Impaired activation of adipocyte lipolysis in familial combined hyperlipidemia.

The pathophysiology of familial combined hyperlipidemia (FCHL) is unknown, but altered lipid turnover in peripheral tissues as well as hepatic overproduction of apolipoprotein B have been suggested as possible causes. In the present study, we explored whether a change in triglyceride breakdown by lipolysis in fat cells is present in FCHL. Lipolysis activation by catecholamines was examined in isolated subcutaneous adipocytes from 10 patients with FCHL and 22 healthy control subjects. Lipolysis rate was linear for at least 3 h in both groups. However, a marked (approximately 65%) decrease in the lipolytic response to noradrenaline was found in FCHL. This was also true when lipolysis was maximally stimulated at the receptor level with isoprenaline (nonselective beta-adrenergic agonist), at the adenylyl cyclase level with forskolin, or at the level of the protein kinase hormone-sensitive lipase complex with dibutyryl cAMP. The maximum enzymatic activity of hormone-sensitive lipase was decreased by approximately 40% in FCHL. On the other hand, the lipolytic sensitivity of alpha 2-, beta 1-, and beta 2-adrenoceptors was normal in this condition, as was the number and affinity of beta 1- and beta 2-adrenoceptors. Variations in the maximum lipolysis rate correlated significantly with the variations in hormone-sensitive lipase activity in the whole material, and with the serum values for triglycerides, HDL cholesterol and apoB lipoprotein within the control group, but the serum triglyceride values in FCHL were higher than this correlation predicted. In conclusion, the data demonstrate a marked resistance to the lipolytic effect of catecholamines in fat cells from patients with FCHL, in spite of normal adrenoceptor function. The lipolytic defect appears predominantly to be due to a defect in hormone-sensitive lipase, and may be of importance in the pathophysiology of FCHL.

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.

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

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.

Mental distress in treatment seeking young adults (18-25 years) with severe obesity compared with population controls of different body mass index levels: cohort study.

Young adults (18-25) with severe obesity constitute a challenging patient group, and there is limited evidence about their mental health status compared to population controls. Mental distress in treatment seeking young adults with severe obesity (n = 121, mean body mass index [BMI] = 39.8 kg m-2 ) was compared with matched (1:3 for age, gender and socioeconomic status) population controls of normal weight (n = 363, mean BMI = 22.4 kg m-2 ), as well as unmatched population controls with class I obesity (n = 105, mean BMI = 32.1 kg m-2 ) or severe obesity (n = 41, mean BMI = 39.7 kg m-2 ). Mental distress was measured by the General Health Questionnaire-12 (GHQ-12), and we quantified physician-diagnosed depression, present anxiety and suicide attempts. Poisson regression and linear regression analysis were used for analysing differences in mental distress between groups. Treatment seekers experienced more mental distress than normal weight controls as measured by continuous (adjusted mean: 3.9 vs. 2.2 points, P <0.001) and categorical (cut-off for mental distress ≥3 points, RR: 1.76, P <0.001) GHQ-12 scores, depression (RR: 2.18, P < 0.001), anxiety (RR: 1.97, P < 0.001) and suicide attempts (RR: 2.04; P = 0.034). Treatment seekers also experienced more mental distress as measured by continuous GHQ-12 than controls with class I obesity (adjusted mean: 2.3 points) or severe obesity (adjusted mean: 2.1; both, P < 0.001). Young adult treatment seekers with severe obesity constitute a risk group for mental distress compared to population controls of different BMI levels.

Conservative treatment of obesity in an academic obesity unit. Long-term outcome and drop-out.

