Showing papers by "Peter Arner published in 1997"

Human beta-2 adrenoceptor gene polymorphisms are highly frequent in obesity and associate with altered adipocyte beta-2 adrenoceptor function.

Abstract: Catecholamines play a central role in the regulation of energy expenditure, in part by stimulating lipid mobilization through lipolysis in fat cells The beta-2 adrenoceptor (BAR-2) is a major lipolytic receptor in human fat cells To determine whether known polymorphisms in codons 16, 27, and 164 of this receptor play a role in obesity and subcutaneous adipocyte BAR-2 lipolytic function, we investigated a group of 140 women with a large variation in body fat mass Only the polymorphisms in codons 16 and 27 were common in the study population The Gln27Glu polymorphism was markedly associated with obesity with a relative risk for obesity of approximately 7 and an odds ratio of approximately 10 Homozygotes for Glu27 had an average fat mass excess of 20 kg and approximately 50% larger fat cells than controls However, no significant association with changes in BAR-2 function was observed The Arg16Gly polymorphism was associated with altered BAR-2 function with Gly16 carriers showing a fivefold increased agonist sensitivity and without any change in BAR-2 expression However, it was not significantly linked with obesity These findings suggest that genetic variability in the human BAR-2 gene could be of major importance for obesity, energy expenditure, and lipolytic BAR-2 function in adipose tissue, at least in women

Leptin secretion from adipose tissue in women. Relationship to plasma levels and gene expression.

Abstract: The role of expression and secretion of the ob gene product, leptin, for the regulation of plasma leptin levels has been investigated in vitro using abdominal subcutaneous adipose tissue of 20 obese, otherwise healthy, and 11 nonobese women. Body mass index (BMI, mean+/-SEM; kg/m2) in the two groups was 41+/-2 and 23+/-1, respectively. Fat cell volume was 815+/-55 pl in the obese and 320+/-46 pl in the nonobese group. In the obese group, plasma leptin concentrations and adipose leptin mRNA (relative to gamma actin) were increased five and two times, respectively. Moreover, adipose tissue secretion rates per gram lipid weight or per fat cell number were also increased two and seven times, respectively, in the obese group. There were strong linear correlations (r = 0.6-0.8) between plasma leptin, leptin secretion, and leptin mRNA. All of these leptin measurements correlated strongly with BMI and fat cell volume (r = 0.7- 0.9). About 60% of the variation in plasma leptin could be attributed to variations in leptin secretion rate, BMI, or fat cell volume. We conclude that elevated circulating levels of leptin in obese women above all result from accelerated secretion rates of the peptide from adipose tissue because of increased ob gene expression. However, leptin mRNA, leptin secretion, and circulating leptin levels are all more closely related to the stored amount of lipids in the fat cells of adipose tissue than they are to an arbitrary division into obese versus nonobese.

Differential Regulation of the p80 Tumor Necrosis Factor Receptor in Human Obesity and Insulin Resistance

Abstract: Previous studies have shown that tumor necrosis factor (TNF)-alpha production from adipose tissue is elevated in rodent and human obesity and plays an important role in insulin resistance in experimental animal models. In this study, we examined the adipose expression of both TNF receptors (TNFR1 and TNFR2) in human obesity and demonstrated that obese female subjects express approximately twofold more TNFR2 mRNA in fat tissue and approximately sixfold more soluble TNFR2 in circulation relative to lean control subjects. In contrast, TNFR1 expression and protein levels were similar in these subjects. TNFR2 expression levels in adipose tissue were strongly correlated with BMI (r = 0.65, P < 0.001) and level of hyperinsulinemia (P < 0.001), an indirect measure of insulin resistance, as well as level of TNF-alpha mRNA expression in fat tissue (r = 0.56, P < 0.001). These results suggest that TNFR2 might play a role in human obesity by modulating the actions of TNF-alpha.

