Waist circumference to assess reversal of insulin resistance following weight reduction after bariatric surgery: cohort and cross-sectional studies.

OBJECTIVE: To validate the use of waist circumference to assess reversal of insulin resistance after weight loss induced by bariatric surgery. DESIGN: In cross-sectional studies, threshold values for insulin resistance were determined with homeostasis model assessment of insulin resistance (HOMA-IR) (algorithm based on fasting plasma glucose and insulin) in 1018 lean subjects and by hyperinsulinemic euglycemic clamp (clamp) in 26 lean women. In a cohort study on 211 patients scheduled for bariatric surgery, HOMA-IR and waist circumference were measured before and 1.5-3 years after weight reduction. In a subgroup of 53 women, insulin sensitivity was also measured using clamp. RESULTS: The threshold for insulin resistance (90th percentile) was 2.21 (mg dl(-1) fasting glucose × mU l(-1) fasting insulin divided by 405) for HOMA-IR and 6.118 (mg glucose per kg body weight per minute) for clamp. Two methods to assess reversal of insulin resistance by measuring waist circumference were used. A single cutoff value to <100 cm for waist circumference was associated with reversal of insulin resistance with an odds ratio (OR) of 49; 95% confidence interval (CI)=7-373 and P=0.0002. Also, a diagram based on initial and weight loss-induced changes in waist circumference in patients turning insulin sensitive predicted reversal of insulin resistance following bariatric surgery with a very high OR (32; 95% CI=4-245; P=0.0008). Results with the clamp cohort were similar as with HOMA-IR analyses. CONCLUSIONS: Reversal of insulin resistance could either be assessed by a diagram based on initial waist circumference and reduction of waist circumference, or by using 100 cm as a single cutoff for waist circumference after weight reduction induced by bariatric surgery.

Regional impact of adipose tissue morphology on the metabolic profile in morbid obesity.

AIMS/HYPOTHESIS: The aim of this study was to determine whether the mean size of fat cells in either visceral or subcutaneous adipose tissue has an impact on the metabolic and inflammatory profiles in morbid obesity. METHODS: In 80 morbidly obese women, mean visceral (omental) and subcutaneous fat cell sizes were related to in vivo markers of inflammation, glucose metabolism and lipid metabolism. RESULTS: Visceral, but not subcutaneous, adipocyte size was significantly associated with plasma apolipoprotein B, total cholesterol, LDL-cholesterol and triacylglycerols (p ranging from 0.002 to 0.015, partial r ranging from 0.3 to 0.4). Subcutaneous, but not visceral, adipocyte size was significantly associated with plasma insulin and glucose, insulin-induced glucose disposal and insulin sensitivity (p ranging from 0.002 to 0.005, partial r ranging from -0.34 to 0.35). The associations were independent of age, BMI, body fat mass or body fat distribution. Adipose tissue hyperplasia (i.e. many small adipocytes) in both regions was significantly associated with better glucose, insulin and lipid profiles compared with adipose hypertrophy (i.e. few large adipocytes) in any or both regions (p ranging from <0.0001 to 0.04). Circulating inflammatory markers were not associated with fat cell size or corresponding gene expression in the fat cell regions examined. CONCLUSIONS/INTERPRETATION: In morbidly obese women region-specific variations in mean adipocyte size are associated with metabolic complications but not systemic or adipose inflammation. Large fat cells in the visceral region are linked to dyslipidaemia, whereas large subcutaneous adipocytes are important for glucose and insulin abnormalities. Hyperplasia (many small adipocytes) in both adipose regions may be protective against lipid as well as glucose/insulin abnormalities in obesity.

Beta3-adrenoceptor function and long-term changes in body weight.

