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.

Mechanisms underlying regional differences in lipolysis in human adipose tissue.

Catecholamine-induced lipolysis was investigated in nonobese females and males. Isolated subcutaneous adipocytes were obtained from the abdominal and gluteal regions. The lipolytic effect of noradrenaline was four to fivefold more marked in abdominal adipocytes than in gluteal fat cells. This regional difference was more apparent in females than in males. No site differences were observed when lipolysis was stimulated with agents acting at different postreceptor levels. The beta-adrenergic lipolytic sensitivity was 10-20 times greater in abdominal adipocytes from both sexes than in gluteal adipocytes. Abdominal adipocytes from females showed a 40 times lower alpha 2-adrenergic antilipolytic sensitivity than did gluteal adipocytes, but the adenosine receptor sensitivity was similar in both sites. Beta-receptor affinity for agonists displayed no site or sex variation. Abdominal adipocytes showed a twofold increased beta-adrenoceptor density than did gluteal cells from both sexes. The alpha 2-adrenoceptor density was similar in all regions, but in females the affinity of clonidine for these sites was 10-15 times lower in the abdominal fat cells compared with gluteal cells. In conclusion, regional differences in catecholamine-induced lipolysis are regulated at the adrenoceptor level, chiefly because of site variations in beta-adrenoceptor density. Further variations in the affinity properties of alpha 2-adrenergic receptor in females may explain why the regional differences in catecholamine-induced lipolysis are more pronounced in women than in men.

Beta-adrenoceptor expression in human fat cells from different regions.

The expression of beta-adrenoceptors (BAR) was investigated in abdominal and gluteal fat cells of 32 nonobese men and women using radioligand binding and RNA excess solution hybridization. In both sexes the number of BAR binding sites was about twice as high in abdominal as in gluteal fat cells (P less than 0.01). Northern blot analysis of total RNA from adipose tissue showed hybridization of the BAR1 probe to an mRNA species of about 2.5 kb and of the BAR2 probe to an mRNA species of approximately 2.2 kb. The steady-state mRNA levels of BAR 1 and BAR 2 were also about twice as high in abdominal as in gluteal adipocytes of men and women (P less than 0.01). In abdominal fat cells the mRNA levels were approximately 45 and 30 molecules/cell for BAR1 and BAR2, respectively. There were no regional or sex variations in BAR 1 and BAR 2 mRNA stability. The apparent half-life of mRNA for both receptor subtypes was approximately 6 h in both regions. The mRNA levels for beta actin did not differ between the two regions in either sex. Thus, differences in expression of the genes encoding for BAR 1 and BAR 2 can explain why abdominal fat cells have more BAR than gluteal fat cells. This variation in gene expression may be a molecular mechanism underlying the well known regional differences in catecholamine-induced lipolysis activity between central and peripheral adipose tissue.

Catecholamine-induced lipolysis in adipose tissue of the elderly.

Age-dependent alterations in the effects of catecholamines on lipolysis were investigated in 25 young (21-35 yr) and 10 elderly (58-72 yr) healthy, nonobese subjects using isolated adipocytes obtained from abdominal subcutaneous tissue. Basal lipolysis was not affected by aging, while the rate of catecholamine-stimulated lipolysis was reduced by 50% in the elderly subjects (P less than 0.005). To elucidate the mechanisms behind this phenomenon lipolysis was stimulated with agents that act at well-defined steps in the lipolytic cascade, from the receptor down to the final step: the activation of the protein kinase/hormone-sensitive lipase complex. All agents stimulated lipolysis at a 50% lower rate in elderly as compared with young subjects (P less than 0.05 or less). However, half-maximum effective concentrations of the lipolytic agents were similar in both groups. The antilipolytic effects of alpha 2-adrenoceptor agonists were also the same in young and old subjects. Moreover, the stoichiometric properties of the beta- and alpha 2-receptors did not change with increasing age. In vivo studies performed on the same individuals likewise demonstrated an impaired lipolytic responsiveness, with 50% lower plasma glycerol concentrations during exercise in the elderly subjects (P less than 0.05), in spite of a normal rise in plasma norepinephrine. The plasma glycerol levels correlated strongly to the glycerol release caused by catecholamine-stimulated lipolysis in vitro in both young and elderly subjects (r = 0.8-0.9, P less than 0.001). In conclusion, a decreased activation of the hormone-sensitive lipase complex appears to be the mechanism underlying a blunted lipolytic response of fat cells to catecholamine stimulation in elderly subjects. This finding may, explain the age-dependent decreased lipolytic response to exercise in vivo.

