The aim of this study was to elucidate the roles of the ␤ 1 -and the ␤ 2 -adrenoceptors in thermogenesis and lipid utilization in obesity. The ␤ 1 -adrenoceptor study was performed in 9 obese and 10 lean men and consisted of 4 30-min periods during which subjects received consecutive infusions of 0, 3, 6, and 9 g/kg fat-free mass (FFM)⅐min dobutamine. Energy expenditure, lipid oxidation, and plasma nonesterified fatty acids and glycerol concentrations increased similarly in both groups during ␤ 1 -adrenergic stimulation. The ␤ 2 -adrenoceptor study was performed in 10 obese and 11 lean men and involved 3 45-min periods during which 0, 50, and 100 ng/kg FFM⅐min salbutamol were given in combination 1.2 g/kg FFM⅐min atenolol (bolus, 50 g/kg FFM). During ␤ 2 -adrenergic stimulation, the increases in energy expenditure and plasma nonesterified fatty acids and glycerol concentrations were reduced in the obese group. Furthermore, lipid oxidation significantly increased in the normal weight group, but remained similar in the overweight group. In conclusion, these data suggest that ␤ 1 -adrenoceptor-mediated metabolic processes are similar in both groups, but ␤ 2 -adrenoceptor-mediated increases in thermogenesis and lipid utilization are impaired in the obese. (J Clin Endocrinol Metab 86: [2191][2192][2193][2194][2195][2196][2197][2198][2199] 2001) T HE SYMPATHETIC nervous system plays an important role in the regulation of thermogenesis and lipid utilization. Studies in which the endogenous catecholamines norepinephrine (1, 2) and epinephrine (3-5) (both nonselective ␣-and ␤-adrenoceptor agonists) are infused show significant increases in energy expenditure, lipid oxidation, and lipolysis. The roles of the individual adrenoceptor subtypes in thermogenesis have also been studied. ␣-Adrenergic stimulation does not affect whole body thermogenesis (3, 6), whereas nonselective ␤-adrenergic stimulation with isoprenaline significantly increases energy expenditure and lipid utilization (7). During only ␤ 1 -adrenergic stimulation with dobutamine (8, 9) or only ␤ 2 -adrenergic stimulation with salbutamol (6) or terbutaline (10), energy expenditure, lipid oxidation, and lipolysis increase as well. In rats, ␤ 3 -adrenergic stimulation leads to significant increases in energy expenditure and lipid utilization (11,12). However, the rat ␤ 3 -adrenoceptor differs pharmacologically from the human ␤ 3 -adrenoceptor (13, 14), and consequently, the specific ␤ 3 -adrenoceptor agonists used in rats are only weak agonists in humans. Until now, no highly selective ␤ 3 -adrenoceptor agonist or antagonist has been available for administration in humans.Obese subjects may show an impaired response of thermogenesis during norepinephrine infusion (15, 16), but responses similar to those in lean subjects are also frequently found during norepinephrine (17, 18), epinephrine (5, 19), and isoprenaline (7) infusion. Others only found an impaired thermogenic response when very obese men were compared with very lean men (20) or only during ove...

The use of dobutamine as selective beta(1)-adrenoceptor agonist in in vivo studies on human thermogenesis and lipid utilization was investigated in 20 men. At 2.5, 5, and 10 microg x kg(-1) x min(-1), dobutamine induced significant increases in energy expenditure, lipid oxidation, and lipolysis. The beta(1)-adrenoceptor antagonist atenolol (bolus: 42.5 microg/kg, infusion: 1.02 microg x kg(-1) x min(-1)) blocked all dobutamine-induced effects on thermogenesis and lipid utilization. All parameters remained at levels comparable to those during saline infusion. The dose of atenolol used did not inhibit beta(2)-adrenoceptor-specific changes in energy expenditure, lipid oxidation, and lipolysis during salbutamol infusion (85 ng x kg(-1) x min(-1)). This indicates that atenolol was specific for beta(1)-adrenoceptors and did not camouflage concomitant beta(2)-adrenoceptor stimulation during dobutamine infusion. Therefore, we conclude that dobutamine can be used as a selective beta(1)-adrenoceptor agonist at dosages