Sex Differences in Visceral Fat Lipolysis and Metabolic Complications of Obesity

Abstract: Cardiovascular complications of obesity are more common in men than women. Sex differences in visceral fat lipolysis may be of importance in this respect, since increased release of free fatty acids (FFAs) from visceral fat to the liver by the portal venous system has been thought to cause several metabolic complications due to obesity, such as hypertension, hyperlipidemia, and glucose intolerance. The aim of this study was to investigate sex differences in clinical characteristics and visceral fat mobilization in obesity. Obese subjects (22 male and 23 female) undergoing elective surgery were matched for body mass index and age. The males had both higher waist-to-hip ratio (WHR), sagittal diameter, blood pressure, fat-cell volume, plasma insulin, glucose, and triglyceride and lower HDL cholesterol levels than the females. The rate of norepinephrine-induced FFA and glycerol release was twofold higher in men ( P =.02). No significant reutilization of FFA was observed. The difference in maximum norepinephrine-induced rate of lipolysis between men and women was independent of both WHR and sagittal diameter and was an independent regressor for levels of plasma glucose and plasma HDL cholesterol. Fat-cell volume was an independent regressor for plasma triglycerides and blood pressure. No sex differences in the lipolytic sensitivity to β 1 - or β 2 -adrenoceptor–specific agonists or in the antilipolytic effect of insulin were observed. However, the lipolytic β 3 -adrenoceptor sensitivity was 12 times higher ( P =.004) and the antilipolytic α 2 -adrenoceptor sensitivity 17 times lower ( P =.003) in men. Furthermore, lipolysis induced by agents acting at the adenylate cyclase and protein kinase A levels were almost twofold enhanced in men. However, no sex difference in maximum hormone-sensitive lipase activity was observed. In conclusion, in obesity, catecholamine-induced rate of FFA mobilization from visceral fat to the portal venous system is higher in men than women. This phenomenon is partly due to a larger fat-cell volume but also to a decrease in the function of α 2 -adrenoceptors, an increase in the function of β 3 -adrenoceptors, and an increased ability of cyclic AMP to activate hormone-sensitive lipase. These factors may contribute to gender-specific differences in metabolic and cardiovascular disturbances accompanied by obesity.

Absolute concentrations of glycerol and lactate in human skeletal muscle, adipose tissue, and blood.

Abstract: The absolute concentrations of glycerol and lactate were studied with microdialysis of adipose tissue and skeletal muscle in normal-weight subjects. The basal interstitial glycerol concentration was 232 +/- 33, 96 +/- 8, and 59 +/- 6 mumol/l in fat, muscle, and arterialized plasma, respectively (P = 0.0002). This relationship was maintained during both euglycemic hyperinsulinemia, when glycerol decreased in all three compartments, and hypoglycemia, when glycerol first decreased and then increased in fat, muscle, and blood (P = 0.0001 for both). Basal interstitial lactate concentrations were similar in adipose tissue (1.1 +/- 0.2 mmol/l) and skeletal muscle (1.9 +/- 0.4 mmol/l) and higher than in arterialized blood (0.6 +/- 0.1 mmol/l, P = 0.002). During hyperinsulinemia and hypoglycemia, lactate increased (P = 0.0001) and the tissue-blood relationship was maintained (P = 0.04). In conclusion, adipose tissue and skeletal muscle mobilize glycerol and lactate at rest. Glycerol and lactate production are influenced by hyperinsulinemia and hypoglycemia in both tissues. Adipose tissue appears to be the major site of glycerol production, whereas skeletal muscle and fat may be equally important for lactate production.

Impaired adipocyte lipolysis in nonobese women with the polycystic ovary syndrome: a possible link to insulin resistance?