OBJECTIVE: The aim of this study was to explore the outcome and the problems of drop-out in the treatment of obese outpatients at an academic obesity unit. DESIGN: A two-year clinical treatment evaluation. SUBJECTS: A total of 117 obese subjects, 83 women and 34 men, mean aged 50 (23-70) years, with an average body mass index (BMI) of 39.0 kg/m2 (28.8- 64.7). INTERVENTION: All treatment was based on group therapy and included behaviour modification and nutrition counselling. A team of nurses, dieticians, a physiotherapist, a psychotherapist and a physician supervised the treatment. Two programmes were used. Group 1 initially received a low-calorie diet (LCD) for seven weeks combined with the behaviour treatment programme. Group 2 was treated with the behaviour treatment programme only. All subjects were offered complementary treatment according to their medical needs. RESULTS: There was a continuous drop-out of subjects during the two-year treatment period with an overall drop-out rate of 53%. Anthropometric characteristics, medical history or reasons for drop-out had no impact on the drop-out rate. In completers the weight reduction after two years was 9.2 [+/-10.8 standard deviation (S.D.) kg. In non-completers the weight reduction of the last observed weight measurement was 4.7 (+/-7.9 S.D.) kg. After year two, the weight reduction in Group 1 was 8.8 (+/-12.2 S.D.) kg, and in Group 2 was 9.7 (+/-8.0 S.D.) kg. CONCLUSION: This study has showed the difficulties of long-term clinical treatment of obese outpatients, even in a specialised obesity clinic. The findings demonstrate that educated and experienced staff together with an extended package of treatment options is not enough to keep patients in treatment for two years. However though the drop-out rate was high, two thirds of the included subjects reduced their weight, which is a satisfactory result in a clinical setting. The drop-out rate and the reasons for dropping out could give a clue in which direction the diagnostics and analysis of the subject's individual needs in health care should be directed.

Secretion of tumor necrosis factor-alpha shows a strong relationship to insulin-stimulated glucose transport in human adipose tissue.

Some animal models suggest that tumor necrosis factor (TNF)-alpha is a key component in obesity-linked insulin resistance because it inhibits insulin receptor signaling and glucose transport in insulin-sensitive tissues. However, in vivo data in humans have given conflicting results regarding the relationship between circulating TNF-alpha levels and insulin sensitivity. In the present study, the potential local role of TNF-alpha on insulin action in human subcutaneous adipose tissue was studied in 42 obese women (BMI 39+/-10 kg/m2). We found a strong inverse correlation between adipose TNF-alpha secretion and maximum insulin-stimulated glucose transport in adipocytes that was independent of fat cell volume, age, and BMI (P < 0.001, r = 0.58). As much as one-third of the variation in insulin-stimulated glucose transport could be accounted for by variations in TNF-alpha secretion. There was no significant correlation (r = 0.11) between secretion of adipose plasminogen activator inhibitor 1 and glucose transport. Furthermore, subcutaneous adipose tissue of 4 obese women (BMI 40+/-4) incubated with TNF-A for 24 h showed a one-third concentration-dependent inhibition of insulin-stimulated glucose transport (P < 0.01). In conclusion, adipose TNF-alpha may be an important specific and local factor in adipose tissue that influences the ability of insulin to stimulate glucose transport in human fat cells, at least in obese women.

Leptin secretion from subcutaneous and visceral adipose tissue in women.

Upper body obesity is a risk factor for type 2 diabetes. Little is known about the regulation of body fat distribution, but leptin may be involved. This study examined the secretion of leptin in subcutaneous and omental fat tissue in 15 obese and 8 nonobese women. Leptin secretion rates were two to three times higher in subcutaneous than in omental fat tissue in both obese and nonobese women (P < 0.0001 and P < 0.001, respectively). There was a positive correlation between BMI and leptin secretion rates in both subcutaneous (r = 0.87, P < 0.0001) and omental (r = 0.74, P < 0.0001) fat tissue. Furthermore, leptin secretion rates in subcutaneous and omental fat tissue correlated well with serum leptin levels (r = 0.84, P < 0.0001 and r = 0.73, P = 0.001, respectively), although in multivariate analysis, the subcutaneous leptin secretion rate was the major regressor for serum leptin (F = 42). Subcutaneous fat cells were approximately 50% larger than omental fat cells, and there was a positive correlation between fat cell size and leptin secretion rate in both fat depots (r = 0.8, P < 0.01). Leptin (but not gamma-actin) mRNA levels were twofold higher in subcutaneous than in omental fat tissue (P < 0.05). Thus the subcutaneous fat depot is the major source of leptin in women owing to the combination of a mass effect (subcutaneous fat being the major depot) and a higher secretion rate in the subcutaneous than in the visceral region, which in turn could be due to increased cell size and leptin gene expression.

Evidence for a major role of skeletal muscle lipolysis in the regulation of lipid oxidation during caloric restriction in vivo.