BACKGROUND: The endogenous factors contributing to long-term changes in body weight are not known but the regulation of energy metabolism by different beta-adrenoceptors (beta(1)-AR, beta(2)-AR, beta(3)-AR) or alpha-adrenoceptors (alpha(2)-AR) may play a role. METHODS: In a prospective study, we investigated beta-AR and alpha(2)-AR subtype function in subcutaneous fat cells of 85 healthy, non-obese women by using a standardized bioassay of lipolysis. Of these 73 were re-investigated on an average 10 years later to compare baseline function of beta(1)-AR, beta(2)-AR, beta(3)-AR and alpha(2)-AR with longitudinal weight changes. RESULTS: Weight change over time was normally distributed ranging from-4 kg/m(2) to +6 kg/m(2) in body mass index. Long-term changes in body weight correlated inversely with beta(3)-AR function at base line (r=0.5, P=0.001). Those with low beta(3)-AR function gained weight, whereas the opposite was observed with those who had a high beta(3)-AR function. Nineteen percent of weight changes could be explained by beta(3)-AR status. No relationship with weight changes was observed as regards the function of alpha(2)-AR, beta(1)-AR or beta(2)-AR function. CONCLUSIONS: Beta(3)-ARs are important for long-term changes in body weight putting energy metabolism in adipose tissue in frontline among endogenous factors that regulate body weight in adulthood.

The role of adrenal scintigraphy in the preoperative management of primary aldosteronism.

BACKGROUND AND AIMS: Differentiation between the two major subgroups of primary aldosteronism, bilateral hyperplasia and aldosterone producing adenoma is essential since therapy in the former is medical and in the latter surgical. The aim of the present study was to evaluate the clinical utility of adrenocortical scintigraphy in the management of primary aldosteronism. MATERIAL AND METHODS: [131I] norcholesterol (NP-59) scintigraphy with dexamethasone suppression for subclassification and lateralization of primary aldosteronism was evaluated in 49 patients with long-term follow-up after diagnosis and treatment. RESULTS: Thirty-three patients with the diagnosis of aldosterone producing adenoma were operated with adrenalectomy. Preoperative scintigraphy showed lateralized isotope uptake in 27/33 patients while 6 showed no uptake. Twenty-two were cured and three significantly improved. Thus, in 25/33 (76%), scintigraphy showed the correct side as the patients benefited of surgery. Two patients did not improve. Fourteen patients with a probable diagnosis of bilateral hyperplasia had normal scintigraphies. CONCLUSIONS: In the present retrospective study we found limited sensitivity of NP-59 scintigraphy. However, when a lateralized scintigraphic uptake is achieved it has a high accuracy. Scintigraphy may be used as an adjunct in cases where adrenal venous sampling is inconclusive.

No difference in lipolysis or glucose transport of subcutaneous fat cells between moderate-fat and low-fat hypocaloric diets in obese women.

The objective of the present study was to evaluate the effect of two different diets on lipolysis and lipogenesis in subcutaneous fat cells from obese women. In a ten-week nutritional intervention study, forty women were randomly assigned to a hypoenergetic-2,514 kJ (- 600 kcal/day) diet of either moderate-fat/moderate-carbohydrate or low-fat/high-carbohydrate content. Body weight was equally reduced by approximately 7.5 % in both diet groups (p = 0.58). A subcutaneous adipose tissue biopsy was obtained for subsequent measurement of triglyceride breakdown (lipolysis) using drugs active at different steps of the lipolytic signaling cascade, and lipid synthesis (glucose transport) before and after intervention. No difference was found between the two diet groups at the maximum rate of either lipolysis or adrenoceptor sensitivity (p-values: 0.14 - 0.97). Inhibition of lipolysis by insulin was also similar in both diet groups before and after intervention. Finally, insulin-stimulated glucose transport did not show any changes that could be attributed to the type of diet. In conclusion, our data suggest that macronutrient diet composition has no major influence on glucose transport or mobilization of triglycerides in human subcutaneous fat cells of obese women.

Mechanisms behind gender differences in circulating leptin levels.

OBJECTIVES: To investigate gender differences in circulating leptin levels and adipose tissue production of leptin. DESIGN SETTING AND SUBJECTS: Thirty-two men and 63 women with a large interindividual variation in body mass index (BMI), but otherwise healthy, were investigated after an overnight fast. Body fat (bioimpedance), abdominal subcutaneous adipose tissue secretion of leptin in vitro and serum leptin were determined. RESULTS: Although there was no gender difference in mean BMI or fat cell size, mean percentage body fat was 49 in women and 36 in men (P < 0.001). At each level of BMI, serum leptin levels were about two times higher in women than in men (P < 0.001). Adipose tissue secretion rate of leptin in men was two-thirds of that in women (P < 0.05). The gender differences in body fat content, serum leptin and leptin secretion were observed in obese (BMI > 27 kg m-2) as well as non-obese subjects. Serum leptin levels (P < 0.001) and leptin secretion rate (P < 0.01) correlated positively with body fat content in either sex. However, the gender differences in serum leptin (P < 0.001) and leptin secretion rate (P < 0.01) remained statistically significantly different even when the values were adjusted for body fat. CONCLUSION: The gender difference in circulating leptin concentrations can be due to at least two different mechanisms. A higher proportion of adipose tissue and increased production rate of leptin per unit mass of adipose tissue might explain why women have higher circulating leptin levels than men.

