Showing papers by "Peter Arner published in 1999"

Catecholamine-induced lipolysis in obesity.

Abstract: Catecholamines are the only hormones with pronounced lipolytic action in man. A number of in vivo and in vitro studies suggest that there is lipolytic resistance to catecholamines in subcutaneous adipose tissue, which is the major fat depot in obese subjects. This is due to multiple alterations in catecholamine signal transduction, involving decreased expression and function of beta2-adrenoceptors, increased function of alpha2-adrenoceptors and decreased ability of cyclic monophosphate (AMP) to stimulate hormone sensitive lipase. A sedentary life-style, which usually characterizes obesity, may contribute to the catecholamine resistance. However, hereditary/genetic factors may also be involved. Recently, decreased expression and function of hormone sensitive lipase has been found in subcutaneous adipocytes of non-obese subjects with heredity for obesity. In addition, polymorphisms in the genes for beta2-adrenoceptors, beta3-adrenoceptors and hormone sensitive lipase, associate with obesity. On the other hand, catecholamine-induced lipolysis in visceral adipose tissue is increased in obesity due to increased function of beta3-adrenoceptors (major finding), decreased function of alpha2-adrenoceptors and increased ability of cyclic AMP to stimulate lipolysis. When the findings in different adipose regions are considered together, it appears that there is a redistribution of lipolysis and thereby fatty acid mobilization in obesity, favouring the visceral fat depot. This leads to an increase in the circulating fatty acid levels in the portal vein, which connects visceral fat with the liver. As a consequence, the liver function may be altered leading to hyperinsulinemia, hyperglycemia and dyslipidemia, which usually accompany the obese state.

Adrenoceptor genes in human obesity.

Abstract: The genes causing obesity in rodent models have been characterized, but do not seem to be important for human obesity. Recently the putative association between obesity and polymorphism in human beta-adrenergic receptor genes have been studied intensely in the light of the important role of these receptors in the regulation of energy mobilization and utilization. A polymorphism (Trp64Arg) in the beta3-adrenergic receptor gene is associated with obesity (relative risk approximately 2) in some but not all investigations on Caucasian and Japanese populations. When expressed in artificial cell systems, the polymorphism is associated with alterations of the beta -adrenoceptor. The genetic allele variance influences also the native receptor function when measured in isolated human fat cells. The human beta2-adrenoceptor gene shows a high degree of polymorphism. The role of beta2-receptor gene polymorphism for obesity has so far only been investigaed in women. A Gln27Glu variant is markedly associated with obesity with a relative risk for obesity of approximately 7 and odds ratio of approximately 10. Women who are homozygous for 27Glu have approximately 20 kg higher fat mass than controls. Thus, polymorphism in genes coding for different beta-adrenoceptor subtypes may be important for the development of human obesity.

Polymorphism of the human beta3-adrenoceptor gene forms a well-conserved haplotype that is associated with moderate obesity and altered receptor function.

Abstract: k g / m 2 ) carried the 3 -Arg haplotype, compared with 11% of those who had a lower BMI (<31 kg/m 2 ), P = 0.02. Furthermore, BMI was ~2 kg/m 2 higher in Arg carriers compared with subjects who were Trp homozygous (P = 0.01) in the lower BMI group. No association of the 3 -Arg haplotype with metabolic parameters or blood pressure was found. F i n a l l y, the sensitivity for CGP12177 (a selective 3 - r e c e p t o r agonist) in visceral adipocytes was decreased 10-fold in 3 Arg compared with that in 3 - Trp subjects (P = 0.01). In conclusion, in this study, a well-conserved 3 -Arg haplotype is associated with moderate overweight and decreased receptor function. The 3 -adrenoceptor, which is mainly expressed in adipose tissue, is a candidate gene for the development of obesity and diabetes (2). Recently, a missense mutation in the coding region of the 3 -adrenoceptor gene was reported that results in the substitution of tryptophan to arginine at codon 64 (Trp64Arg) as reviewed (3). Subjects with the Arg variant had earlier onset of diabetes, increased capacity to gain weight, higher 2-h glucose levels, and higher waist-tohip ratios (WHRs) than did the wild-type subjects. However, several investigators have failed to demonstrate such relationships (4‐7). Furthermore, except for two studies performed in Japanese subjects (8,9), no reports have been able to present an increased frequency of the Arg variant in obesity. Moreover, neither in vitro (7) nor in vivo (10) studies have hitherto shown any significant consequence on adipocyte 3 -adrenoceptor function in subjects with the Trp to Arg substitution. Bearing in mind the reported opposing results on the importance of the Trp64Arg genetic variation, we examined the possibility that several different genetic variants in the 3 -adrenoceptor gene may exist in humans and that they also are functional. The study, which was approved by the Ethics Committee of Karolinska Institute, Stockholm, consisted of 211 nonrelated male or female Swedish subjects (both parents born in Scandinavia) who were either healthy volunteers not selected for body weight (n = 141) or otherwise healthy and drug-free subjects referred to the Department of Medicine because of uncomplicated obesity (n = 70). The subjects were between 19 and 70 years old and were investigated as outpatients. Obese subjects on recent antiobesity treatment or who were treated for diabetes, dyslipidemia, or hypertension were excluded. BMI (kilograms per meter squared) ranged from 18 to 38 kg/m 2 among volunteers and from 31 to 60 kg/m 2 in the subjects referred for obesity treatment. Maybe because of selection, the distribution of BMI was bimodal, with a clear cutoff point at 31 kg/m 2 . Subjects above this cutoff point were d e fined as belonging to the obese group, BMI = 40.9 ± 5.6 kg/m 2 (mean ± SD), and those below were defined as belonging to

