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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Leptin has been called a hormone of reproduction, and seems to link fat and fertility. It has been speculated that the neurotransmitter norepinephrine (NE) (noradrenaline), possibly via the sympathetic nervous system, may represent the afferent signal which modulates leptin release from adipocytes. The purpose of this study was to produce a state of decreased sympathetic output by using the catecholamine synthesis inhibitor alpha-methyl-para-tyrosine (AMPT), in order to study the effect of this compound on the secretion of leptin from fat cells. Ten subjects (five women and five men) received a total of 5 x 1 g doses of AMPT or 5 x 50 mg promethazine (active placebo) over a 26 h period, separated by 4-6 weeks using a randomized, double-blind, placebo-controlled, cross-over design. Blood samples for hormone measurements were obtained over 24 h (18 time points) on day 2 of each experiment. Urinary measurement of the NE metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) on study day 2 served as a marker of the effectiveness of AMPT as an inhibitor of NE synthesis. The daily excretion of this metabolite decreased from 1.56 +/- 0.22 mg in the placebo experiment to 0.53 +/- 0.1 mg in the active experiment (P < 0.05). Plasma leptin concentrations measured in the control group in women and men were similar to those reported previously in lean subjects with a body mass index < 27.5 kg/m2. Leptin concentrations in women were 3-fold higher than in men. Leptin is secreted in a circadian rhythm in both sexes with an increase of nocturnal concentrations by approximately 50%. Two-way analysis of variance reveals no significant difference in leptin secretion between the control and active groups in women and men. In summary, preliminary results do not support the hypothesis that NE represents the afferent signal from the central nervous system which modulates leptin release from adipocytes in the human. Further studies are needed to define the role of the sympathetic nervous system as well as NE in the regulation of leptin secretion and its involvement in obesity and reproduction.
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PMID:Prolonged inhibition of presynaptic catecholamine synthesis does not alter leptin secretion in normal-weight men and women. 961 31

1. Obesity influences the responsiveness of the microcirculation; constriction is augmented probably reflecting heightened sympathetic nervous activity. 2. The responsiveness of the microcirculation in the forearm to constriction and dilation was therefore examined in 14 men and women with varying degrees of abdominal adiposity, to determine the potential effects of sympathetic nervous activity and adiposity on flow. Changes in basal blood flow were measured by venous occlusion plethysmography during intra-arterial infusions of noradrenaline, acetylcholine and sodium nitroprusside and after temporary ischaemia. Total body noradrenaline spillover was also measured, as an index of sympathetic neuronal activity. 3. Parameters of obesity were found to influence the responsiveness of the microcirculation. Changes in vascular resistance with noradrenaline (100 ng/min) were positively correlated with body weight, body mass index and waist circumference (r=0.63, P=0.02), whereas waist circumference was negatively correlated with post-ischaemia vasodilatation (r=-0.76, P=0.002). Acetylcholine-induced vasodilatation was inversely related to body mass index (r=-0.53, P=0.053). 4. Basal blood flow did not correlate with adiposity. Furthermore, vasodilatation with 800 ng/min sodium nitroprusside was inversely correlated with total body noradrenaline spillover (r=-0. 77, P<0.001); and changes in flows with noradrenaline (constriction) and post-ischaemia (dilation) were inversely related (r=-0.56, P=0. 035). 5. These findings, taken together, are consistent with increased local sympathetic neuronal responsiveness and diminished nitric-oxide-mediated dilation in the forearm vasculature with increasing body adiposity.
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PMID:Control of the forearm microcirculation: interactions with measures of obesity and noradrenaline kinetics. 968 May 3