Abstract: The polycystic ovary syndrome (PCOS) is the most common hyperandrogenic disorder among women and is characterized by metabolic and cardiovascular aberrations similar to those seen in the so-called insulin resistance syndrome. The regulation of lipolysis was investigated in isolated abdominal sc adipocytes from 10 nonobese women with PCOS and in 11 age- and body mass index-matched healthy women. Eight PCOS women were reinvestigated after 3 months of treatment with combined oral contraceptives containing ethinyl estradiol and norethisterone, which normalized hyperandrogenicity. The PCOS women showed a marked resistance to the lipolytic effect of noradrenaline due to defects at two different levels in the lipolytic cascade: first, a 7-fold reduction in sensitivity to the beta 2-selective agonist terbutaline (P < 0.005), which could be ascribed to a 50% lower beta 2-adrenoceptor density (P < 0.02) as determined with radioligand binding; there was no difference with regard to dobutamine (beta 1) or clonidine (alpha 2-sensitivity) or beta 1-adrenoceptor density; second, the maximum lipolytic response was also 35% lower (P < 0.02) in the PCOS women compared to that in the healthy women. This was seen with all beta-adrenergic agonists and the postreceptor-acting agents forskolin (activating adenylyl cyclase) and dibutyryl cAMP (activating protein kinase). Neither beta 2-adrenoceptor sensitivity or density nor the reduced lipolytic responsiveness was restored by 3 months of oral contraceptives treatment. The results indicate the existence of a marked impairment of catecholamine-induced lipolysis in nonobese PCOS women displaying early features of the insulin resistance syndrome due to multiple lipolysis defects as a lower beta 2-adrenoceptor density and reduced function of the protein kinase, hormone-sensitive lipase complex. These lipolysis defects are identical to those observed in the insulin resistance (metabolic) syndrome and could be a primary pathogenic mechanism for the development of these disorders.

Relationship between circulating leptin and peripheral fat distribution in obese subjects.

Abstract: BACKGROUND: Abdominal obesity is an important risk factor for the development of non-insulin dependent diabetes mellitus and other atherogenic disorders. The recently discovered fat-derived hormone leptin has been proposed to regulate adiposity through stimulation of satiety and increased energy expenditure. This study was undertaken to examine the relationship between fasting plasma leptin, body fat distribution and atherogenic complications in markedly obese adult subjects. SUBJECTS: The study comprised 29 women and 26 men who all were obese but otherwise healthy (body mass index, BMI, 33–60 kg/m2). RESULTS: In 37 of the obese subjects, who were characterized in detail, the fasting plasma leptin levels correlated with plasma insulin (−0.34) but not in a significant way with blood pressure, insulin sensitivity, plasma glucose tolerance or circulating concentrations of glucose, lipoproteins, catecholamines or plasminogen activator inhibitor-1. In the whole patient material the fasting plasma leptin levels were two times higher in women than in men who had similar body mass index values (P<0.0001), In spite of the fact that all subjects were massively obese, the plasma leptin values correlated positively with BMI (r=0.39, P=0.004). On the other hand, there was a negative correlation between plasma leptin and waist-to-hip ratio (r=0.65, P=0.0001), which was independent of BMI. CONCLUSION: Except for a quite weak relationship with fasting plasma insulin, leptin appears not to be associated with classical metabolic atherogenic complications to obesity. Instead, it may protect obese subjects with a gynoid fat distribution from metabolic complications. About 40% of the variation in leptin in massively obese subjects could in fact be explained by peripheral fat distribution.

Self-Monitoring of Blood Glucose in Type I Diabetic Patients: Comparison With Continuous Microdialysis Measurements of Glucose in Subcutaneous Adipose Tissue During Ordinary Life Conditions

Abstract: OBJECTIVE To evaluate whether frequent self-monitoring of blood glucose (SMBG) sufficiently reflects the true diurnal glucose control during ordinary daily life in type I diabetic patients. RESEARCH DESIGN AND METHODS By using a microdialysis technique, continuous monitoring of adipose tissue glucose was performed in 24 type I diabetic patients during ambulatory conditions. A microdialysis probe was implanted subcutaneously and perfused by a portable microinfusion pump. Dialysate fractions were collected in 1- to 2-h samples during 3 consecutive days. The diurnal microdialysis glucose profiles were compared with those obtained by SMBG recordings performed seven times a day. RESULTS In seven patients, the SMBG profiles showed marked aberrations as compared to the continuous microdialysis glucose recordings; during the 3-day study period, 5–6 inconsistencies were registered. In only 4 patients (17%) did SMBG provide a valid reflection (0–2 inconsistencies) of the diurnal glucose profile, whereas in 13 patients the SMBG recordings paralleled the diurnal adipose tissue glucose profiles in an intermediate way (3–4 major inconsistencies). The inaccuracy of the SMBG data was due more often to the fact that wide glucose swings remained unrecognized, rather than to erroneous testing techniques ( P P CONCLUSIONS In many type I diabetic patients, the true diurnal variability in glycemia is too great to be accurately reflected even by frequent self-monitoring of blood glucose.

