Anders Thörne

A pilot study of long-term effects of a novel obesity treatment: omentectomy in connection with adjustable gastric banding

AIM: To determine whether visceral fat reduction in connection with bariatric surgery could improve weight loss and metabolic profile of obese subjects.PATIENTS AND METHODS: In a one-center, randomized and controlled pilot trial we assigned 50 subjects with severe obesity (body mass index >35 kg/m2) to either adjustable gastric banding (AGB) alone (11 men and 14 women), or AGB plus surgical removal of the total greater omentum (11 men and 14 women). The patients were followed at regular intervals for 2 y and examined at 0 and 24 months with respect to body composition and metabolic profile.RESULTS: No significant differences between control and omentectomized patients were observed at baseline. The removed greater omentum constituted 0.8±0.4% (mean±s.d.) of total body fat. At 2 y follow-up there was an expected decrease in body weight and an improvement in metabolic profile in both groups. Although omentectomized subjects tended to lose more weight than control subjects the difference was not statistically significant and changes in waist-to-hip ratio and saggital diameter did not differ between groups. However, the improvements in oral glucose tolerance, insulin sensitivity and fasting plasma glucose and insulin were 2–3 times greater in omentectomized as compared to control subjects (P from 0.009 to 0.04), which was statistically independent of the loss in body mass index. No differences in blood lipids between the groups were recorded. No adverse effects related to omentectomy were observed.CONCLUSIONS: Omentectomy, when performed together with AGB, has significant positive and long-term effects on the glucose and insulin metabolic profiles in obese subjects.

Regional difference in insulin inhibition of non-esterified fatty acid release from human adipocytes: relation to insulin receptor phosphorylation and intracellular signalling through the insulin receptor substrate-1 pathway

Summary Increased mobilization of non-esterified fatty acids (NEFA) from visceral as opposed to peripheral fat depots can lead to metabolic disturbances because of the direct portal link between visceral fat and the liver. Compared with peripheral fat, visceral fat shows a decreased response to insulin. The mechanisms behind these site variations were investigated by comparing insulin action on NEFA metabolism with insulin receptor signal transduction through the insulin receptor substrate-1 (IRS-1) pathway in omental (visceral) and subcutaneous human fat obtained during elective surgery. Insulin inhibited lipolysis and stimulated NEFA re-esterification. This was counteracted by wortmannin, an inhibitor of phosphaditylinositol (PI) 3-kinase. The effects of insulin on antilipolysis and NEFA re-esterification were greatly reduced in omental fat cells. Insulin receptor binding capacity, mRNA and protein expression did not differ between the cell types. Insulin was four times more effective in stimulating tyrosine phosporylation of the insulin receptor in subcutaneous fat cells (p < 0.001). Similarly, insulin was two to three times more effective in stimulating tyrosine phosphorylation of IRS-1 in subcutaneous fat cells (p < 0.01). This finding could be explained by finding that IRS-1 protein expression was reduced by 50 ± 8 % in omental fat cells (p < 0.01). In omental fat cells, maximum insulin-stimulated association of the p85 kDa subunit of PI 3-kinase to phosphotyrosine proteins and phosphotyrosine associated PI 3-kinase activity were both reduced by 50 % (p < 0.05 or better). Thus, the ability of insulin to induce antilipolysis and stimulate NEFA re-esterification is reduced in visceral adipocytes. This reduction can be explained by reduced insulin receptor autophosphorylation and signal transduction through an IRS-1 associated PI 3-kinase pathway in visceral adipocytes. [Diabetologia (1998) 41: 1343–1354]

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

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

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

Aims/hypothesisThe 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.MethodsIn 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.ResultsVisceral, 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/interpretationIn 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.

Sex Differences in Visceral Fat Lipolysis and Metabolic Complications of Obesity

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

Effects of glycaemia on glucose transport in isolated skeletal muscle from patients with NIDDM: in vitro reversal of muscular insulin resistance.

SummaryWe investigated the influence of altered glucose levels on insulin-stimulated 3-0-methylglucose transport in isolated skeletal muscle obtained from NIDDM patients (n=13) and non-diabetic subjects (n=23). Whole body insulin sensitivity was 71% lower in the NIDDM patients compared to the non-diabetic subjects (p <0.05), whereas, insulin-mediated peripheral glucose utilization in the NIDDM patients under hyperglycaemic conditions was comparable to that of the non-diabetic subjects at euglycaemia. Following a 30-min in vitro exposure to 4 mmol/l glucose, insulin-stimulated 3-0-methylglucose transport (600 pmol/l insulin) was 40% lower in isolated skeletal muscle strips from the NIDDM patients when compared to muscle strips from the non-diabetic subjects. The impaired capacity for insulin-stimulated 3-0-methylglucose transport in the NIDDM skeletal muscle was normalized following prolonged (2 h) exposure to 4 mmol/l, but not to 8 mmol/l glucose. Insulin-stimulated 3-0-methylglucose transport in the NIDDM skeletal muscle exposed to 8 mmol/l glucose was similar to that of the non-diabetic muscle exposed to 5 mmol/l glucose, but was decreased by 43% (p <0.01) when compared to non-diabetic muscle exposed to 8 mmol/l glucose. Despite the impaired insulin-stimulated 3-0-methylglucose transport capacity demonstrated by skeletal muscle from the NIDDM patients, skeletal muscle glycogen content was similar to that of the non-diabetic subjects. Kinetic studies revel a Km for 3-0-methylglucose transport of 9.7 and 8.8 mmol/l glucose for basal and insulin-stimulated conditions, respectively. In conclusion, the impaired capacity for insulinstimulated glucose transport in skeletal muscle from patients with NIDDM appears to protect the cell from excessive glucose uptake under hyperglycaemic conditions. Furthermore, the in vitro normalization of the decreased insulin-stimulated glucose transport in NIDDM skeletal muscle following exposure to 4 mmol/l glucose suggests that glycaemia per se has a profound effect on the regulation of muscular glucose transport.

