Norepinephrine Induces Lipolysis in β₁/β₂/β₃-Adrenoceptor Knockout Mice

Abstract

Catecholamines are major stimulants of adipose tissue metabolism. Norepinephrine and epinephrine act through three subtypes of ␤-adrenoceptors (␤-AR) expressed in the adipocytes. The aim of this work was to study the mechanisms of lipid mobilization in ␤ 1 /␤ 2 /␤ 3 -AR triple-knockout (␤-less) mice. Glycerol and nonesterified fatty acids released from isolated adipocytes were measured as an index of lipolytic activity. There was no difference between the two genotypes for basal lipolysis and lipolytic response to corticotropin or to agents acting at the adenylyl cyclase and protein kinase A levels. The lipolytic response to norepinephrine and ␤-AR agonists was blunted in ␤-less mice. However, a residual low-affinity lipolytic effect was observed in the presence of catecholamines and ␤ 3 -AR agonists but not of ␤ 1 -or ␤ 2 -AR agonists. cAMP levels were increased by a ␤-AR agonist in white and brown adipocytes of ␤-less mice. The residual lipolytic effect was blocked by ␤-AR antagonists. It was mediated neither by ␣ 1 -or ␣ 2 -AR nor by dopaminergic, serotonergic, and histaminergic receptors. Bioinformatic analyses do not provide evidence for a fourth ␤-AR. We conclude that the residual lipolytic effect observed in ␤-less mice can be attributed to an unknown Gs-protein-coupled receptor with low affinity for catecholamines.

Changes in plasma lipids with psychosocial stress are related to hypertension status and the norepinephrine stress response

“…Lipolysis is thought to occur through catecholamine stimulation of adrenergic receptors expressed on the cellsurface membrane of fat cells [20,42] Notably, some recent findings also suggest additional mechanisms for NE-induced lipolysis, not related to adrenoceptors [42]. Our data further suggest that during acute stress hypertension might be associated with hitherto unknown lipid metabolic processes that are unrelated to NE change and stress-hemoconcentration [17].…”

Thematic review series: Adipocyte Biology. Sympathetic and sensory innervation of white adipose tissue

“…A more adipocyte-specific approach to the issue of b-adrenoceptors and lipolysis occurs in vitro with isolated white adipocytes from b-less mice (228). Basal lipolysis is no different between wild-type and b-less mice, and not surprising is the lack of lipolytic responses to b 1 -and b 2 -adrenoceptor agonists (228). There is, however, a 5-fold remaining lipolytic response to NE and the pan-badrenoceptor agonist isoproterenol as well as a 2-fold lipolytic response to CL316243, a specific b 3 -adrenoceptor agonist (228).…”

“…Basal lipolysis is no different between wild-type and b-less mice, and not surprising is the lack of lipolytic responses to b 1 -and b 2 -adrenoceptor agonists (228). There is, however, a 5-fold remaining lipolytic response to NE and the pan-badrenoceptor agonist isoproterenol as well as a 2-fold lipolytic response to CL316243, a specific b 3 -adrenoceptor agonist (228). These and other data (228) suggest the possibility of developmental compensatory responses for the lack of b-adrenoceptors and/or an as yet unidentified b 4 -adrenoceptor.…”

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

“…The b-ARs are well known mediators of adipocyte metabolism through their regulation of cAMP levels in both white and brown fat (8) and are lipolytic (9). However, the b 1 /b 2 /b 3 -AR triple KO mice still display norepinephrine-induced lipolysis, suggesting involvement of another AR subtype (10). a 2 -AR and in particular a 2A -AR stimulation inhibits insulin secretion (11) and are anti-lipolytic (12).…”