Dobutamine as selective β<sub>1</sub>-adrenoceptor agonist in in vivo  studies on human thermogenesis and lipid utilization

Schiffelers, S.L.H.; Harmelen, Vanessa van; Grauw, H. A. J. de; Saris, W. H. M.; Baak, Marleen A. van

doi:10.1152/jappl.1999.87.3.977

Cited by 32 publications

(30 citation statements)

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“…The maximum dose we used was 9 g/kg FFM⅐min, which is comparable with 7.5 g/kg BW⅐min and thus lies within the range of ␤ 1 -adrenoceptor specificity. Our earlier study (9) also showed that the ␤ 2 -adrenoceptor agonist salbutamol in a concentration of 85 ng/kg BW⅐min (or 100 ng/kg FFM⅐min) also induced ␤ 1 -adrenoceptor-specific changes in lipid utilization. Addition of the ␤ 1 -adrenoceptor antagonist atenolol prevented simultaneous ␤ 1 -adrenergic stimulation, but did not affect ␤ 2 -adrenoceptor-specific changes.…”

Section: Discussionmentioning

confidence: 69%

“…The interpretation of the data from our study highly depends on the selectivity of the ␤-adrenoceptor agonists used. An earlier study from our group (9) showed that dobutamine induced ␤ 1 -adrenoceptor-specific changes in thermogenesis and lipid utilization in dosages of 10 g/kg BW⅐min or less. The maximum dose we used was 9 g/kg FFM⅐min, which is comparable with 7.5 g/kg BW⅐min and thus lies within the range of ␤ 1 -adrenoceptor specificity.…”

Section: Discussionmentioning

confidence: 88%

“…␣-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).…”

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confidence: 99%

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1- and 2-Adrenoceptor-Mediated Thermogenesis and Lipid Utilization in Obese and Lean Men

Schiffelers¹

2001

Journal of Clinical Endocrinology & Metabolism

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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...

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Section: Discussionmentioning

confidence: 69%

Section: Discussionmentioning

confidence: 88%

mentioning

confidence: 99%

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1- and 2-Adrenoceptor-Mediated Thermogenesis and Lipid Utilization in Obese and Lean Men

Schiffelers¹

2001

Journal of Clinical Endocrinology & Metabolism

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“…5,6 During selective b 1 -adrenergic stimulation, lipolysis, lipid oxidation and energy expenditure increase. 7,8 Free fatty acids (FFA), needed for lipid oxidation, are released from the adipose tissue by stimulating its b 1 -adrenoceptors. The increase in lipid oxidation and thermogenesis is assumed to be localized predominantly in skeletal muscle, 9,10 but this tissue contains mainly b 2 -adrenoceptors and presumably no b 1 -adrenoceptors.…”

Section: Introductionmentioning

confidence: 99%

The effect of an increased free fatty acid concentration on thermogenesis and substrate oxidation in obese and lean men

2001

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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.

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“…Healthy young men treated with a synthetic beta-3 agonist had a reduction in 24-h RQ, 90 indicating an increase in fat oxidation. In addition, infusions of betaadrenergic agonists not only increase energy expenditure but also increase fat oxidation 91,92 and improve insulin sensitivity. As such, it is possible that the sympathetic nervous system (SNS), acting through the beta-3 adrenoreceptor or other adrenoreceptors, regulates fat oxidation.…”

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Failure of fat cell proliferation, mitochondrial function and fat oxidation results in ectopic fat storage, insulin resistance and type II diabetes mellitus

2004

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BACKGROUND:It is widely accepted that increasing adiposity is associated with insulin resistance and increased risk of type II diabetes. The predominant paradigm used to explain this link is the portal/visceral hypothesis. This hypothesis proposes that increased adiposity, particularly in the visceral depots, leads to increased free-fatty acid flux and inhibition of insulin-action via Randle's effect in insulin-sensitive tissues. OBJECTIVES: In this review, limitations of this paradigm will be discussed and two other paradigms that may explain established links between adiposity and insulin resistance/diabetes will be presented. (a) Ectopic fat storage syndrome. Three lines of evidence support this concept. Firstly, failure to develop adequate adipose tissue mass (also known as 'lipodystrophy') results in severe insulin resistance and diabetes. This is thought to be the result of ectopic storage of lipid into liver, skeletal muscle and the pancreatic insulin-secreting beta cell. Secondly, most obese patients also shunt lipid into the skeletal muscle, the liver and probably the beta cell. The importance of this finding is exemplified by several studies demonstrating that the degree of lipid infiltration into skeletal muscle and liver highly correlates with insulin resistance. Thirdly, increased fat cell size is highly associated with insulin resistance and the development of diabetes. Increased fat cell size may represent the failure of the adipose tissue mass to expand and therefore to accommodate an increased energy influx. Taken together, these observations support the 'acquired lipodystrophy' hypothesis as a link between adiposity and insulin resistance. Ectopic fat deposition is therefore the result of additive or synergistic effects including increased dietary intake, decreased fat oxidation and impaired adipogenesis. (b) Endocrine paradigm. This concept was developed in parallel with the 'ectopic fat storage syndrome' hypothesis. Adipose tissue secretes a variety of endocrine hormones such as leptin, interleukin-6, angiotensin II, adiponectin and resistin. From this viewpoint, adipose tissue plays a critical role as an endocrine gland, secreting numerous factors with potent effects on the metabolism of distant tissues. CONCLUSIONS: The novel paradigms of ectopic fat and fat cell as an endocrine organ probably will constitute a new framework for the study of the links between our obesigenic environment and the risk of developing diabetes.

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Dobutamine as selective β₁-adrenoceptor agonist in in vivo studies on human thermogenesis and lipid utilization

Cited by 32 publications

References 16 publications

1- and 2-Adrenoceptor-Mediated Thermogenesis and Lipid Utilization in Obese and Lean Men

1- and 2-Adrenoceptor-Mediated Thermogenesis and Lipid Utilization in Obese and Lean Men

The effect of an increased free fatty acid concentration on thermogenesis and substrate oxidation in obese and lean men

Failure of fat cell proliferation, mitochondrial function and fat oxidation results in ectopic fat storage, insulin resistance and type II diabetes mellitus

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Dobutamine as selective β1-adrenoceptor agonist in in vivo studies on human thermogenesis and lipid utilization

Cited by 32 publications

References 16 publications

1- and 2-Adrenoceptor-Mediated Thermogenesis and Lipid Utilization in Obese and Lean Men

1- and 2-Adrenoceptor-Mediated Thermogenesis and Lipid Utilization in Obese and Lean Men

The effect of an increased free fatty acid concentration on thermogenesis and substrate oxidation in obese and lean men

Failure of fat cell proliferation, mitochondrial function and fat oxidation results in ectopic fat storage, insulin resistance and type II diabetes mellitus

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Dobutamine as selective β₁-adrenoceptor agonist in in vivo studies on human thermogenesis and lipid utilization