Lipolytic catecholamine resistance due to decreased beta 2-adrenoceptor expression in fat cells.

The existence of lipolytic beta-adrenoceptor (BAR) resistance was investigated in vivo and in isolated abdominal subcutaneous adipocytes in 65 healthy and drug-free subjects. The concentration of isoprenaline (nonselective BAR agonist) causing half-maximum lipolysis effect (ED50) varied bimodally and 10(6)-fold between individuals but was almost constant in the same subject when measured two times at rest or before and 30 min after exercise. The subjects were categorized as having either high or low isoprenaline sensitivity. The former group had a 50% reduced in vivo lipolytic response to exercise and mental stress, despite a 50% increased plasma noradrenaline response (P < 0.01) and a 350% increased plasma adrenaline response (P < 0.02). In fat cells the lipolytic ED50 values for noradrenaline and terbutaline (BAR2 agonist) were 10 times lower (P < 0.001) in low-sensitive subjects, but the maximum lipolytic actions of these agents (and of isoprenaline) were similar in both groups. The action on lipolysis of dobutamine (BAR1 agonist), forskolin (stimulating adenylate cyclase), dibutyryl cyclic AMP (activating protein kinase), clonidine (alpha 2-adrenergic agonist), or phenyl isopropyladenosine (adenosine receptor agonist) were almost identical in high- and low-sensitivity subjects. ED50 for isoprenaline correlated with ED50 for terbutaline (r = 0.75), but not with ED50 for dobutamine. In high-sensitivity subjects the number of BAR2 was almost three-fold increased (P < 0.002) and the steady-state adipocyte mRNA level for BAR2 was sixfold increased (P < 0.005). BAR2 affinity as well as BAR1 number, affinity and mRNA expression were similar in both groups. In 11 cholecystectomy patients (otherwise healthy) lipolytic ED50 for beta agonists correlated in omental and subcutaneous fat cells (r = 0.85 for isoprenaline; r = 0.95 for terbutaline). In conclusion, lipolytic resistance to catecholamines is present in vivo in apparently healthy subjects due to reduced expression of BAR2 in adipocytes.

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.

Abnormal action of catecholamines on lipolysis in adipocytes of type I diabetic patients treated with insulin.

Catecholamine-induced lipolysis was investigated in adipocytes obtained before and after 30 min of exercise from 10 insulin-treated type I (insulin-dependent) diabetic men and 10 male matched control subjects. The alpha 2-adrenoceptor-mediated antilipolytic effect of catecholamines was normal, but the beta-adrenoceptor-mediated lipolytic sensitivity was increased 10-fold (P less than .01) in diabetic subjects before and after exercise. The latter correlated inversely (r greater than .7) with the circulating norepinephrine level, which was significantly reduced in diabetic subjects. Basal lipolysis and lipolysis activated at different steps distal to the beta-receptor were similar in the two groups. There was no major change in the total number of beta- and alpha-adrenoceptors in the diabetic patients. However, the proportion of high-affinity beta-adrenoceptors was significantly increased in these patients compared with control subjects. In the diabetic patients, approximately 50% of the beta-adrenoceptors were in a high-affinity state, compared to approximately 30% in the control subjects (P less than .025). In diabetic subjects there was an enhanced plasma glycerol response to exercise, despite a blunted plasma norepinephrine response. The data suggest enhanced sensitivity of catecholamine-induced lipolysis in type I diabetes due to an increase in the number of high-affinity (i.e., coupled) beta-adrenoceptors in fat cells. This mechanism may be due to low levels of circulating norepinephrine and may also explain the exaggerated lipolytic response to exercise in the diabetic state.