A lipolytic process in skeletal muscle has recently been demonstrated. However, the physiological importance of this process is unknown. We investigated the role of skeletal muscle lipolysis for lipid utilization during caloric restriction in eight obese women before and after 11 days of very low-calorie diet (VLCD) (2.2 MJ per day). Subjects were studied with indirect calorimetry and microdialysis of skeletal muscle and adipose tissue in order to analyze substrate utilization and glycerol (lipolysis index) in connection with a two-step euglycemic-hyperinsulinemic (12 and 80 mU/m(2). min) clamp. Local blood flow rates in the two tissues were determined with (133)Xe-clearance. Circulating free fatty acids and glycerol decreased to a similar extent during insulin infusion before and during VLCD, and there was a less marked insulin-induced reduction in lipid oxidation during VLCD. Adipose tissue glycerol release was hampered by insulin infusion to the same extent ( approximately 40%) before and during VLCD. Skeletal muscle glycerol release was not influenced by insulin before VLCD. However, during VLCD insulin caused a marked (fivefold) (P < 0.01) increase in skeletal muscle glycerol release. The effect was accompanied by a fourfold stimulation of skeletal muscle blood flow (P < 0.01). We propose that, during short-term caloric restriction, the reduced ability of insulin to inhibit lipids, despite a preserved antilipolytic effect of the hormone in adipose tissue, is caused by an augmented mobilization of fat from skeletal muscle, and that a physiological role of muscle lipolysis provides a local source of fatty acids.

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.

Comparison of hormone-sensitive lipase activity in visceral and subcutaneous human adipose tissue.

The possible role of hormone-sensitive lipase (HSL) in determining regional differences in lipolysis activation in humans was studied in vitro. Small adipose tissue biopsies were obtained from the abdominal sc and omental regions during surgery in 21 subjects spanning a wide range of body mass index (22-50 kg/m2). In lipolysis experiments, isolated fat cells were incubated with lipolytic agents acting at different levels in the lipolytic cascade. The activity and messenger ribonucleic acid expression of HSL were determined. The maximum lipolytic capacity was higher in sc than in omental fat cells as were HSL activity and messenger ribonucleic acid expression. The maximum lipolysis rate was significantly correlated to HSL activity. This is in accordance with the role of HSL as the rate-limiting step of lipolysis. However, adipocytes were 24% larger in the sc than in the omental region, and the lipolysis rate was significantly correlated to fat cell size regardless of either the region of origin or gender. This indicates that the regulation of HSL activity in healthy subjects, which appears to occur at a transcriptional level, is to a large extent dependent on fat cell size.

Effect of glucocorticosteroid treatment on glucocorticoid receptor expression in human adipocytes.

The influence of glucocorticoid excess on expression of the glucocorticoid receptor (GR) and beta-adrenoceptor subtype was studied in isolated adipocytes obtained by sc fat biopsies from 17 healthy individuals. The biopsies were taken before and after 7 days of treatment with 25 mg prednisolone, given orally. GR and beta 1- and beta 2-adrenoceptor messenger ribonucleic acid (mRNA) levels were measured with a solution hybridization assay, and the number of beta 1- and beta 2-adrenoceptor binding sites was determined in radioligand binding experiments. GR protein levels were determined by Western blot analysis using an anti-GR antibody. Both GR protein and GR mRNA levels decreased significantly (P < 0.05) by about 50% after treatment, whereas no significant changes were demonstrated in either beta 1- or beta 2-adrenoceptor mRNA levels. The number of beta 2-adrenoceptor-binding sites, however, increased by 70% after treatment (P < 0.05), whereas the number of beta 1-adrenoceptor binding sites was not affected. The affinity of each receptor subtype was not significantly altered by steroid treatment. In conclusion, an in vivo glucocorticoid excess decreases GR mRNA as well as GR protein levels and selectively increases beta 2-adrenoceptor density in sc fat cells of healthy individuals. This indicates that glucocorticoids modulate human adipose metabolism by altering the expression of regulatory proteins at various mRNA and post-mRNA levels.

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.

Reduced hormone-sensitive lipase activity is not a major metabolic defect in Finnish FCHL families.

The pathogenetic mechanisms behind familial combined hyperlipidemia (FCHL) are unknown. However, exaggerated postprandial lipemia and excessive serum free fatty acid (FFA) concentrations have drawn attention to altered lipid storage and lipolysis in peripheral adipose tissue. Hormone-sensitive lipase (HSL) is the enzyme responsible for intracellular lipolysis in adipocytes and a decrease of adipocyte HSL activity has been demonstrated in Swedish FCHL subjects. The aim of the study was to investigate if adipose tissue HSL activity had any effect on lipid phenotype and if low HSL activity and FCHL were linked in Finnish FCHL families. A total of 48 family members from 13 well-characterized Finnish FCHL families and 12 unrelated spouses participated in the study. FCHL patients with different lipid phenotypes (IIA, IIB, IV) did not differ in adipose tissue HSL activity from each other or from the 12 normolipidemic spouses (P = 0.752). In parametric linkage analysis using an affecteds-only strategy the low adipose tissue HSL activity was not significantly linked with FCHL phenotype. However, we found a significant sibling-sibling correlation for the HSL trait (0.51, P < 0.01). Thus, a modifying or interacting role of HSL in the pathogenesis of FCHL could not be excluded.