Noradrenaline-induced lipolysis in isolated mesenteric, omental and subcutaneous adipocytes from obese subjects.

Abstract: OBJECTIVE: The action of noradrenaline on human mesenteric, omental and subcutaneous adipocytes was compared. We also determined whether regional differences in the noradrenaline-effect were linked to variations in adrenoceptor subtype function. DESIGN: The lipolytic effects of different concentrations of noradrenaline (b1-, b2-, bb3- and a2-adrenoceptor agonist), isoprenaline (b1-, bb2- and b3-adrenoceptor agonist) and selective bb1-, bb2- and bb3-adrenoceptor agonists (dobutamine, terbutaline and CGP 12177, respectively) were studied in adipocytes isolated from the three adipose tissue regions in the same subject. In addition, the effect of the a2-adrenoceptor antagonist, yohimbine, was studied on noradrenalineinduced glycerol release. SUBJECTS: Thirteen otherwise healthy obese subjects (nine females, four males). RESULTS: The noradrenaline-induced lipolytic response did not differ between omental and mesenteric adipocytes but was 50% higher than in subcutaneous adipocytes (P< 0.05). Furthermore, noradrenaline sensitivity and intrinsic activity (in relation to isoprenaline) were higher in the two visceral fat cells than in the subcutaneous fat cells. The intrinsic activity of noradrenaline increased close to that of isoprenaline when yohimbine was added to the incubation system. Isoprenaline sensitivity was five times higher in the two visceral fat cells than in the subcutaneous fat cells. For CGP 12177, sensitivity and intrinsic activity did not differ between mesenteric and omental adipocytes, but was higher in these two regions when compared to subcutaneous adipocytes. For dobutamine and terbutaline no significant regional differences were found. CONCLUSION: bb3-adrenoceptor action is enhanced and a2-adrenoceptor action is decreased in both mesenteric and omental adipocytes as compared to subcutaneous adipocytes. However, the two visceral fat depots show no difference in adrenoceptor function. The difference in b3- and a2-adrenoceptor function might explain why noradrenaline induced lipolysis is increased in the two visceral fat depots, as compared to the subcutaneous fat depot.

Adipose tissue lipoprotein lipase and hormone-sensitive lipase. Contrasting findings in familial combined hyperlipidemia and insulin resistance syndrome

Abstract: The metabolism of free fatty acids (FFA) is altered in two common atherosclerosis-promoting disorders: familial combined hyperlipidemia (FCHL) and insulin resistance syndrome (IRS). It has been suggested that these two conditions may have a common etiology. The enzymes lipoprotein lipase (LPL) and hormone-sensitive lipase (HSL) are rate-limiting steps for the turnover of fatty acids in adipose tissue, because they hydrolyze extracellular triglycerides in lipoproteins (LPL) and intracellular triglycerides in adipocytes (HSL). The present study was undertaken to simultaneously determine the activities of LPL and HSL in subcutaneous adipose tissue from male patients with FCHL and IRS. LPL and HSL activity was investigated in 10 nonobese FCHL patients and compared with 10 matched healthy nonobese subjects, and in 8 essentially normolipidemic IRS patients (who did not have overt diabetes mellitus) and compared with 9 nonobese matched control subjects. LPL activity was 43% lower in patients with IRS (P...

A circadian rhythm in lipid mobilization which is altered in IDDM.