A nitric oxide-mediated mechanism regulates lipolysis in human adipose tissue in vivo.

Abstract: 1. Possible nitric oxide (NO)-mediated effects on lipolysis were investigated in vivo in human subcutaneous adipose tissue using microdialysis, as well as in vitro on isolated fat cells of non-obese, healthy volunteers. NO donors were added to the ingoing dialysate solvents. 2. Changes in lipolysis and local blood flow were investigated by measuring glycerol levels and ethanol ratios, respectively, in the microdialysates. 3. It was shown that the NO synthase inhibitor, N(G)-monomethyl L-arginine (L-NMMA), but not the biologically inactive enantiomer N(G)-monomethyl D-arginine (D-NMMA), increased glycerol levels in the microdialysates without causing a change of local blood flow. In addition, L-NMMA increased glycerol levels in the microdialysate when local blood flow was stimulated with hydralazine. 4. Nitric oxide gas as well as the NO donor, nitroglycerine, reduced glycerol release from isolated adipocytes in vitro. 5. Expression of inducible nitric oxide synthase (iNOS) in human adipose tissue was shown by Western blot analysis. Biologically active NOS was demonstrated by measuring total enzymatic activity. 6. In conclusion, the data demonstrate that inhibition of NO release in subcutaneous adipose tissue results in an increased lipolysis in vivo. These effects, which were also observed in vitro, are independent of local blood flow changes. Furthermore, the demonstration of enzymatic NOS activity and the expression of inducible nitric oxide synthase (iNOS) in adipose tissue indicate that locally synthesized NO may play a role in the physiological control of lipolysis in human adipose tissue.

The different effects of a Gln27Glu β2‐adrenoceptor gene polymorphism on obesity in males and in females

Abstract: . Objectives. To investigate the role of a polymorphism in codon 27 (Gln27Glu) of the β2-adrenoceptor gene for obesity in males compared to previously investigated females with an association of this polymorphism to obesity. Design. Population-based study. Setting. Medical department at a University Hospital. Subjects. A total of 138 non-related Swedish males with body mass indexes (BMI) in the range 19.4–53.4 kg m−2 were recruited as: healthy volunteers, healthy obese subjects and subjects undergoing surgery for uncomplicated gallstone or abdominal hernia. In order to investigate the impact of gender, the results were compared with a subset of an earlier investigated female population of 109 Swedish females. Obesity was defined as a BMI > 27 kg m−2. Main outcome measures. Genotype examination of β2-adrenoceptor polymorphism in codon 27 with polymerase chain reaction and restriction fragment length polymorphism. Results. The allele frequency of Gln27 and Glu27 did not differ between males and females when obese and non-obese subjects were investigated together. However, in obese males, the frequency of the Glu27 allele was significantly decreased (P = 0.034), whereas the frequency of this allele was increased in obese females (P = 0.013). No impact of the female androgen status on the distribution of the Gln27Glu polymorphism could be demonstrated in the obese females. Conclusion. A positive association between obesity and the Glu27 genetic variant in the β2-adrenoceptor exists in females, whereas in males there is a negative correlation between Glu27 and obesity. The findings suggest that different genetic factors contribute to obesity in males and females.

