Acute β-adrenoceptor mediated glucose clearance in brown adipose tissue; a distinct pathway independent of functional insulin signaling

Abstract

Objectiveβ-adrenoceptor mediated activation of brown adipose tissue (BAT) has been associated with improvements in metabolic health in models of type 2 diabetes and obesity due to its unique ability to increase whole body energy expenditure, and rate of glucose and free fatty acid disposal. While the thermogenic arm of this phenomenon has been studied in great detail, the underlying mechanisms involved in β-adrenoceptor mediated glucose uptake in BAT are relatively understudied. As β-adrenoceptor agonist administration results in increased hepatic gluconeogenesis that can consequently result in secondary pancreatic insulin release, there is uncertainty regarding the importance of insulin and the subsequent activation of its downstream effectors in mediating β-adrenoceptor stimulated glucose uptake in BAT. Therefore, in this study, we made an effort to discriminate between the two pathways and address whether the insulin signaling pathway is dispensable for the effects of β-adrenoceptor activation on glucose uptake in BAT.MethodsUsing a specific inhibitor of phosphoinositide 3-kinase α (PI3Kα), which effectively inhibits the insulin signaling pathway, we examined the effects of various β-adrenoceptor agonists, including the physiological endogenous agonist norepinephrine on glucose uptake and respiration in mouse brown adipocytes in vitro and on glucose clearance in mice in vivo.ResultsPI3Kα inhibition in mouse primary brown adipocytes in vitro, did not inhibit β-adrenoceptor stimulated glucose uptake, GLUT1 synthesis, GLUT1 translocation or respiration. Furthermore, β-adrenoceptor mediated glucose clearance in vivo did not require insulin or Akt activation but was attenuated upon administration of a β3-adrenoceptor antagonist.ConclusionsWe conclude that the β-adrenergic pathway is still functionally intact upon the inhibition of PI3Kα, showing that the activation of downstream insulin effectors is not required for the acute effects of β-adrenoceptor agonists on glucose homeostasis or thermogenesis.

Vanadium-dependent activation of glucose transport in adipocytes by catecholamines is not mediatedviaadrenoceptor stimulation or monoamine oxidase activity

“…The inhibitory effect of the β 3 -AR agonist CL 316243 observed in adipocytes from WT mice and reproduced to a lesser extent in rat adipocytes is in perfect agreement with previous reports on glucose transport inhibition in adipocytes by β-AR stimulation[ 31 , 51 , 53 , 54 ]. This also explains the slightly enhanced basal uptake found in the "β-less" mice, but contrasts with other previous studies claiming that CL 316243 stimulates glucose uptake in mouse brown adipocytes in culture[ 55 ] as well as β-AR activation under in-vivo conditions[ 42 ]. Indeed, such controversy does not appear to have great relevance for the regulation of glucose uptake in human adipocytes, the β 3 -adrenergic component of which is remarkably weak[ 56 ], and in which short-term CL 316243 administration neither induces alterations in the early insulin signalling cascade nor changes the basal level of glucose uptake[ 57 ].…”

“…Thus, further exploration consisted of testing whether adrenergic receptors, which bind catecholamines, were involved in their stimulatory action on hexose uptake. Hence, diverse β-adrenoreceptor (β-AR) agonists have already been reported to modulate glucose transport activity in adipocytes, but with contradictory effects, from stimulatory[ 40 - 42 ] to inhibitory[ 31 , 43 ] depending on the nature (white, beige, brown) of the adipocytes, the animal species[ 44 ], and the experimental conditions tested.…”

Myosin 1c: A novel regulator of glucose uptake in brown adipocytes

“…We previously showed that β-adrenoceptor stimulation increases expression, de novo synthesis, and translocation of these newly synthesized GLUT1 transporters to the plasma membrane, increasing glucose uptake [ 2 , 4 , 8 ]. To investigate whether glucose uptake as induced through Myo1c inhibition is regulated in a similar manner, quantitative PCR was performed to measure glucose transporter gene expression in brown and white adipocytes.…”

“…The proliferation and maintenance of cells are constantly regulated so that the tissue will have appropriate capacity [ 27 ], and these morphological changes need to be rigorously regulated as over- or understimulation of this potent tissue under the wrong physiological conditions could have devasting implications on survival during birth and throughout life. Upon adrenergic exposure, BAT has been shown to consume, in addition to fatty acids, high amounts of glucose both in vitro and in vivo to the extent that it can affect body glucose clearance both acutely and chronically to support lipogenesis and thermogenesis [ [28] , [29] , [30] , [31] , [32] , [33] , [34] , [35] , [36] , [37] , [38] ], with β-adrenergic stimulation increasing GLUT1 translation and translocation [ 8 ]. However, glucose uptake will not occur to the same extent under thermoneutral conditions when the need to combust additional fuel is unnecessary, although we [ 35 ] and others [ 39 ] have previously shown that β-adrenergic glucose uptake into brown adipocytes is a distinct and parallel pathway to non-shivering thermogenesis.…”

“…Whereas insulin-stimulated glucose uptake in BAT is regulated via glucose transporter 4 (GLUT4) translocation to the plasma membrane, β-adrenergic stimulation utilizes glucose transporter 1 (GLUT1) as the major mediator to uptake glucose [ [2] , [3] , [4] , [5] , [6] ]. We previously showed that β-AR-mediated glucose uptake to BAT in rodents occurs primarily through the β 3 -AR, involving an increase in cAMP levels and activation of mammalian target of rapamycin complex 2 (mTORC2), resulting in both de novo synthesis and translocation of GLUT1 to the plasma membrane independent of phosphatidylinositol 3 kinase (PI3K), Akt activation, and UCP1 expression [ 4 , 7 , 8 ]. However, many factors concerning the glucose uptake mechanism in BAT are still unknown.…”