Abstract: It is not clear how circadian lipolysis and circulating concentrations of non-esterified fatty acids (NEFA) are altered in intensively treated insulin-dependent diabetic (IDDM) patients. Ten IDDM patients on an intensive insulin regimen and eight healthy control subjects were investigated under ordinary living conditions for 27 h by microdialysis of subcutaneous adipose tissue. The true tissue glycerol concentration and adipose blood flow changes were monitored as an index of lipolysis. A circadian pattern in adipose tissue lipolysis was observed in both groups, decreasing during the day and increasing during evening-night. The daytime decrease was normal, but the evening-night rise was elevated in IDDM (p = 0.03). Circulating NEFA decreased during the day and increased at night. The latter increase was enhanced threefold in IDDM (p = 0.003) and correlated with fasting glucose levels (r = 0.77). Nocturnal growth hormone (GH) was increased fivefold in IDDM and correlated to nocturnal lipolysis (r = 0.83). Adipose tissue blood flow increased during the night in a similar fashion in both groups. Near-normalization of glucose for 24 h in IDDM did not affect the nocturnal increases in NEFA, GH and lipolysis. In conclusion, a circadian rhythm in lipolysis was found. Increased lipolytic rates during evening-night may at least in part raise nocturnal circulating NEFA. Nocturnal NEFA and lipolysis are further enhanced in IDDM, maybe due to elevated GH, but not to insulinopenia or hyperglycaemia.

Catecholamine-induced adipocyte lipolysis in human hyperthyroidism.

Abstract: Increased lipid mobilization in thyrotoxicosis is attributed to amplification of catecholamine action in fat cells by thyroid hormones. We investigated the adrenergic regulation of lipolysis in isolated sc abdominal fat cells obtained from 14 patients with thyrotoxicosis and 18 control subjects. Ten of the hyperthyroid subjects were also reinvestigated after antithyroid treatment. The thyrotoxic state was associated with a 3-fold increase in maximum norepinephrine-induced lipolysis (P < 0.005), unaltered sensitivity to dobutamine (selective beta 1-adrenoceptor agonist) and clonidine (selective alpha 2-adrenoceptor agonist), but 15 times enhanced sensitivity to terbutaline (selective beta 2-adrenoceptor agonist; P < 0.01). Moreover, thyrotoxicosis was accompanied by a 3-fold increase in beta 2-adrenoceptor number (P < 0.005), but unchanged beta 1-adrenoceptor levels. Further, the lipolytic effects of dibutyryl cAMP (activating protein kinase A and thereby hormone-sensitive lipase) and forskolin (activating adenylate cyclase) were about 60% enhanced (P < 0.005). No change in the maximum activity of the hormone-sensitive lipase could be demonstrated in the hyperthyroid state compared to that in the euthyroid state. The observed abnormalities in lipolysis and beta 2-adrenoceptor number were normalized after antithyroid treatment. It is concluded that in human hyperthyroidism, the interactions between thyroid hormone and catecholamines in adipocytes involve abnormalities at both receptor and postreceptor levels. The former mechanism seems to be a selective increase in the expression of the beta 2-adrenoceptors. The latter mechanism involves increased ability of cAMP to activate hormone-sensitive lipase, but not a change in maximum enzyme capacity.

Is familial combined hyperlipidaemia a genetic disorder of adipose tissue

Abstract: Familial combined hyperlipidaemia is a common cause of coronary heart disease. Its aetiology is heterogeneous. The genetic and metabolic basis of the disorder has not yet been defined. This review discusses the putative role of adipose tissue in the pathogenesis of familial combined hyperlipidaemia.

Low circulating leptin levels in protein‐energy malnourished chronically ill elderly patients

