Effects of insulin and norepinephrine on glucose transport and metabolism in rat brown adipocytes

Abstract

Glucose is an important fuel for rat brown adipose tissue in vivo and its utilization is highly sensitive to insulin. In this study, the different glucose metabolic pathways and their regulation by insulin and norepinephrine were examined in isolated rat brown adipocytes, using [6-'4C]glucose as a tracer. Glucose utilization was stimulated for insulin concentrations in the range of 40-1000 pU/ml. Furthermore, the addition of adenosine deaminase (200 mU/ml) or adenosine (10 pM) did not alter insulin sensitivity of glucose metabolism. The major effect of insulin (1 mU/ml) was a respective 7-fold and 5-fold stimulation of lipogenesis and lactate synthesis, whereas glucose oxidation remained very low. The 5-fold stimulation of total glucose metabolism by 1 mU/ml of insulin was accompanied by an 8-fold increase in glucose transport. In the presence of norepinephrine (8 pM), total glucose metabolism was increased 2-fold. This was linked to a 7-fold increase of glucose oxidation, whereas lipogenesis was greatly inhibited (by 72%). In addition, norepinephrine alone did not modify glucose transport. The addition of insulin to adipocytes incubated with norepinephrine, induced a potentiation of glucose oxidation, while lipogenesis remained very low. In conclusion, in the presence of insulin and norepinephrine glucose is a oxidative substrate for brown adipose tissue. However the quantitative importance of glucose as oxidative fuel remains to be determined.Brown adipose tissue (BAT) was primarily considered as a site for thermogenesis during cold exposure [I]. More recently, brown fat has also been involved as a possible regulator of the energy balance. Indeed, thermic activity of BAT is increased by chronic overfeeding [2] and in obese rodents, the diet-induced thermogenesis is decreased [3 -51. BAT lipid metabolism has been widely investigated since fatty acids are known to be the major oxidative substrate for non-shivering thermogenesis, and also to be implicated in the regulation of proton conductance in brown adipose mitochondria [6 -81. Glucose metabolism in BAT was considered more recently. The possibility of a high glucose utilization by this tissue was first suggested by the fact that enzymes of glycolysis have a high activity in BAT [9]. Subsequently, it has been shown that glucose utilization in rat BAT, when expressed per unit wet weight, is in the same range of values as in skeletal muscle and white adipose tissue [lo-121. Moreover, BAT glucose utilization is extremely sensitive to insulin. In the presence of physiological hyperinsulinemia, BAT glucose utilization can represent 10% of the total glucose turnover rate [12]. It has also been shown that in conditions of decreased insulin sensitivity, glucose utilization by BAT was altered [12]. More particularly, a defect in BAT glucose utilization is one of the primary metabolic alterations present during the appearance of obesity in the young obese Zucker rat [13]. This suggests that glucose utilization in BAT might be an important factor in the regulation of th...

α1- and β1-Adrenoceptor Signaling Fully Compensates for β3-Adrenoceptor Deficiency in Brown Adipocyte Norepinephrine-Stimulated Glucose Uptake

“…Norepinephrine and adrenergic agents induce glucose uptake in brown adipocytes in vivo (45)(46)(47) and in vitro (7,15,17,18,46,48). It has been discussed which adrenergic receptor subtype(s) mediates the norepinephrine effect on glucose uptake.…”

“…Cultured brown adipocytes have previously been characterized to express an intact adrenergic-and insulin-signaling system (10 -14), and in vitro glucose uptake is stimulated in brown adipocytes by norepinephrine and adrenergic agents (7,(15)(16)(17)(18).…”

The Brown Adipose Cell: A Unique Model for Understanding the Molecular Mechanism of Insulin Resistance

“…Under physiological insulin stimulation, BAT has an extremely high rate of glucose metabolism (10% of the total Thiazolidinediones (TZD) are a new class of antidiabetic agents that act by improving insulin sensitivity in various glucose turnover rate in the rat) [88,89], and a number of metabolic genes are induced. Among them, insulin plays an important role in the regulation of UCP-1 expression in vivo [90].…”

Insulin stimulates hormone‐sensitive cyclic GMP‐inhibited cyclic nucleotide phosphodiesterase in rat brown adipose cells

“…Noradrenaline and insulin are thought to have synergistically positive effects on long-term regulation of thermogenesis in BAT. With respect to short-term regulation, insulin stimulates lipogenesis and glucose transport, and noradrenaline stimulates lipolysis, fl-oxidation of fatty acids, glucose oxidation and glucose transport, and suppresses lipogenesis [32]. Thus, in regulation of lipogenesis and lipolysis, insulin and noradrenaline are counter regulatory, and at least some of the effects of insulin in BAT as in white adipose cells may involve activation of an insulin-sensitive cGIP1.…”