The role of α₁-adrenergic receptors in regulating metabolism: increased glucose tolerance, leptin secretion and lipid oxidation

Abstract

The role of α-adrenergic receptors (α-ARs) and their subtypes in metabolism is not well known. Most previous studies were performed before the advent of transgenic mouse models and utilized transformed cell lines and poorly selective antagonists. We have now studied the metabolic regulation of the α- and α-AR subtypes in vivo using knock-out (KO) and transgenic mice that express a constitutively active mutant (CAM) form of the receptor, assessing subtype-selective functions. CAM mice increased glucose tolerance while KO mice display impaired glucose tolerance. CAM mice increased while KO decreased glucose uptake into white fat tissue and skeletal muscle with the CAM α-AR showing selective glucose uptake into the heart. Using indirect calorimetry, both CAM mice demonstrated increased whole body fatty acid oxidation, while KO mice preferentially oxidized carbohydrate. CAM α-AR mice displayed significantly decreased fasting plasma triglycerides and glucose levels while α-AR KO displayed increased levels of triglycerides and glucose. Both CAM mice displayed increased plasma levels of leptin while KO mice decreased leptin levels. Most metabolic effects were more efficacious with the α-AR subtype. Our results suggest that stimulation of α-ARs results in a favorable metabolic profile of increased glucose tolerance, cardiac glucose uptake, leptin secretion and increased whole body lipid metabolism that may contribute to its previously recognized cardioprotective and neuroprotective benefits.

ASAS-SSR Triennnial Reproduction Symposium: Looking Back and Moving Forward—How Reproductive Physiology has Evolved: Fetal origins of impaired muscle growth and metabolic dysfunction: Lessons from the heat-stressed pregnant ewe1

“…Catecholamines and inflammatory cytokines are important regulators of myoblast function and muscle growth (Barnes et al, 2017;Merrick et al, 2017). Adrenergic regulation is primarily facilitated by β2 receptors which are the most highly expressed isoform in skeletal muscle, although β1 receptors and to a lesser extent β3 and α 1D receptors are also present (Kim et al, 1991;Shi et al, 2017). Growth studies in animals have led to the use of isoform-specific β adrenergic agonists as growth-promoting feed supplements for finishing livestock, which can increase meat yield of feedlot cattle by up to 40% (Johnson et al, 2014).…”

Acute exposure of primary rat soleus muscle to zilpaterol HCl (β2 adrenergic agonist), TNFα, or IL-6 in culture increases glucose oxidation rates independent of the impact on insulin signaling or glucose uptake

“…Thus, the impact that adrenergic stimulation has on a specific tissue is a function of the specific receptor type or types that it expresses. In skeletal muscle, β2 adrenergic receptors are the most highly-expressed isoform, but β1 receptors and to a lesser extent β3 and α 1D receptors are also present [7, 8]. Growth studies in animals [9] have led to the development of isoform-specific β adrenergic growth promoters that are used as feed additives in the livestock industry to increase meat yield per animal [10].…”

Current Developments on the Role of α1-Adrenergic Receptors in Cognition, Cardioprotection, and Metabolism

“…A few early studies suggested that α 1 -AR stimulation inhibits memory functions in monkeys (Arnsten and Jentsch, 1997;Mao et al, 1999) or in chickens (Gibbs and Summers, 2001) but used very low replicates, very high concentrations of ligands rendering them non-selective or attributed to species variation. Ross et al, 2003;Rorabaugh et al, 2005;Gupta et al, 2009;Shi et al, 2016Shi et al, , 2017 However, as will be discussed, most of the recent studies indicate that α 1 -AR stimulation increases various types of memory in both formation and storage.…”

“…α 1 -AR Stimulation Increases Glucose Tolerance α 1 -AR stimulation is known to increase glucose uptake in the heart or in primary myocytes (Doenst and Taegtmeyer, 1999;Egert et al, 1999;Shi et al, 2016Shi et al, , 2017Sato et al, 2018;Papay and Perez, 2020). The systemically expressing CAM α 1A but not the CAM α 1B -AR mice increased glucose uptake into the heart and only the α 1A -AR KO mice displayed decreased glucose uptake into the heart (Shi et al, 2017). In corroboration, the α 1A -selective agonist, A61603 increased glucose uptake into primary cardiomyocytes or human α 1A -AR transfected Chinese hamster ovary (CHO) cells (Sato et al, 2018).…”