The role of the sympathetico-adrenal system in the pathogenesis of arterial hypertension in pubertal hypothalamic syndrome was studied in 29 males with pubertal hypothalamic syndrome and 13 healthy subjects, aged 15-23 years. The activity of the sympathetico-adrenal system was assessed in terms of the plasma dopamine, noradrenaline, and adrenaline concentrations as determined by HPLC using a high-sensitivity detector. Patients with stable arterial hypertension had significantly reduced levels of adrenaline, probably because of loss of phenylethanol methyltransferase activity, which may demonstrate that the sympathetico-adrenal system is not involved in the genesis and maintenance of arterial hypertension in pubertal hypothalamic syndrome. Patients with a body mass index of more than 35.0 kg/m2 had significant reductions in noradrenaline levels, evidently because of loss of tyrosine hydroxylase, whose activity is regulated by corticotrophin. Catecholamine levels were independent of the duration of illness, the duration of hypertension, or the stage of obesity.
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PMID:State of the sympathetico-adrenal system in patients with hypothalamic pubertal syndrome. 968 41

Obesity is linked to functional brown adipose tissue (BAT) atrophy, partially due to adipocyte apoptosis. The brown adipocytes of obese rats have lower Bcl-2/Bax mRNA and protein ratios than those of their lean littermates. Exposure to a low temperature for three days markedly increased the Bcl-2/Bax ratio, by increasing the noradrenergic output to BAT, which has previously been shown to reduce apoptotic cell death. This effect could be mimicked in vitro by the addition of noradrenaline (NA) to brown adipocytes differentiated in culture. Micromolar NA concentrations increased the Bcl-2/Bax mRNA and protein ratios, and protected against serum deprivation-induced apoptosis. We conclude that NA acts by modulating bcl-2 and bax gene expression.
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PMID:Bcl-2 and Bax are involved in the sympathetic protection of brown adipocytes from obesity-linked apoptosis. 968 70

Polycystic ovary syndrome (PCOS) is one of the most common endocrinopathies affecting women of reproductive age; it is associated with hyperandrogenism, hyperinsulinemia, and dyslipidemia. This study was designed to assess the long term effects of a pure androgen receptor blocker, flutamide, on the lipid profile in women with PCOS and to examine the possible mechanisms by which androgens may exert their influence. Seventeen women with PCOS (10 obese and 7 lean) were studied. All subjects received a 12-week course of oral flutamide (500 mg/day). The baseline and posttreatment evaluations included lipid profile, androgen levels, insulin sensitivity, and serum catecholamine determinations. The primary outcome was the change in the ratio of low density lipoproteins (LDL) to high density lipoproteins (HDL). Treatment with flutamide was associated with a significant decrease in the LDL/HDL ratio by 23% (P = 0.005), in total cholesterol by 18% (P < 0.0001), in LDL by 13% (P = 0.002), and in triglycerides by 23% (P = 0.002). Flutamide treatment was also associated with a trend toward an increase in HDL (by 14%; P = 0.14). The effects on lipid profile were found regardless of obesity and were not associated with a change in weight. Furthermore, actions of flutamide on lipid metabolism were not associated with significant changes in circulating adrenaline or noradrenaline, glucose metabolism, or insulin sensitivity. This report has demonstrated for the first time that treatment with the pure antiandrogen, flutamide, may improve the lipid profile and that this effect may be due to direct inhibition of androgenic actions.
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PMID:The effect of a pure antiandrogen receptor blocker, flutamide, on the lipid profile in the polycystic ovary syndrome. 970 34