Role of gender and genetic variance in plasminogen activator inhibitor-1 secretion from human adipose tissue.

Gender and the 4G/5G polymorphism in the plasminogen activator inhibitor 1 (PAI-1) gene are believed to play a role in the regulation of plasma PAI-1 activity. Adipose tissue has been found to be an important source of PAI-1. The possible influence of gender and the 4G/5G polymorphism in the PAI-1 gene on PAI-1 secretion from abdominal subcutaneous adipose tissue was investigated in 59 women and 32 men. The subjects were apparently healthy, although they differed markedly inter-individually in body mass index (21-53 kg/m2). The 4G/5G polymorphism did not influence the adipose secretion rate of PAI-1 or plasma PAI-1 activity. There was no gender difference in the adipose secretion of PAI-1. In multiple regression, including body mass index (BMI), waist-to-hip ratio (WHR), plasma insulin and plasma triglycerides as the independent and adipose PAI-1 secretion as the dependent variable, only BMI and plasma triglycerides correlated independently with adipose PAI-1 secretion (r = 0.54, p <0.05; r = 0.51, p <0.05, respectively). Men had a two times higher plasma PAI-1 activity than women (p <0.05). This gender difference was mainly due to gender differences in WHR. In multiple regression analysis, BMI and WHR were identified to be independently correlated with plasma PAI-1 activity (r = 0.60, p <0.05; r = 0.52, p = 0.01, respectively). In conclusion, neither gender nor the 4G/5G polymorphism in the PAI-1 gene are associated with secretion of PAI-1 from abdominal subcutaneous adipose tissue.

A marked upregulation of uncoupling protein 2 gene expression in adipose tissue of hyperthyroid subjects.

Recently, a family of uncoupling protein (UCP) genes has been discovered. The role of these genes is unknown, but it has been suggested that they are involved in regulating resting metabolic rate. In this study, we hypothesised that thyroid hormone status may influence the expression of UCP2 mRNA. The adipose tissue levels of UCP2 mRNA were measured in eight female subjects before and after treatment for thyrotoxicosis. All subjects in the hyperthyroid condition had markedly enhanced plasma levels of thyroxine (62.0 +/- 6.9 vs. 17.9 +/- 1.7, p = 0.012) and triiodothyronine (37.9 +/- 6.9 vs. 5.9 +/- 0.9, p = 0.012), accelerated heart rate (94 +/- 7 vs. 69 +/- 5, p = 0.012), decreased BMI (24.5 +/- 1.9 vs. 25.1 +/- 1.9, p = 0.025) and decreased percentage body fat (32.8 +/- 4.4 vs. 37.1 +/- 4.5, p = 0.018), as compared to the euthyroid state. Using RT-competitive-PCR, the UCP2 mRNA levels were found to be 2.5-fold upregulated in hyperthyroidism (10.4 +/- 1.7 vs. 4.2 +/- 1.3 amol/microg RNA, p = 0.012). In contrast, no difference in expression levels of the reference gene 18SrRNA was seen in the hyperthyroid versus the euthyroid state (317 +/- 49 vs. 279 +/- 25 amol/microg RNA, p = 0.48) but the difference in UCP2 mRNA levels between the hyper- and euthyroid state remained when UCP2 was related to 18SrRNA (p = 0.012). In conclusion, thyrotoxicosis markedly increases the expression of UCP2 mRNA in adipose tissue, which suggests a role for thyroid hormones in the regulation of this uncoupling protein in man.

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

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.

The different effects of a Gln27Glu beta 2-adrenoceptor gene polymorphism on obesity in males and in females.

OBJECTIVES: To investigate the role of a polymorphism in codon 27 (Gln27Glu) of the beta 2-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 beta 2-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 beta 2-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.

