 agonist/β 1,2 antagonist, LUB. The relative mRNA expression reported for β 1 , β 2 , and β 3 adrenergic receptors was greater in subcutaneous than intramuscular adipose tissue, and the β 2 adrenergic receptor subtype was the most abundant mRNA in both tissues.…”

Improving efficiency in the feedlot industry

“…Bovine subcutaneous and intramuscular adipose tissue has an increased concentration of β2 receptors. All subtypes have increased concentration in the subcutaneous adipose tissue compared to intramuscular adipose tissue (Hwang et al, 2021). Therefore, beta-agonists have greater activity in subcutaneous adipose tissue then in intramuscular adipose tissues.…”