Hormone-Sensitive Lipase Serine Phosphorylation and Glycerol Exchange Across Skeletal Muscle in Lean and Obese Subjects : Effect of β-Adrenergic Stimulation

OBJECTIVE—Increased intramuscular triacylglycerol (IMTG) storage is a characteristic of the obese insulin-resistant state. We aimed to investigate whether a blunted fasting or β-adrenergically mediated lipolysis contributes to this increased IMTG storage in obesity

Association of a beta-2 adrenoceptor (ADRB2) gene variant with a blunted in vivo lipolysis and fat oxidation

Background and aims:Obesity is associated with a blunted beta-adrenoceptor-mediated lipolysis and fat oxidation. We investigated whether polymorphisms in codon 16, 27 and 164 of the beta (2)-adrenoceptor gene (ADRB2) and exon 10 of the G protein beta (3)-subunit gene (GNB3) are associated with alterations in in vivo lipolysis and fat oxidation.Design and methods:Sixty-five male and 43 female overweight and obese subjects (body mass index (BMI) range: 26.1-48.4 kg/m(2)) were included. Energy expenditure (EE), respiratory quotient (RQ), circulating free fatty acid (FFA) and glycerol levels were determined after stepwise infusion of increasing doses of the non-selective beta-agonist isoprenaline (ISO).Results:In women, the Arg16 allele of the ADRB2 gene was associated with a blunted increase in circulating FFA, glycerol and a decreased fat oxidation during ISO stimulation. In men, the Arg16 allele was significantly associated with a blunted increase in FFA but not in glycerol or fat oxidation.Conclusion:These results suggest that genetic variation in the ADRB2 gene is associated with disturbances in in vivo beta-adrenoceptor-mediated lipolysis and fat oxidation during beta-adrenergic stimulation in overweight and obese subjects; these effects are influenced by gene-gender interactions.International Journal of Obesity advance online publication, 28 November 2006; doi:10.1038/sj.ijo.0803499

Gender differences in adrenergic regulation of lipid mobilization during exercise.

Gender differences in adrenergic regulation of lipid mobilization during exercise. Hellstrom L, Blaak E, Hagstrom-Toft E. Department of Medicine, Huddinge Hospital, Karolinska Institute, Sweden. Gender differences in adrenergic regulation of glycerol levels in subcutaneous, abdominal adipose tissue were investigated during submaximal exercise in non-obese, healthy men and women, using microdialysis. During exercise, glycerol levels in venous plasma and venous serum concentrations of free fatty acids increased more in women and reached about two-fold higher values than in men (p < 0.005 or less). Plasma noradrenaline and insulin did not differ between the sexes, whereas plasma adrenaline was two-fold higher in men than in women during exercise (p < 0.01). The glycerol levels in adipose tissue increased during exercise and decreased in the post-exercise period in either sex. When the non-selective beta adrenoceptor blocking agent propranolol was added to the microdialysis perfusate before exercise was initiated, the subsequent increase in dialysate glycerol was significantly diminished in both sexes (p < 0.05). A similar addition of the alpha adrenoceptor blocking agent phentolamine, however, caused a significant further rise in tissue glycerol in men (p < 0.05), whereas the exercise induced increase in glycerol levels remained unaffected by phentolamine in women. Adipose tissue blood flow did not change during exercise in either men or women. In either sex, dialysate lactate levels increased during exercise. This increase was not altered if alpha- or beta-blocking agents were added to the perfusate. In summary, during short term submaximal work, women have a higher increase in circulating lipid than men. This appears, at least in part, to be due to a sex difference in the adrenergic regulation of lipid mobilization during exercise. In men exercise activates beta- as well as alpha-adrenergic receptors in adipose tissue, whereas only beta receptors are activated in adipose tissue of women. Finally, methodological investigations indicate that microdialysis is a valid method for short-term exercise experiments

Various phosphodiesterase subtypes mediate the in vivo antilipolytic effect of insulin on adipose tissue and skeletal muscle in man

The antilipolytic effect of insulin on human abdominal subcutaneous adipose tissue and skeletal muscle during local inhibition of cAMP-phosphodiesterases (PDEs) was investigated in vivo, by combining microdialysis with a euglycaemic, hyperinsulinaemic clamp. During hyperinsulinaemia, the glycerol concentration decreased by 40% in fat and by 33% in muscle. Addition of the selective PDE3-inhibitor amrinone abolished the insulin-induced decrease in adipose glycerol concentration, but did not influence the glycerol concentration in skeletal muscle. Nor did the PDE4-selective inhibitor rolipram or the PDE5-selective inhibitor dipyridamole influence the insulin-induced decrease in muscle tissue glycerol. However, the non-selective PDE-inhibitor theophylline counteracted the antilipolytic action of insulin at both sites. The specific activity of PDEs was also determined in both tissues. PDE3-activity was 36.8+/-6.4 pmol x min(-1) x mg(-1) in adipose tissue and 3.9+/-0.5 pmol x min(-1) x mg(-1) in muscle. PDE4-activity in skeletal muscle was high, i.e., 60.7+/-10.2 pmol x min(-1) x mg(-1) but 8.5 pmol x min(-1) x mg(-1) or less in adipose tissue. In conclusion, insulin inhibits lipolysis in adipose tissue and skeletal muscle by activation of different PDEs, suggesting a unique metabolic role of muscle lipolysis

Major differences in noradrenaline action on lipolysis and blood flow rates in skeletal muscle and adipose tissue in vivo

AIMS/HYPOTHESIS: The regulation of skeletal muscle lipolysis is not fully understood. In the present study, the effects of systemic and local noradrenaline administration on lipolysis and blood flow rates in skeletal muscle and adipose tissue were studied in vivo. METHODS: First, circulating noradrenaline levels were raised tenfold by a continuous i.v. infusion (n=12). Glycerol levels (an index of lipolysis) were measured in m. gastrocnemius and in abdominal adipose tissue using microdialysis. Local blood flow was determined with the (133)Xe clearance technique and whole-body lipolysis rates assessed with a stable glycerol isotope technique ([(2)H(5)] glycerol). Second, interstitial glycerol levels in m. gastrocnemius, m. vastus and adipose tissue were measured by microdialysis during local perfusion with noradrenaline (10(-8)-10(-6) mol/l) (n=10). Local blood flow was monitored with the ethanol perfusion technique. RESULTS: With regard to systemic noradrenergic stimulation, no change in fractional release of glycerol (difference between tissue and arterial glycerol) was seen in skeletal muscle. In adipose tissue it transiently increased twofold (p<0.0001), and the rate of appearance of glycerol in plasma showed the same kinetic pattern. Blood flow was reduced by 40% in skeletal muscle (p<0.005) and increased by 50% in adipose tissue (p<0.05). After noradrenaline stimulation in situ, a discrete elevation of skeletal muscle glycerol was registered only at the highest concentration of noradrenaline (10(-6) mol/l) (p<0.05). Adipose tissue glycerol doubled already at the lowest concentration (10(-8) mol/l) (p<0.05). In skeletal muscle a decrease in blood flow was seen at the highest noradrenaline concentrations (p<0.05). CONCLUSIONS/INTERPRETATION: Lipolysis and blood flow rates are regulated differently in adipose tissue and skeletal muscle. Adipose tissue displays a high, but transient (tachyphylaxia) sensitivity to noradrenaline, leading to stimulation of both lipolysis and blood flow rates. In skeletal muscle, physiological concentrations of noradrenaline decrease blood flow but have no stimulatory effect on lipolysis rates