Divergent effects of weight reduction and oral anticonception treatment on adrenergic lipolysis regulation in obese women with the polycystic ovary syndrome.

Abstract: The influence of weight reduction and female sex hormones on the regulation of lipolysis was investigated in isolated abdominal sc adipocytes from 20 obese hyperandrogenic women with polycystic ovary syndrome (PCOS). Nine PCOS women were reinvestigated after 8-12 weeks of weight reduction therapy (WR) with a very low calorie diet, inducing a mean loss of 8 +/- 3 kg, and 8 PCOS women were reinvestigated after 12 weeks of treatment with combined oral contraceptives (OC), containing ethinyl estradiol and norethisterone; the remaining 3 subjects were drop-outs. Both WR and OC normalized hyperandrogenicity. WR caused a 50% reduction of basal lipolysis rate and a 5- to 7-fold increased noradrenaline and terbutaline sensitivity (P < 0.02); the latter could be ascribed to a 2-fold increased beta2-adrenoceptor density (P < 0.02) as determined with radioligand binding. There was no change with regard to dobutamine (beta1-adrenoceptor sensitivity) or clonidine, (alpha2-adrenoceptor sensitivity) or to beta1-adrenoceptor density. OC treatment did not influence the basal lipolysis rate or beta2- or alpha2-adrenoceptor sensitivity, but lowered the beta1-adrenoceptor sensitivity 7-fold (P < 0.03) without a reduction in beta1-adrenoceptor density. The OC treatment effect was not observed when forskolin and dibutyryl cAMP, acting on adenylate cyclase or protein kinase A, respectively, were used, suggesting a partial uncoupling of beta1-adrenoceptors. WR therapy, but not OC therapy, caused, in addition to changes in lipolysis function, improved in vivo insulin sensitivity and lower plasma noradrenaline levels. These findings suggest that factors other than hyperandrogenicity modulate lipolysis regulation in obese subjects with PCOS. Disturbances in sympathetic pathways could be of pathogenic importance.

Microdialysis: use in human exercise studies.

Abstract: Microdialysis has been used for 25 years to study brain function in vivo. Recently, it has been developed for investigations on peripheral tissues. A microdialysis catheter is an artificial blood vessel system which can be placed in the extracellular space of various tissues such as adipose tissue and skeletal muscle in order to examine these tissues in situ. Molecules are collected from the tissue by the device and their true interstitial concentration can be estimated. Metabolically-active molecules can be delivered to the interstitial space through the microdialysis probe and their action on the tissue can be investigated locally without producing generalized effects. It is also possible to study local tissue blood flow with microdialysis by adding a flow marker (usually ethanol) to the microdialysis solvent. The microdialysis technique is particularly useful for studies of small and water-soluble molecules. A number of important observations on the in vivo regulation of lipolysis, carbohydrate metabolism and blood flow in human skeletal muscle and adipose tissue have been made recently using microdialysis.

The role of sulphonylurea in combination therapy assessed in a trial of sulphonylurea withdrawal

Abstract: AIMS: To evaluate the effect of adding insulin to sulphonylurea (SU) and the effect of SU withdrawal on glycaemic control in Type 2 diabetic patients who failed on treatment with SU alone.METHOD: One hundred and seventy-five patients were included in a placebo-controlled multicentre study. During phase I (4 months), premixed insulin was added to glibenclamide therapy; during phase II (1-4 months, depending on response) the insulin dose was fixed, while placebo or glibenclamide replaced the open SU therapy. Insulin sensitivity (KITT), beta-cell function (C-peptide) and metabolic control (HbA1c) were monitored.RESULTS: HbA1c improved from 9.65% to 7.23% (P or =40% during phase II were defined as 'SU responders' by protocol. In a multivariate analysis only a long duration of diabetes was associated with SU response. There were more GAD-antibody-positive patients among non-responders (18% vs. 4%, P = 0.0263).CONCLUSIONS: Poor glycaemic control in combination with preserved insulin sensitivity and lack of GAD antibodies predicts a beneficial response to combination therapy, which can be achieved in 75% of patients with SU failure. (Less)

In vivo studies on insulin permeability of an immunoisolation device intended for islet transplantation using the microdialysis technique.

Abstract: In this study, insulin was injected into TheracyteTM immunoisolation devices to analyze changes in the permeability of the device over time after implantation. The recovery of insulin was s