Sibutramine (BTS 54 524; N-[1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl]-N,N-dimethylamine hydrochloride monohydrate) is a novel 5-HT (serotonin) and noradrenaline reuptake inhibitor (SNRI) anti-obesity drug. Sibutramine reduces the food intake of rodents and this effect is partially or completely reversed by pretreating with 5-HT or noradrenaline antagonists, indicating that both neurotransmitters are involved in sibutramine's hypophagic effect. In addition, fluoxetine and nisoxetine, which are selective reuptake inhibitors of 5-HT and noradrenaline, respectively, have no effect on food intake when given alone, but they profoundly inhibit food intake when given in combination (equivalent to the actions of the SNRI, sibutramine), demonstrating a synergistic interaction of those two monoamines in the control of ingestive behaviour. Sibutramine reduces food intake by enhancing the physiological response of post-ingestive satiety. This reduction of food intake is a CNS-mediated effect because it is induced by intracerebroventricular injection of sibutramine's potently active secondary and primary amine metabolites (BTS 54 354 and BTS 54 505). Sibutramine increases energy expenditure (thermogenesis) in rats. Once again, whilst fluoxetine and nisoxetine have no thermogenic effect when given alone, the combination of these two selective monoamine reuptake inhibitors profoundly enhances thermogenesis, demonstrating a synergistic interaction of 5-HT and noradrenaline neurotransmission in the regulation of energy expenditure. Sibutramine-induced thermogenesis is abolished by administration of a high non-selective dose of atenolol or ICI 118,551 which blocks beta3-adrenoceptors in addition to beta1- and beta2-adrenoceptors, but not by a low dose of atenolol or ICI 118,551 which blocks beta1- and beta2-adrenoceptors, respectively. Glucose utilization studies demonstrate that sibutramine-induced thermogenesis is mediated via selective sympathetic activation of brown adipose tissue, and it is a centrally mediated effect because it is prevented by pretreating the animals with the ganglionic blocker, chlorisondamine. The SNRI mode of action of sibutramine is clearly differentiated from those of the two major classes of anti-obesity drugs, viz, the 5-HT releasing agents, for example, fenfluramine and dexfenfluramine, and the noradrenaline + dopamine-releasing agents, for example, dexamphetamine. In the case of the 5-HT-releasing agents, this mechanism has been linked in animal studies to profound and prolonged depletion and dysfunction of CNS 5-HT neurons. With noradrenaline + dopamine-releasing agents, it is the enhancement of central dopaminergic function which is believed to be responsible for their stimulant, rewarding and reinforcing properties and it is their releasing mechanism which makes them such powerful psychostimulant drugs of abuse. By utilizing noradrenaline and 5-HT for its anti-obesity effects, sibutramine is differentiated from other weight-reducing drugs which act through either 5-HT alone or noradrenaline + dopamine. In addition, sibutramine is further differentiated because it enhances monoamine function by reuptake inhibition, rather than by monoamine release.
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PMID:Sibutramine: a novel anti-obesity drug. A review of the pharmacological evidence to differentiate it from d-amphetamine and d-fenfluramine. 975 40

Visceral adiposity has a strong and independent association with obesity and its related co-morbidities, particularly metabolic complications such as cardiovascular disease and type II diabetes. Waist circumference and waist-to-hip ratio (WHR) are both secondary indicators of visceral obesity. This paper examines the effect of sibutramine, a new serotonin and noradrenaline re-uptake inhibitor, on weight reduction and changes in fat distribution. A meta-analysis of four long-term, placebo-controlled, double-blind studies showed significantly greater mean decreases in waist circumference in sibutramine-treated subjects compared with placebo (P < 0.001). Similar results were seen for WHR, with 15 mg sibutramine daily producing a significant reduction of 0.02 compared with placebo (P < 0.02). Changes in fat distribution have been examined using computerised tomography (CT) scans as part of the Sibutramine Trial of Obesity Reduction and Maintenance (STORM). Preliminary results showed a mean weight loss from baseline of 11.2 +/- 6.3 kg after 6 months of 10 mg sibutramine treatment. Decreases in total abdominal fat (18%), total subcutaneous fat (17%) and total visceral fat (22%) were observed, and there was a significant increase in the subcutaneous-to-visceral fat ratio (P = 0.04). These changes in fat levels and distribution were associated with improvements in related risk factors such as fasting blood glucose and insulin levels, and blood pressure. In conclusion, sibutramine produces statistically and clinically significant decreases in waist circumference and WHR, and preferentially reduces visceral fat levels.
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PMID:Sibutramine and fat distribution: is there a role for pharmacotherapy in abdominal/visceral fat reduction? 975 42