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

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.

Catecholamine-induced adipocyte lipolysis in human hyperthyroidism.

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.

Fosinopril versus enalapril in the treatment of hypertension: a double-blind study in 195 patients.

The new angiotensin-converting enzyme (ACE) inhibitor fosinopril was compared with the ACE inhibitor enalapril in a multicenter (n = 11), multinational (Denmark, Finland, Iceland, Norway, and Sweden), double-blind, randomized, parallel-group 24-week study in 195 patients with mild to moderate essential hypertension [supine diastolic blood pressure, (SDBP) > or = 95 to < or = 110 mm Hg]. After discontinuing all previous antihypertensive medication, patients were entered into a placebo lead-in period of 4-6 weeks, followed by 24 weeks of randomized treatment with the active compounds administered with a double-dummy technique. The dose of fosinopril was 20 mg, which could be increased to 40 mg after 8 weeks (average 25.6 mg); that of enalapril was 10 mg, which could be increased to 20 mg after 8 weeks (average 12.9 mg). Hydrochlorothiazide 12.5 mg could be added after 16 weeks and was administered to 27% of the patients in the fosinopril group and to 30% in the enalapril group. All drugs were administered once daily. Supine systolic BP (SSBP) decreased from 157 to 143 mm Hg in the fosinopril group (p < 0.01), and from 159 to 147 mm Hg in the enalapril group (p < 0.01). SSDP decreased from 100 to 89 mm Hg in the fosinopril group (p < 0.01) and from 100 to 92 mm Hg in the enalapril group (p < 0.01). Throughout the study period, fosinopril reduced SSBP and SDBP numerically more than did enalapril, by 0-3 mm Hg. Adverse events (AE) caused withdrawal of study medication in 8 patients in the fosinopril group and in 14 patients in the enalapril group (NS). The number of reported AE was not statistically different in the two groups. Inhibition of the ACE was assessed in a subgroup of patients (n = 26, 13 in each group). Fosinopril caused a greater inhibition of ACE at the doses used in the present study, which was statistically significant. Both fosinopril and enalapril caused statistically significant reductions in BP of a similar magnitude, and both agents were well tolerated. However, fosinopril was consistently numerically slightly more effective than enalapril in reducing BP. There were fewer withdrawals due to AE (NS) in the fosinopril group, and the overall recorded AE were fewer in the fosinopril group (NS).

The metabolic syndrome is related to beta 3-adrenoceptor sensitivity in visceral adipose tissue.

The metabolic syndrome is a well-known risk for the development of cardiovascular disease. In the present study the possible importance of an altered visceral adipocyte beta-adrenoceptor function in this syndrome was investigated. In 65 subjects of both sexes undergoing elective surgery for non-malignant disorders, the metabolic syndrome phenotype and the lipolytic sensitivity for various beta-adrenoceptor subtype agonists in omental adipocytes were determined. The study group represented a wide range of abdominal adipose tissue distribution (waist-to-hip ratios 0.76-1.13), but was otherwise apparently healthy. The subjects were divided into three subgroups according to their waist-to-hip (WHR) ratios: 1) WHR < 0.92; 2) WHR 0.92-1.04; 3) WHR > 1.04. The subgroups demonstrated significant differences regarding body mass index, sagittal diameter, systolic and diastolic blood pressures, plasma concentrations of glucose, insulin, triglycerides and HDL-cholesterol (p = 0.005-0.0001). Furthermore, in omental adipocytes beta 3-adrenoceptor sensitivity, but not beta 1-and beta 2-adrenoceptor sensitivities, differed significantly between the WHR subgroups (p = 0.0001). beta 3-adrenoceptor sensitivity was also related to the other components of the metabolic syndrome, although a strong covariation between WHR and beta 3-adrenoceptor sensitivity vs blood pressure and the metabolic parameters was found. The present data provide evidence of a relationship between upperbody obesity and its associated metabolic complications and also, an increased visceral fat beta 3-adrenoceptor sensitivity. We suggest that the latter finding results in an augmented release of non-esterified fatty acids from the visceral fat depot to the portal venous system. This may in turn contribute to the development of the metabolic syndrome.

Lipolytic and cardiac responses to various forms of stress in humans.

