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A Marette

Publications and source records attributed to A Marette.

61 records · Page 4Linked to original sources
PubMed1991

Noradrenaline stimulates glucose transport in rat brown adipocytes by activating thermogenesis. Evidence that fatty acid activation of mitochondrial respiration enhances glucose transport.

The mechanisms by which noradrenaline, lipolytic agents and long-chain fatty acids stimulate glucose transport were investigated in rat brown adipocytes. Glucose transport was evaluated with tracer D-[U-14C]glucose and cell respiration was measured polarographically. Noradrenaline increased basal oxygen consumption (8-10-fold) and glucose transport (4-5-fold) in a dose-dependent manner, with a maximal stimulation at 100 nM. The stimulatory effects of noradrenaline on respiration and glucose transport were selectively mimicked by dibutyryl cyclic AMP (DBcAMP), 3-isobutyl-1-methylxanthine, cholera toxin and physiological concentrations of palmitic acid. Cytochalasin B completely blocked the effects of these agents on glucose transport. The beta-adrenergic antagonist propranolol inhibited noradrenaline-induced glucose transport, but did not affect the action of DBcAMP, palmitic acid or cholera toxin on this process. The specific inhibitor of mitochondrial carnitine palmitoyltransferase, 2-tetradecylglycidic acid (McN 3802) (50 microM), inhibited the stimulatory effects of noradrenaline (100 nM) and palmitic acid (0.5 mM) on both glucose transport and mitochondrial respiration. Significantly, McN 3802 failed to affect insulin (1 nM) action under identical experimental conditions. These results demonstrate that (a) the stimulatory effects of noradrenaline on brown-adipocyte respiration and glucose transport can be dissociated from those induced by insulin, and (b) noradrenaline increases glucose transport indirectly, by activating adenylate cyclase via beta-adrenergic pathways and by stimulating mitochondrial oxidation of fatty acids.

1-Methyl-3-isobutylxanthine↗
PubMed1991

Major thermogenic defect associated with insulin resistance in brown adipose tissue of obese diabetic SHR/N-cp rats.

The effects of norepinephrine and insulin on thermogenesis were investigated in adipocytes isolated from brown adipose tissue (BAT) of obese non-diabetic LA/N-cp rats (obese LA), obese diabetic SHR/N-cp rats (obese SHR), and their corresponding lean controls. The maximal calorigenic response (Vmax) and the sensitivity [50% effective concentration (EC50)] to norepinephrine (1 microM) were markedly reduced in brown adipocytes from obese SHR rats compared with their lean controls (3- to 4-fold decrease in the Vmax and 50% increase in the EC50 value). In the same cells, there was a similar decrease in the respiratory response to dibutyryl adenosine 3',5'-cyclic monophosphate, indicating the presence of a major postreceptor defect. Remarkably, total BAT cytochrome oxidase activity (an index of cellular mitochondrial content) was also diminished three to four times in obese SHR rats, suggesting that a reduced BAT mitochondrial content is responsible for the decreased thermogenesis. Ultrastructural studies revealed that the cytoplasm of brown adipocytes from obese SHR rats contained a large lipid droplet, numerous tiny droplets, and few atypical mitochondria with loosely packed cristae. Adipocytes from obese SHR rats were also characterized by a significant resistance to the antithermogenic effect of insulin but not to that of the nonmetabolizable adenosine analogue N6-phenylisopropyl adenosine. In contrast, all the above biochemical parameters were normal in obese LA rats. These results demonstrate that the marked insulin resistance in BAT of obese SHR rats is associated with a decreased responsiveness and sensitivity to norepinephrine, indicating the presence of receptor and postreceptor defects. It is suggested that insulin resistance and/or diabetes in SHR/N-cp rats lead to a decreased mitochondriogenesis in BAT, which results in a reduced thermogenic capacity, thereby contributing to the development of obesity.

Adipose Tissue, Brown↗
PubMed1991

Mechanism linking insulin resistance to defective thermogenesis in brown adipose tissue of obese diabetic SHR/N-cp rats.

We previously reported that the decreased sensitivity of brown adipose tissue (BAT) from obese Zucker rats to the calorigenic effects of norepinephrine is associated with a marked resistance to insulin, and we suggested that this defect may explain, at least in part, the increased energy gain efficiency of fa/fa rats. To test whether insulin resistance and/or diabetes leads to a reduced BAT thermogenesis in other genetic models of obesity, we compared BAT metabolic properties of obese Zucker rats with that of obese-nondiabetic LA/N-cp and obese-diabetic SHR/N-cp rats. It was found that the responsiveness and sensitivity of isolated brown adipocytes to the calorigenic effects of norepinephrine (10-100 mM) were markedly reduced in SHR/N-cp rats as compared to their lean controls (the Vmax was decreased by 3-4 times and the EC50 value was doubled). In the same cells, there was a similar decrease in the respiratory effects of dibutyryl cAMP (DBcAMP), revealing the presence of a major post-receptor defect. Remarkably, total cytochrome oxidase activity (an index of cell mitochondrial content) was also decreased by 3-4 times in SHR/N-cp rats, suggesting that a reduced BAT mitochondrial content is responsible for the defective thermogenesis. Similarly to Zucker rats, adipocytes isolated from SHR/N-cp rats were resistant to the metabolic effects of insulin (glucose transport and antithermogenesis). Cells from obese Zucker rats were also desensitized to the metabolic effects of norepinephrine and insulin but their thermogenic capacity was not reduced. In contrast, all the above parameters were normal in obese-nondiabetic LA/N-cp rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue, Brown↗
PubMed1990

Defective metabolic effects of norepinephrine and insulin in obese Zucker rat brown adipose tissue.