Sibutramine is a serotonin and noradrenaline re-uptake inhibitor (SNRI) which induces weight loss via a dual mode of action: enhancing both satiety and energy expenditure. Sibutramine exerts its in vivo effects predominantly via its secondary and primary amine metabolites. Following oral ingestion, sibutramine is well absorbed and undergoes extensive first pass metabolism. Sibutramine produces statistically and clinically significant, dose-related weight loss over the range 5-30 mg once daily; active weight loss occurs for 6 months. Long-term studies of up to 1 year have found that weight loss is maintained with continued sibutramine therapy. Sibutramine-induced weight loss is associated with beneficial changes in obesity-related risk factors, such as serum lipids, uric acid levels, and glycaemic control (in patients with type 2 diabetes). Subcutaneous/visceral fat ratio was found to increase significantly under sibutramine treatment, indicating that relatively more visceral fat than subcutaneous fat is lost. Sibutramine is well tolerated; side-effects are generally mild, non-treatment limiting, and consistent with the known mechanism of action of the drug. Overall, studies have found sibutramine to be an effective weight loss agent with a good safety profile.
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PMID:Anti-obesity drugs: what does sibutramine offer? An analysis of its potential contribution to obesity treatment. 979 80

Sibutramine is an orally administered centrally acting weight management agent apparently devoid of amphetamine-like abuse potential. Its primary (M2; BTS 54,505) and secondary (M1; BTS 54,354) amine metabolites are pharmacologically active and are thought to induce the natural processes leading to enhancement of satiety and thermogenesis by inhibiting serotonin (5-hydroxytryptamine, 5-HT) and noradrenaline (norepinephrine) reuptake. In clinical trials, once-daily sibutramine was administered at dosages of < or = 30 mg for < or = 24 weeks and 10 or 15 mg for 1 year in conjunction with reduced calorie intake, increased daily exercise and advice on eating behaviour. Dose-related bodyweight loss was greater with sibutramine than with placebo. Clinical effects were most commonly apparent at dosages > or = 10 mg/day. Weight loss of > 1% within the first month of treatment appears indicative of good long term response with sibutramine. Weight loss was maintained during therapy for 1 year; longer term data are lacking. Weight regain occurred after treatment cessation in studies of < or = 24 weeks' duration; data from longer trials are unavailable. Up to 15% of patients in < or = 6-month studies did not respond to treatment irrespective of dose. Obese patients with type 2 (non-insulin-dependent) diabetes or hypertension lost significantly more mean bodyweight with sibutramine than with placebo, although weight loss was less than that in obese patients without comorbidities. The effect of sibutramine on mean fasting blood glucose levels and plasma lipid levels was unclear. Sibutramine, compared with placebo, statistically significantly increased blood pressure and heart rate in obese patients with or without hypertension when given for up to 12 months. However, after 12 weeks' treatment in hypertensive obese patients, diastolic blood pressure was reduced by similar amounts with sibutramine or placebo. Concerns over potential pressor effects with sibutramine are reflected in the manufacturer's dosage and administration recommendations.
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PMID:Sibutramine. A review of its contribution to the management of obesity. 987 96

The afferent signals that evoke changes in energy intake with regard to body weight regulation are presumed to arise partly from body stores, with the most likely candidate being adipose tissue depots. However, clinical investigation of the neuronal circuitry involved in the central nervous system's processing of such satiety signals remains largely unexplored. Using percutaneously placed catheters in either the right or left internal jugular veins, we were able to quantify the release of central nervous system monoamine and indoleamine neurotransmitters in 64 weight-stable male subjects with varying degrees of adiposity. Veno-arterial plasma concentration differences and internal jugular blood or plasma flow were used, according to the Fick Principle, to quantify the amount of neurotransmitter stemming from the brain. By combining this technique with a noradrenaline and adrenaline isotope dilution method for examining neuronal transmitter release, we were able to examine the association between central nervous system neurotransmitters and efferent sympathetic nervous outflow and adrenomedullary function in human obesity. We found that brain 5-hydroxytryptamine (serotonin) turnover is chronically elevated in proportion to adiposity and is increased postprandially to a similar degree in lean and obese individuals. There was no difference in the degree of sympathetic nervous activity or rate of adrenaline secretion in the subjects examined. It therefore seems that in human obesity, in the face of a chronic elevation in peripheral satiety signals, brain serotonergic processes are switched on accordingly, but the subsequent physiological response involving a reduction in food intake, increased thermogenesis and sympathetic activity is in some way impeded.
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PMID:Human obesity is associated with a chronic elevation in brain 5-hydroxytryptamine turnover. 991


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