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.

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.

Adrenergic regulation of lipolysis in human adipocytes: findings in hyper- and hypothyroidism.

In isolated sc adipocytes removed from hyperthyroid patients, the specific binding of [3H]dihydroalprenolol and [125I]iodocyanopindolol was greater than that in adipocytes from normal subjects. Based on Scatchard analysis of the [125I] iodocyanopindolol data, this difference was due to a significant (P less than 0.01) increase in adrenoceptor number, which was 1.72 +/- 0.18 (+/- SEM) pmol/10(7) cells in the hyperthyroid patients and 0.94 +/- 0.16 pmol/10(7) cells in the normal subjects. When the patients were restudied when they were euthyroid, a significant decrease in the specific binding of the two radioligands was found. In hyperthyroidism, the lipolytic responsiveness (maximum effect) to norepinephrine was increased 5-fold, and that to isopropylnorepinephrine was increased 2-fold. No changes in either the binding of [3H]yohimbine or the antilipolytic effect of clonidine were found. In isolated adipocytes from hypothyroid patients, the specific binding of [3H]dihydroalprenolol and [125I]iodocyanopindolol did not differ from that in the normal subjects. The basal rate of lipolysis (P less than 0.025) and the lipolytic responsiveness to isopropylnorepinephrine (P less than 0.025) were significantly lower than normal, and the response to norepinephrine was almost completely abolished in the hypothyroid state. The sensitivity and responsiveness to clonidine were comparable in the adipocytes of the hypothyroid patients and normal subjects. There was no difference between hypothyroid patients and normal subjects in the binding of [3H]yohimbine. We conclude that the sc adipocytes in hyperthyroidism have beta-adrenergic, but not alpha 2-adrenergic abnormalities. Although there was a moderate increase in the beta-adrenoceptor density in hyperthyroidism, the most important abnormality, namely the increased responsiveness to the catecholamines, seems to be located beyond the receptor level. On the other hand, in hypothyroidism, there was no evidence of changes in either the alpha 2- or the beta-adrenoceptors. The chief abnormality in hypothyroidism, decreased responsiveness to beta-adrenergic agonists, also would appear to be localized beyond the adrenoceptor level.

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.

Adrenergic regulation of human adipose tissue metabolism in situ during mental stress.

The adrenergic regulation of adipose tissue lipolysis and glucose metabolism was investigated in situ during a standardized mental stress test in 11 nonobese, healthy subjects, using microdialysis of the extracellular water space in sc adipose tissue. Microdialysis probes were inserted in the abdominal sc fat, and were perfused using solvents with or without adrenoceptor blocking agents. The tissue dialysate concentrations of glycerol (lipolysis index) glucose, lactate, and pyruvate were determined. The glycerol concentration in adipose tissue increased markedly during the stress test and decreased in the poststress period. A similar kinetic pattern was observed in blood. In situ administration of the nonselective beta-adrenoceptor blocking agent propranolol almost completely prevented the stress-induced increase in adipose tissue glycerol levels, whereas a nonselective alpha-adrenoceptor blocking agent (phentolamine) was ineffective in this respect. Plasma levels of glucose and lactate remained unaltered during and after the stress test; at the same time plasma pyruvate decreased moderately. By contrast, glucose, lactate, and pyruvate in adipose tissue increased by 25-30% during or after the stress (P < 0.05). The increase in lactate and pyruvate in adipose tissue after the stress was completely off-set by alpha-adrenoceptor blockade in situ, whereas beta-adrenoceptor blockade in situ did not influence the kinetic pattern of these metabolites. It is concluded that the lipolytic activity in human adipose tissue is markedly enhanced during mental stress, owing to adrenergic mechanisms that are mediated via beta-adrenoceptors. After mental stress, adipose tissue glucose utilization is decreased and routed toward nonoxidative pathways. The latter seems to involve adrenergic effects that are mediated via alpha-adrenoceptors.

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.

Beta-adrenoreceptor subtype expression in human liver.