Regional variation in plasminogen activator inhibitor-1 expression in adipose tissue from obese individuals.

High plasma plasminogen activator inhibitor-1 (PAI-1) activity is a frequent finding in obesity and adipose tissue has recently been suggested to be a source of circulating PAI-1 in humans. In the present study, differences in adipose tissue gene expression and protein secretion rate of PAI-1 between subcutaneous and visceral adipose tissue was analysed in specimens obtained from 22 obese individuals. The secretion rate of PAI-1 was two-fold higher in subcutaneous adipose tissue than in visceral adipose tissue (292 +/- 50 vs 138 +/- 24 ng PAI-1/10(7) cells, P <0.05). In accordance with the secretion data, subcutaneous adipose tissue contained about three-fold higher levels of PAI-1 mRNA than visceral adipose tissue (2.43 +/- 0.37 vs 0.81 +/- 0.12 attomole PAI-1 mRNA/microg total RNA, P <0.00 ). PAI-1 secretion from subcutaneous but not from visceral adipose tissue correlated significantly with cell size (r = 0.43, P<0.05). In summary, subcutaneous adipose tissue secreted greater amounts of PAI-1 and had a higher PAI-1 gene expression than visceral adipose tissue from the same obese individuals. Bearing in mind that subcutaneous adipose tissue is the largest fat depot these finding may be important for the coagulation abnormalities associated with obesity.

Effects of childhood abuse on adult obesity: a systematic review and meta-analysis.

Controversy exists surrounding the role of childhood abuse in obesity development. This is a meta-analysis of observational studies on the role of childhood abuse in adult obesity. Systematic searches of PubMed, PsycInfo, Medline and CINAHL resulted in 23 cohort studies (4 prospective, 19 retrospective) with n=112,708 participants, containing four abuse types (physical, emotional, sexual, general). Four studies reported dose-response effects. A random effects model was used to quantify effect sizes, meta-regression/subgroup analysis for identifying potential moderating variables and Egger's test for publication bias. Adults who reported childhood abuse were significantly more likely to be obese (odds ratio [OR]: 1.34, 95% confidence interval [CI]: 1.24-1.45, P<0.001). All four types of abuse were significantly associated with adult obesity: physical (OR: 1.28, 95% CI: 1.13-1.46), emotional (OR: 1.36, 95% CI: 1.08-1.71), sexual (OR: 1.31, 95% CI: 1.13-1.53) and general abuse (OR: 1.45, 95% CI: 1.25-1.69). Severe abuse (OR: 1.50, 95% CI: 1.27-1.77) was significantly more associated with adult obesity (P=0.043) compared with light/moderate abuse (OR: 1.13, 95% CI: 0.91-1.41). We found no significant effects of study design (prospective vs. retrospective, P=0.07), age (P=0.96) or gender (P=0.92). Publication bias was evident (Egger's test P=0.007), but effect sizes remained statistically significant in sensitivity analyses. Childhood abuse was clearly associated with being obese as an adult, including a positive dose-response association. This suggests that adverse life experiences during childhood plays a major role in obesity development, potentially by inducing mental and emotional perturbations, maladaptive coping responses, stress, inflammation and metabolic disturbances.

Influence of heredity for obesity on adipocyte lipolysis in lean and obese subjects.