Abstract: Cederholm T, Arner P, Palmblad J (Karolinska Institute at the Centre for Inflammation & Hematology Research, and Huddinge University Hospital, Huddinge, Sweden). Low circulating leptin levels in protein-energy malnourished chronically ill elderly patients. J Intern Med 1997; 242: 377–82. Objective To evaluate serum leptin, a fat cell-derived protein, levels in relation to the malnutrition often observed in chronic disease. Design A comparison of circulating leptin concentrations in malnourished chronically ill elderly and in age-matched controls. Setting A university-affiliated teaching hospital in Stockholm, Sweden. Subjects Nineteen protein–energy malnourished elderly patients (74 ± 1 years) with various chronic nonmalignant diseases and 18 healthy controls (72 ± 1 years). Main outcome measures Serum leptin levels measured by radioimmunoassay technique, nutritional status as expressed by body mass index (kg m−2), triceps skin fold, arm muscle circumference and serum albumin, and serum orosomucoid concentrations indicating inflammatory status. Results Patients and controls displayed body mass indexes of 17.4 ± 0.7 and 25.0 ± 1.1 (P < 0.001), respectively. Triceps skin fold (TSF) measurements revealed a pronounced fat depletion in the patients, being 8.5 ± 0.9 and 22.3 ± 1.5 mm (P < 0.001) in female and 6.1 ± 0.7 and 10.8 ± 0.8 mm (P < 0.001) in male patients and controls, respectively. Patient serum leptin concentrations were less than half of the corresponding concentrations in the controls, 4.3 ± 1.1 and 9.3 ± 1.3 ng mL−1 (P < 0.01), respectively. The highest leptin concentrations were registered in female controls, 12.1 ± 1.6 ng mL−1. The serum leptin levels in the controls correlated with TSF (r= 0.74; P < 0.001). No such correlation was found in the patients. Conclusions Serum leptin levels were low and did not seem to be directly associated with fat and muscle depletion in elderly patients with chronic illness, whereas they appeared to be positively correlated to body fat in healthy elderly.

Lipolysis in human fat cells obtained under local and general anesthesia

Abstract: OBJECTIVES: As adipose tissue is usually obtained during local or general anesthesia in clinical studies, these two forms of anesthesia were presently compared as regards lipolysis induced by catecholamines in isolated human fat cells. DESIGN: Fat samples from the abdominal subcutaneous region were obtained first during local anesthesia (lidocaine) given so that the anesthetic agent did not influence lipolysis and second, during gastric banding under general anesthesia (propofol) immediately after skin incision. SUBJECTS: Eleven obese patients, drug free and otherwise healthy. MEASUREMENTS: Isolated fat cells were incubated in the presence or absence of increasing concentrations of different lipolysis agents, acting at adrenoceptor or various post-receptor levels in the lipolytic cascade. Glycerol release to the incubation medium was measured as an index of lipolysis. RESULTS: All agonists caused a concentration dependent increase (terbutaline, dobutamine, CGP 12177, forskolin, dibutyryl cyclic AMP, isoprenaline and noradrenaline) or inhibition (clonidine) of glycerol release. The comparison of data from local and general anesthesia procedures showed no statistical difference in glycerol response for any of the drugs used. CONCLUSIONS: Adrenergic regulation of lipolysis is not influenced by the mode of sampling, at least not in subcutaneous fat cells of obese subjects obtained during local anesthesia with lidocaine as compared to general anesthesia with propofol.

Forskolin potentiates isoprenaline-induced glycerol output and local blood flow in human adipose tissue in vivo.

Abstract: Department of Vascular Surgery, Huddinge University Hospital, Karolinska Institute, Sweden. The synergistic action of forskolin on beta-adrenoceptor-mediated glycerol output and changes in local blood flow were investigated in situ, in human adipose tissue of healthy subjects, by the use of microdialysis. The addition of isoprenaline 0.1-1.0 microM or forskolin 10-100 microM to the perfusion solvent caused a concentration-dependent, marked and sustained increase in the levels of glycerol in the dialysate (lipolysis index) as compared to the solvent alone. On a molar basis, isoprenaline was almost one thousand times more potent than forskolin. Isoprenaline caused a rapid and concentration-dependent decrease in the ethanol clearance ratio (index of local blood flow, i.e. a decrease in ethanol ratio implies an increase in blood flow). Forskolin had no effect on the ethanol ratio at either 1.0 microM or 10 microM, while forskolin at 100 microM induced a significant decrease in the ethanol ratio. When adipose tissue was pre-treated with forskolin, the subsequent addition of isoprenaline to the microdialysate resulted in a significantly higher glycerol output and a significantly more prominent decrease in the ethanol ratio than with isoprenaline alone. In conclusion, the data demonstrate that forskolin and the (beta-adrenoceptor-agonist both stimulate lipolysis and local blood flow in human adipose tissue in vivo. Furthermore, forskolin, at concentrations that are ineffective alone, potentiates the actions of isoprenaline on lipolysis and blood flow.