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

OBJECTIVE: The action of noradrenaline on human mesenteric, omental and subcutaneous adipocytes was compared. We also determined whether regional differences in the noradrenaline-effect were linked to variations in adrenoceptor subtype function. DESIGN: The lipolytic effects of different concentrations of noradrenaline (β1-, β2-, β3- and α2-adrenoceptor agonist), isoprenaline (β1-, β2- and β3-adrenoceptor agonist) and selective β1-, β2- and β3-adrenoceptor agonists (dobutamine, terbutaline and CGP 12177, respectively) were studied in adipocytes isolated from the three adipose tissue regions in the same subject. In addition, the effect of the α2-adrenoceptor antagonist, yohimbine, was studied on noradrenaline-induced glycerol release. SUBJECTS: Thirteen otherwise healthy obese subjects (nine females, four males). RESULTS: The noradrenaline-induced lipolytic response did not differ between omental and mesenteric adipocytes but was 50% higher than in subcutaneous adipocytes (P<0.05). Furthermore, noradrenaline sensitivity and intrinsic activity (in relation to isoprenaline) were higher in the two visceral fat cells than in the subcutaneous fat cells. The intrinsic activity of noradrenaline increased close to that of isoprenaline when yohimbine was added to the incubation system. Isoprenaline sensitivity was five times higher in the two visceral fat cells than in the subcutaneous fat cells. For CGP 12177, sensitivity and intrinsic activity did not differ between mesenteric and omental adipocytes, but was higher in these two regions when compared to subcutaneous adipocytes. For dobutamine and terbutaline no significant regional differences were found. CONCLUSION: β3-adrenoceptor action is enhanced and α2-adrenoceptor action is decreased in both mesenteric and omental adipocytes as compared to subcutaneous adipocytes. However, the two visceral fat depots show no difference in adrenoceptor function. The difference in β3- and α2-adrenoceptor function might explain why noradrenaline induced lipolysis is increased in the two visceral fat depots, as compared to the subcutaneous fat depot.

Electrochemical treatment of tumours

The electrochemical treatment (EChT) of tumours implies that tumour tissue is treated with a continuous direct current through two or more electrodes placed in or near the tumour. The treatment offers considerable promise of a safe, simple and relatively noninvasive anti-tumour therapy for treatment of localised malignant as well as benign tumours. Although more than 10,000 patients have been treated in China during the past 10 years, EChT has not yet been universally accepted. The reason for this is the lack of essential preclinical studies and controlled clinical trials. Uncertainties regarding the destruction mechanism of EChT also hinder the development of an optimised and reliable dose-planning methodology. This article reviews the collected Chinese and occidental experiences of the electrochemical treatment of tumours, alone and in combination with other therapies. The current knowledge of the destruction mechanism underlying EChT is presented along with different approaches towards a dose planning methodology. In addition, we discuss our view of different important parameters that have to be accounted for, if clinical trials are to be initiated outside of China.

Fatty acid binding protein expression in different adipose tissue depots from lean and obese individuals.

Abstract.Aims/hypothesis: This study investigated the expression of adipose tissue fatty acid binding proteins (FABPs) in subcutaneous and visceral human adipose tissue depots from lean and obese individuals. Methods: Adipocyte lipid binding protein (ALBP) and keratinocyte lipid binding protein (KLBP) expression was quantified by western blot in subcutaneous and omental adipose tissue from 20 obese and 9 lean individuals. RNA expression was quantified by Northern blot in the obese subjects. Results: In the obese subjects, ALBP protein and RNA expression was higher in subcutaneous compared with omental adipose tissue (increases of 31 ± 14 % and 40 ± 13 % respectively, both p < 0.05), whereas in the lean group, KLBP protein levels were 32 ± 9 % lower in subcutaneous fat (p < 0.03). However, the ALBP/KLBP ratio was greater in subcutaneous compared to omental adipose tissue from both lean and obese subjects: increases of 187 ± 71 % (p = 0.01) and 52 ± 23 % (p = 0.17) respectively for the protein ratio, and 21 ± 6 % for RNA (p = 0.01, obese individuals). In lean subjects, insulin concentrations correlated positively with the ALBP/KLBP protein ratio in both depots (both p≤ 0.03). Conclusion/interpretation: There are regional differences in adipose tissue FABP expression, which could be influenced by obesity. However, the ALBP/KLBP ratio is greater in subcutaneous than visceral adipose tissue in lean as well as in obese subjects. Investigation of adipose tissue FABPs could further our understanding of the role of fatty acids in the insulin resistance syndrome. [Diabetologia (2001) 44: 1268–1273]

The metabolic syndrome is related to β3-adrenoceptor sensitivity in visceral adipose tissue

SummaryThe 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 β-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 β-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 β3-adrenoceptor sensitivity, but not β1 and β2-adrenoceptor sensitivities, differed significantly between the WHR subgroups (p = 0.0001). β3-adrenoceptor sensitivity was also related to the other components of the metabolic syndrome, although a strong covariation between WHR and β3-adrenoceptor sensitivity vs blood pressure and the metabolic parameters was found. The present data provide evidence of a relationship between upper-body obesity and its associated metabolic complications and also, an increased visceral fat β3-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.