The lipolytic and the cardiac responses to 30 min of two different forms of stress--a standardized mental stress test and submaximal bicycle exercise--were investigated in non-obese healthy subjects. This was done by microdialysis of the extracellular space in the abdominal subcutaneous adipose tissue in order to determine lipolysis and electrocardiographic recordings of the heart rate. Glycerol concentrations (lipolysis index) in venous plasma and in adipose tissue dialysate as well as plasma catecholamines and determinations of the heart rate showed marked increases during mental stress (p < 0.001) and physical exercise (p < 0.001), but the patterns of response differed during the two forms of stress. All parameters rose gradually during exercise and decreased continuously in the post-exercise period. During mental stress, however, all parameters peaked within the first 20 min of stimulation and then remained at the same level until after the stress period, when they gradually declined. The maximal increase of glycerol in plasma and adipose tissue during mental stress correlated with the corresponding increase during exercise (r = 0.50-0.60). Such a relationship was not observed with plasma catecholamines or heart rate (r = 0.02-0.29). The peak level of plasma noradrenaline was an independent regressor for the peak levels of glycerol in plasma and adipose tissue as well as for the peak heart rate during mental stress and physical exercise (partial r from 0.35 to 0.64), while the peak level of adrenaline was a regressor for heart rate only during mental stress (partial r = 0.45), when multiple regression analysis was used.(ABSTRACT TRUNCATED AT 250 WORDS)

Multiple lipolysis defects in the insulin resistance (metabolic) syndrome.

Bearing in mind the importance of upper-body obesity for the insulin resistance (or metabolic) syndrome and the abnormalities in free fatty acid metabolism associated with this disorder, the regulation of lipolysis in isolated subcutaneous adipocytes was investigated in 13 72-yr old upper-body obese men with insulin resistance and glucose intolerance and in 10 healthy 72-yr-old men. There was a marked resistance to the lipolytic effect of noradrenaline in the metabolic syndrome due to defects at two different levels in the lipolytic cascade. First, an 80-fold decrease in sensitivity to the beta 2-selective agonist terbutaline (P < 0.001) which could be ascribed to a 50% reduced number of beta 2-receptors (P < 0.005) as determined with radioligand binding. The groups did not differ as regards dobutamine (beta 1) or clonidine (alpha-2) sensitivity, nor beta 1-receptor number. The mRNA levels for beta 1- and beta 2-receptors were similar in the two groups. Second, the maximum stimulated lipolytic rate was markedly reduced in the metabolic syndrome. This was true for isoprenaline (nonselective beta-agonist), forskolin (activating adenylyl cyclase), and dibutyryl cAMP (activating protein kinase). In regression analysis, the observed abnormalities in lipolysis regulation correlated in an independent way with the degree of glucose intolerance (r = -0.67) and beta 2-receptor number with insulin resistance (r = 0.67). In conclusion, the results of this study indicate the existence of lipolytic resistance to catecholamines in the adipose tissue of elderly men with the metabolic syndrome, which may be of importance for impaired insulin action and glucose intolerance. The resistance is located at a posttranscriptional level of beta 2-receptor expression and at the protein kinase-hormone sensitive lipase level.

Catecholamine resistance in fat cells of women with upper-body obesity due to decreased expression of beta 2-adrenoceptors.

Upper-body obesity is an important risk factor for developing non-insulin dependent diabetes. To investigate the possibility that a lipolysis defect is present in this form of obesity, we examined the adrenergic regulation of lipolysis in abdominal subcutaneous fat cells from 25 women with upper-body obesity and 24 non-obese women. Lipolytic noradrenaline sensitivity (but not the maximum rate of lipolysis) was reduced by 10-fold in obese women (p < 0.01). The noradrenaline resistance could be ascribed to a 10-fold decrease in lipolytic beta 2-adrenoceptor sensitivity (p < 0.01). The lipolytic sensitivity of beta 1- and alpha 2-adrenergic receptors was normal in the obese women. A 70% reduction in the cell surface density of beta 2-adrenoceptors was observed compared to the control subjects (p < 0.01). However, beta 1-receptor density as well as steady-state mRNA levels for beta 1- and beta 2-receptors were normal in obese women. Lipolytic noradrenaline sensitivity correlated inversely with BMI (adjusted r2 = 0.76 together with fat cell volume in stepwise regression analysis). The fasting plasma level of free cortisol was 30% lower in obese compared to non-obese women (p < 0.05) but obesity did not influence resting plasma catecholamine levels. Thus, lipolytic catecholamine resistance is present in abdominal obesity, due to low density of beta 2-adrenoceptors, which in its turn may be caused by a post-transcriptional defect in beta 2-receptor expression.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic regulation of lipolysis in fat cells from hyperthyroid and hypothyroid patients.