The pharmacological and gene expressions of beta 1- and beta 2-adrenoceptor subtypes (BAR1 and BAR2) were investigated in human liver by radioligand binding assays, adenylate cyclase experiments, and RNA excess solution hybridization. [125I]Cyanopinodolol, nonlabeled adrenergic agents, and BAR1/BAR2 cRNA were used as probes. The relationship between binding sites for BAR1 and BAR2 was markedly different from that between the basal mRNA expression for the two receptor subtypes. Plasma membranes as well as a microsomel-enriched fraction contained binding sites only for BAR2. The potency of BAR agonists and antagonists in stimulating adenylate cyclase activity of plasma membranes was typical of a BAR2 response. Northern blot analysis of total cellular RNA isolated from liver tissue showed hybridization of the BAR1 probe to a mRNA species of 2.5-2.6 kilobases and of the BAR2 probe to a mRNA species of 2.2-2.3 kilobases. The basal level of BAR1 mRNA was 5-fold higher than of BAR2 mRNA, as assayed by solution hybridization. No difference in BAR subtype mRNA stability was observed, as indicated by a mRNA half-life of approximately 5.5 h for both receptor subtypes. It is concluded that specific factors are involved in the steady state regulation of BAR subtype expression in human liver. This tissue contains solely BAR2 owing to a posttranscriptional block of basal BAR1 expression.

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.

Catecholamine regulation of adipocyte lipolysis after surgery.

The effect of surgical trauma on the regulation of lipolysis was studied in isolated fat cells obtained before and 24 hours after elective cholecystectomy in 12 patients who were not obese and who were healthy otherwise. Surgery was accompanied by a twofold increase of the basal rate of lipolysis and by a significant 50% elevation of the lipolytic effect of catecholamines. The actions of various agents that selectively stimulate lipolysis at different early or late steps in the cyclic adenosine monophosphate system beyond the adrenoreceptors were also increased about 50% after surgery (p less than 0.01). The properties of the beta-adrenoceptors were not altered by surgery, as assessed by radioligand binding and isoprenaline sensitivity. The antilipolytic properties of catecholamines (mediated by alpha 2-adrenoreceptors) were not influenced by cholecystectomy. Lipolysis was not altered in four subjects who had no surgery and who served as control subjects 24 hours after being given the same type of postoperative nutrition as patients who underwent cholecystectomy. We concluded that moderate surgical trauma is associated with increased lipolytic activity of fat cells. This is secondary to an enhanced ability of catecholamines to stimulate lipolysis because of a modification at the most distal steps in the cyclic adenosine monophosphate system, which may involve the protein kinase/hormone sensitive lipase complex.

Effects of mental stress on lipolysis in humans.

Lipid mobilization was investigated in subcutaneous adipose tissue specimens obtained before and after a standardized mental-stress test in 14 non-obese healthy subjects. All participants responded with an increased heart rate and elevation of plasma glycerol levels. Plasma norepinephrine concentrations remained unchanged throughout the test. In six subjects, mental stress induced a significant increase in plasma epinephrine levels, to more than 0.26 nmol/L (responders), while the remaining eight individuals showed a response of less than 0.12 nmol/L (nonresponders). In the responders, a 30% increase in catecholamine-stimulated in vitro lipolysis was found after the mental-stress test, while the lipolytic response in isolated fat cells in vitro decreased slightly in the nonresponders after mental stress. A strong correlation (r = .84) was observed between the increased in vitro lipolytic responsiveness due to mental stress and circulating plasma epinephrine levels. In vitro data suggest that the augmentation in lipolytic activity induced by acute mental stress was caused by alterations between the beta-adrenoceptor and adenylate cyclase, ie, probably an increased coupling between beta-receptors and the stimulatory guanosine triphosphate [GTP]-binding protein (G2). This, in combination with elevated levels of circulating epinephrine, may explain the increased lipolysis during mental stress in some individuals (ie, responders). However, other parallel mechanisms for activation of lipolysis during mental stress must also exist in certain individuals (ie, nonresponders), and seem not to involve the adrenergic system.