OBJECTIVE: To evaluate a possible influence of a hereditary trait for obesity on the regulation of adipocyte metabolism in vitro in subcutaneous fat cells in obese and non-obese subjects. DESIGN: A biopsy from abdominal subcutaneous fat was obtained from consecutive subjects with or without a family trait for obesity. A positive family history of obesity was considered present if one or more of the first degree relatives had a BMI of 27 kg/m2 or more. SUBJECTS: 67 non-obese and 60 obese subjects, age 19-60 y. A family trait for overweight was present in 42 of the lean subjects and in 50 of the obese subjects. MEASUREMENTS: Fat cells were isolated and incubated in vitro with isoprenaline (a non-selective beta-adrenoceptor agonist), forskolin (activates the adenylyl cyclase) and dibutyryl cyclic AMP (stimulates the protein kinase hormone-sensitive lipase complex). Glycerol release was measured and used as lipolytic index. RESULTS: Maximal lipolytic response per g triglycerides was about 50% lower in obese subjects both with and without a positive heredity and in non-obese subjects with a family trait for obesity as compared to non-obese subjects without such trait (P=0.0001). Fat cell volume was twice as high in obese as compared to lean subjects. Drug-induced maximal glycerol release per fat cell in the obese subjects, regardless of family history of obesity, reached a similar level, but did not exceed that of the lean group without heredity. CONCLUSIONS: Obesity is associated with catecholamine resistance with a relatively ineffective lipolysis in fat cells, and presence of a family history of obesity was not associated with a further suppression of lipolysis. In the lean subjects, heredity for obesity significantly influenced lipolysis to similar low levels as in the obese subjects.

Systolic blood pressure is related to catecholamine sensitivity in subcutaneous abdominal fat cells.

A relationship between abdominal obesity and hypertension is well established. In search for an early-onset defect in adipocyte function linking these two conditions, we compared catecholamine sensitivity in subcutaneous abdominal fat cells with 24-hour systolic, mean arterial and diastolic blood pressure in 16 healthy, normotensive subjects. Clear inter-individual variations in the adipocyte lipolytic adrenoceptor sensitivity (pD2) for noradrenaline were observed in dose-response experiments (i.e., about 4 log units). An inverse and independent correlation was found between the 24-hour systolic blood pressure and pD2 for noradrenaline (r = -0.67, p < 0.01). The mean arterial blood pressure was also negatively correlated to peripheral noradrenaline sensitivity (r = -0.58, p < 0.05). However, no significant relationship between the 24-hour diastolic blood pressure and pD2 for noradrenaline was demonstrated. In conclusion we suggest that catecholamine resistance in subcutaneous fat cells may be associated with autonomic dysfunction and impaired blood pressure regulation. This finding is supported by the fact that both noradrenaline sensitivity and 24-hour systolic blood pressure also are correlated to the individual orthostatic heart rate responses, reflecting the sympathetic nervous system tone (r = 0.61, p = 0.01 and r = -0.53, p = 0.03, respectively). The relationship between noradrenaline sensitivity and systolic blood pressure may be of importance in the early development of hypertension in man.

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.

Lipolytic catecholamine resistance linked to alpha 2-adrenoceptor sensitivity--a metabolic predictor of weight loss in obese subjects.

OBJECTIVE: The weight loss achieved during treatment with very-low-calorie diets (VLCD) varies between individuals. The aim of this study was to investigate whether interindividual variations in catecholamine-induced lipolysis are of importance for the rate of weight loss during VLCD. DESIGN: Prospective study. SUBJECTS: Twenty-eight obese, but otherwise healthy and drug-free women aged 20-57 y with BMI 33.3-47.5 kg/m2 were investigated before entering a four week weight reduction program with a calorie-restricted diet. MEASUREMENTS: A subcutaneous adipose tissue biopsy was obtained from the abdominal area. Isolated fat cells were prepared and incubated in vitro with agents acting on lipolysis at defined steps in the lipolytic cascade. Glycerol release was measured and used as a lipolytic index. Following the biopsy, the subjects underwent a four week VLCD treatment. RESULTS: The decrease in body weight in the whole group ranged between 4.8 and 13.5 kg. Dietary compliance was ascertained by daily measurements of urine-ketones and regular interviews and was satisfactory in all subjects throughout the study. Based on percent body weight reduction, the material was divided into two equally sized groups, classified as rapid or slow weight losers. The rapid weight losers were 10-fold more sensitive to the lipolytic effect of noradrenaline (P = 0.04) and 10-fold less sensitive (P = 0.002) to the antilipolytic effect induced by the alpha 2-adrenoceptor agonist clonidine than the slow weight losers. In the whole material, weight loss was significantly correlated (adjusted r2 = 0.25) with alpha 2-adrenoceptor sensitivity. CONCLUSION: Rapid weight loss during VLCD is associated with increased adipocyte lipolytic sensitivity to catecholamines due to decreased alpha 2-adrenoceptor sensitivity, which in turn may promote lipid mobilization. It appears that variations in alpha 2-adrenoceptor sensitivity in adipocytes may be predictive of weight loss during VLCD.