The influence of thyroid hormones on the adrenergic regulation of lipolysis was studied in isolated adipocytes removed from the gluteal region of hyper- and hypothyroid women and compared in adipocytes from euthyroid normal women. Noradrenaline significantly enhanced lipolysis in hyperthyroid patients, whereas noradrenaline inhibited lipolysis in hypothyroid patients compared to that in controls. Moreover, beta-adrenergic sensitivity and responsiveness were 10- and 2-fold increased, respectively, in hyperthyroid patients. In hypothyroid patients, beta-adrenoceptor responsiveness was reduced by 50%, whereas beta-adrenergic sensitivity remained unchanged compared with that in controls. Furthermore, the alpha 2-adrenergic and adenosine-induced antilipolytic effects were similar in all thyroid states. The lowered beta-adrenergic responsiveness seen in hypothyroidism could be mimicked by agents acting at the levels of phosphodiesterase (enprofylline), adenylate cyclase (forskolin) and protein kinase (dibutyryl cAMP). In hyperthyroidism, the increased beta-adrenergic sensitivity and responsiveness were not seen when lipolysis was stimulated at the adenylate cyclase, phosphodiesterase, or protein kinase levels. There was no change in the numbers of adipocyte beta- and alpha 2-adrenoceptors in hypothyroidism. However, the number of beta-adrenergic binding sites was doubled, whereas the fraction and affinities of isoprenaline high affinity sites remained unchanged in hyperthyroidism. Thus, the influence of thyroid hormone on catecholamine-stimulated lipolysis in man acts through different mechanisms when adipocytes are exposed to high or low levels of thyroid hormones. In hyperthyroidism, lipolysis adapts to increasing energy demands through an increase in the beta-adrenoceptor number and, thus, a more effective coupling of the adenylate-cyclase complex. In hypothyroidism, the low lipolytic effect of catecholamines seems to be mainly due to an impairment at the protein kinase level or to the hormone-sensitive lipase itself.

Effect of glucocorticosteroid treatment on beta-adrenoceptor subtype function in adipocytes from patients with asthma.

1. Adrenoceptor subtype function was studied in isolated adipocytes obtained by subcutaneous fat biopsies from nine patients with mild asthma. The biopsies were taken before and after 7 days treatment with 25 mg of prednisolone given orally. Lipolytic activity after stimulation with various adrenergic agent was measured, using glycerol release as an index of lipolysis. The number of beta 1- and beta 2-adrenoceptor binding sites was determined in radioligand binding experiments and beta 1- and beta 2-adrenoceptor mRNA levels were measured with a solution hybridization assay. 2. Lipolytic sensitivity (ED50) to isoprenaline, a non-selective beta-adrenoceptor agonist, increased 50-fold after treatment (P = 0.04). Sensitivity to terbutaline, a selective beta 2-adrenoceptor agonist, increased 25-fold (P = 0.01), whereas the ED50 values for dobutamine, a selective beta 1-adrenoceptor agonist, did not change significantly. Likewise, the sensitivity to the alpha 2-adrenoceptor agonist, clonidine, and to the drugs acting at post-receptor levels did not change significantly. Basal and maximum lipolytic rates on stimulation were not altered by the treatment. 3. The number of beta 2-adrenoceptor binding sites increased by 60% after treatment (P < 0.05), whereas the beta 1-adrenoceptor binding sites were not affected. The affinity of each receptor subtype for the displacing ligand, ICI 118.551, was not significantly altered by steroids. No significant changes were demonstrated in either beta 1- or beta 2-adrenoceptor mRNA levels. 4. Thus, glucocorticoids selectively increase beta 2-adrenoceptor density and function in patients with asthma, studied by using subcutaneous fat cells as an experimental model.