The effects of insulin and norepinephrine on oxygen consumption, lipolysis, and glucose transport were investigated in adipocytes isolated from brown adipose tissue (BAT) of adult (4-5 mo) lean (Fa/?) and obese (fa/fa) Zucker rats. Total BAT protein content and cytochrome oxidase activity were similar in both phenotypes, suggesting that obese rats have a normal mitochondrial content. Light and electron micrographs revealed that brown adipocytes from obese rats contained very large multilocular triglyceride droplets, but their mitochondrial ultrastructure was normal. Norepinephrine, when added in excess (1 microM), stimulated brown adipocyte respiration 8-10 times above basal levels both in lean and obese animals. However, dose-response experiments disclosed that the 50% effective concentration (EC50) was significantly higher in cells isolated from obese rats compared with lean ones (EC50 115 vs. 43 nM, P less than 0.05). The lipolytic sensitivity to norepinephrine was also reduced in adipocytes isolated from obese animals (EC50 83 vs. 12 nM, P less than 0.05). Addition of dibutyryl adenosine 3',5'-cyclic monophosphate to respiring obese rat brown adipocytes restored to normal the defective response to norepinephrine, suggesting that the reduction in catecholamine sensitivity resulted from a deactivation of the receptor-adenylate cyclase complex. On the other hand, the antilipolytic and antithermogenic actions of physiological concentrations of insulin were significantly reduced in obese BAT cells. The sensitivity and responsiveness of obese rat brown adipocytes for insulin-stimulated glucose transport were also markedly decreased (EC50 1 vs. 0.3 nM, P less than 0.05; maximal velocity 3-fold vs. 7-fold).(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue, Brown↗
PubMed1990

Mechanism of norepinephrine stimulation of glucose transport in isolated rat brown adipocytes.

Cold exposure reverses the diabetogenic effects of high-fat feeding and markedly stimulates glucose uptake in rat brown adipose tissue (BAT). Considering that cold exposure increases the plasma levels of norepinephrine and lipolytic hormones, but decreases the levels of insulin, we have examined the effects of these agents on glucose transport in isolated rat brown adipocytes using D-[U-14C]glucose as a tracer. It was found that norepinephrine (0.1 microM), glucagon (0.1 nM) and ACTH (100 nM) all increased brown adipocyte respiration (2-10 times) and glucose transport (2-5 times). Studies with adrenergic agonists and antagonists revealed that norepinephrine increases glucose uptake via beta-adrenergic pathways. On the other hand, insulin also increased glucose transport (6 times) but inhibited (40-60 percent) the calorigenic effects of the lipolytic hormones. Both norepinephrine and glucagon potentiated the submaximal insulin responses for glucose transport, demonstrating the existence of metabolic interactions between norepinephrine-, glucagon-, and insulin-mediated glucose uptake. Remarkably, the stimulatory effects of these lipolytic agents were reproduced by dibutyryl cAMP (1 mM), isobutylmethylxanthine (0.1 mM) and palmitic acid (0.5 mM), suggesting that cAMP increases glucose transport via activation of lipolysis and thermogenesis. Considering that the stimulatory effects of norepinephrine (0.1 microM) on respiration and glucose transport were totally blocked by 2-tetradecylglycidic acid (50 microM), a specific inhibitor of mitochondrial carnitine acyl transferase, it is concluded that norepinephrine increases BAT glucose transport via fatty acid-activation of mitochondrial thermogenesis.

Adipose Tissue, Brown↗
PubMed1989

Stimulation of glucose transport by insulin and norepinephrine in isolated rat brown adipocytes.

The effects of insulin and norepinephrine on glucose transport, glucose uptake, and cell respiration were investigated in isolated rat brown adipocytes. Glucose transport and uptake were determined using [U-14C]-D-glucose and 2-deoxy-[1,2-3H]-D-glucose, respectively. Brown adipocyte respiration was measured polarographically. Dose-response experiments revealed that insulin stimulated D-glucose transport and 2-deoxyglucose uptake between 10(-11) and 10(-7) M with a maximal four- to sixfold stimulation. In the absence of insulin, norepinephrine concentrations ranging from 10(-7) to 10(-7) M also enhanced glucose transport and uptake with a maximal two- to fourfold stimulation. Experiments with alpha- and beta-adrenergic agonists and antagonists showed that the effect of norepinephrine was predominantly mediated via beta-adrenergic pathways. Dibutyryl cyclic AMP and 3-isobutyl-1-methylxanthine also increased glucose transport, suggesting that the effects of norepinephrine are cyclic AMP dependent. Moreover, norepinephrine (10(-8) M) enhanced insulin sensitivity for glucose transport [half-maximum velocity constant (1/2 V max)] but failed to potentiate insulin responsiveness (Vmax). On the other hand, insulin (10(-9) M) had no effect on basal respiration but rapidly inhibited the calorigenic effect of norepinephrine (10(-7) M) by greater than 50%. These results demonstrate that 1) in the absence of insulin, physiological concentrations of norepinephrine stimulate glucose transport via beta-adrenergic pathways, 2) the neurohormone synergistically potentiates brown adipocyte submaximal insulin responses for glucose transport, and 3) insulin counteracts the effects of norepinephrine on brown adipocyte thermogenesis despite the fact that both hormones enhance glucose uptake.

1-Methyl-3-isobutylxanthine↗