Aims/hypothesis. The aim of this study was to investigate whether the β 2 -adrenergically mediated increase in interstitial glycerol concentrations (used as an indicator of local lipolysis) was impaired in the skeletal muscle (the gastrocnemius muscle) of obese subjects compared with in that of lean subjects, and whether any differences in muscle lipolysis were related to differences in intramyocellular muscle triglyceride content. Methods. A microdialysis experiment was performed in the gastrocnemius muscle of eight lean and eight obese men (body fat 22.1±1.6% vs 32.7±1.6% respectively). After determining baseline extracellular glycerol concentrations, the probe was perfused with increasing concentrations of the β 2 -agonist, salbutamol (doses of 1, 10 and 100 µmol/l for 45-min periods). Local blood flow was determined using the ethanol dilution technique. Intramyocellular lipid content was determined using 1 H-magnetic resonance spectroscopy.Results. Compared with that in lean subjects, the β 2 -adrenergically mediated increase in glycerol concentrations (absolute and percentage change) was blunted in obese subjects (at 100 µmol/l of salbutamol, percentage change 12.0±12% vs 48±12%, p<0.05). The decrease in ethanol out : in ratio was less pronounced in the obese individuals (p<0.05), indicating a diminished increase in local muscle blood flow. Intramyocellular lipid content was comparable in both groups. Conclusions/interpretation. The capacity to increase skeletal interstitial glycerol concentrations during direct β 2 -adrenergic stimulation is impaired in obese subjects with normal intramyocellular concentrations, suggesting that this may be an early event in the process of triglyceride accumulation.

OBJECTIVE:To examine whether a certain increase in plasma free fatty acid (FFA) concentration leads to similar increases in lipid oxidation and energy expenditure in obese and lean men. DESIGN: The study protocol consisted of a 30 min baseline period after which subjects received an i.v. bolus of 1000 IE heparin. Then consecutive infusions of 4.9, 9.8 and 19.6 mlakg fat-free mass (FFM) Á min of a lipid heparin mixture were started, each infusion for 30 min. SUBJECTS: Eleven obese and 13 lean men with a mean body mass index (BMI) of 34.2 AE 1.0 ( AE s.e.m.) and 23.9 AE 0.5 kgam 2 and age 46.0 AE 1.0 and 42.6 AE 1.5 y, respectively. MEASUREMENTS: Energy expenditure, respiratory exchange ratio (RER) and carbohydrate and lipid oxidation were continuously measured by indirect calorimetry. At the end of each infusion period, a blood sample was taken for FFA, glycerol, insulin, b-hydroxybutyrate, noradrenaline and adrenaline determination. RESULTS: At baseline, plasma FFA levels were comparable in both groups. Lipid heparin infusion increased plasma FFA concentration by 301 AE 47 mmolal and 332 AE 27 mmolal in obese and lean men. Energy expenditure increased similarly in obese and lean men (0.34 AE 0.08 vs 0.40 AE 0.08 kJamin, NS) during lipid heparin infusion, whereas RER decreased similarly in both groups. Lipid oxidation rates were comparable at baseline and increased similarly in obese and lean men (19 AE 5 vs 13 AE 4 mgamin, NS). Baseline plasma insulin levels were higher in the obese, but did not change during lipid heparin infusion. Plasma b-hydroxybutyrate concentrations were similar at baseline, but increased signi®cantly less in the obese during lipid heparin infusion. Baseline noradrenaline and adrenaline concentrations did not differ signi®cantly between groups. During lipid heparin infusion, plasma noradrenaline levels decreased signi®cantly, but plasma adrenaline levels remained unchanged in both groups. CONCLUSION: A certain increase in plasma FFA concentration leads to similar increases in lipid oxidation and energy expenditure in obese and lean men. The accumulation of fat in obese subjects may therefore be more likely to be due to a defect in adipose tissue lipolysis than a defect in lipid oxidation.

Background and aims: Obesity is associated with a blunted b-adrenoceptor-mediated lipolysis and fat oxidation. We investigated whether polymorphisms in codon 16, 27 and 164 of the b 2 -adrenoceptor gene (ADRB2) and exon 10 of the G protein b 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 b-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 b-adrenoceptor-mediated lipolysis and fat oxidation during b-adrenergic stimulation in overweight and obese subjects; these effects are influenced by gene-gender interactions.