Showing papers by "Peter Arner published in 2003"

The adipocyte in insulin resistance: key molecules and the impact of the thiazolidinediones

Abstract: Globally, the prevalence of obesity is escalating, and insulin resistance resulting from increased (predominantly visceral) adipose tissue mass has been identified as a key factor that could drive parallel rises in type 2 diabetes mellitus (T2DM) prevalence. Correlations between these global epidemics have encouraged investigation into potential molecular links between the related impairments in lipid and glucose homeostasis. This article reviews factors released from adipose tissue that could contribute to the development of insulin resistance and β-cell dysfunction, including tumour necrosis factor α (TNF-α), free fatty acids (FFAs), adiponectin, resistin and leptin. It also considers whether agonists of the peroxisome proliferator-activated receptor γ, which is abundant in adipose tissue, might have an important impact on factors associated with adipocyte metabolism. For example, the thiazolidinediones, a class of oral anti-diabetic agents that reduce insulin resistance and improve β-cell function, might mediate these effects by regulating adipocyte-derived factors, in particular TNF-α and FFAs.

Evidence for an important role of perilipin in the regulation of human adipocyte lipolysis

Abstract: Aims/hypothesis We investigated the role of the adipocyte-specific protein perilipin for lipolysis in humans.

Mechanisms behind lipolytic catecholamine resistance of subcutaneous fat cells in the polycystic ovarian syndrome

Abstract: Lipolytic catecholamine resistance in sc fat cells is observed in polycystic ovarian syndrome (PCOS). The mechanisms behind this lipolysis defect were explored in vitro; sc fat cells were obtained from 10 young, nonobese PCOS women and from 14 matched, healthy control women. Fasting plasma glycerol levels were reduced by one third in PCOS (P < 0.05). Adipocytes of PCOS women were about 25% larger than in the controls (P < 0.05) and had 40% reduced noradrenaline-induced lipolysis (P < 0.05), which could be attributed to a 10-fold decreased β2-adrenoceptor sensitivity (P < 0.05) and low ability of cAMP to activate the protein kinase A (PKA)/hormone-sensitive lipase (HSL) complex (P < 0.05). In PCOS, the adipocyte protein content of β2-adrenoceptors, HSL, and the regulatory IIβ-component of PKA were 70%, 55%, and 25% decreased, respectively (P < 0.001); but there was no change in the amount of the catalytic subunit of PKA or of β1-adrenoceptors. Thus, lipolytic catecholamine resistance of sc adipocytes in PC...

Effects of glucocorticoids on leptin levels and eating behaviour in women.

Abstract: . Udden J, Bjorntorp P, Arner P, Barkeling B, Meurling L, Rossner S (Karolinska Institute at Huddinge University Hospital, Stockholm, Sweden; and Sahlgren's Hospital, Gothenburg, Sweden). Effects of glucocorticoids on leptin levels and eating behaviour in women. J Intern Med 2003; 253: 225–231. Objective. Long-term treatment with glucocorticoids induces weight gain and increased risk to develop obesity-related metabolic complications. The underlying mechanisms are not fully understood. Glucocorticoid therapy has previously been associated with increased levels of circulating leptin. In this study the eating behaviour was therefore studied in relation to leptin levels before and after short-term prednisolone treatment. Design. Within-subject design. Subjects. Twelve healthy postmenopausal women with a mean body mass index (BMI) of 28.9 kg m−2 (±0.8 SEM) volunteered after recruitment by an advertisement in the local paper. Interventions. The subjects received 25 mg prednisolone daily for 7 days. Main outcome measurements. Fasting serum samples were obtained before, during and after treatment for determination of leptin and insulin, glucose and fractionated lipoproteins in plasma. The microstructure of the eating behaviour was registered with a universal eating monitor, VIKTOR. Appetite was estimated by visual analogue rating scales and food intake by a 48-h recall. Results. Serum leptin increased after 2 and 7 days of glucocorticoid administration (P < 0.01), and the food intake measured by VIKTOR after 7 days of treatment (P < 0.05). No statistically significant changes were however, found in the 48-h food- recall or in the subjective appetite registrations. Insulin levels were borderline elevated (P = 0.062) after treatment, but no significant changes of fasting glucose were seen. High density lipoprotein cholesterol (HDL) increased (P < 0.05), whilst low density lipoprotein cholesterol (LDL) decreased (P < 0.05). Conclusion. Food intake was elevated after glucocorticoid administration as observed with an objective, quantitative method, in spite of increased levels of circulating leptin.

Pancreatic beta-Cell Lipotoxicity Induced by Overexpression of Hormone-Sensitive Lipase.

Abstract: Lipid perturbations associated with triglyceride overstorage in β-cells impair insulin secretion, a process termed lipotoxicity. To assess the role of hormone-sensitive lipase, which is expressed and enzymatically active in β-cells, in the development of lipotoxicity, we generated transgenic mice overexpressing hormone-sensitive lipase specifically in β-cells. Transgenic mice developed glucose intolerance and severely blunted glucose-stimulated insulin secretion when challenged with a high-fat diet. As expected, both lipase activity and forskolin-stimulated lipolysis was increased in transgenic compared with wild-type islets. This was reflected in significantly lower triglycerides levels in transgenic compared with wild-type islets in mice receiving the high-fat diet, whereas no difference in islet triglycerides was found between the two genotypes under low-fat diet conditions. Our results highlight the importance of mobilization of the islet triglyceride pool in the development of β-cell lipotoxicity. We propose that hormone-sensitive lipase is involved in mediating β-cell lipotoxicity by providing ligands for peroxisome proliferator-activated receptors and other lipid-activated transcription factors, which in turn alter the expression of critical genes. One such gene might be uncoupling protein-2, which was found to be upregulated in transgenic islets, a change that was accompanied by decreased ATP levels.

The Presence of a Catalytically Inactive Form of Hormone-Sensitive Lipase Is Associated With Decreased Lipolysis in Abdominal Subcutaneous Adipose Tissue of Obese Subjects

Abstract: Hormone-sensitive lipase (HSL)-L is a key enzyme in the mobilization of fatty acids from triglyceride stores in adipocytes. A shorter variant of HSL (HSL-S) was detected in humans. This one is generated through in-frame skipping of exon 6 during the processing of HSL mRNA and results in a protein devoid of lipase activity. The role of HSL-S is unknown. The aims of this study were to identify both HSL variants in adipose tissue biopsies and to determine if the presence of HSL-S is correlated to the lipolytic capacity of adipocytes. The study was performed in human abdominal subcutaneous adipocytes from two groups of seven obese subjects. In the group of subjects with both HSL proteins (L+S) group, two immunoreactive bands (80 and 88 kDa) were detected, whereas only the 88-kDa protein was detected in the group with only the wild-type HSL-protein (L group). In the L+S group, the HSL activity was 20% lower ( P + ) HSL mRNA ratio was twofold higher than in the L group ( P P

No linkage to obesity in candidate regions of chromosome 2 and 10 in a selected sample of Swedish twins.

Abstract: The aim of the current study was to investigate the importance of genetic and environmental effects in the variation of body mass index, and to investigate linkage for obesity to previously reported candidate regions on chromosome 2 and 10. A sample of 1422 twin pairs from the population based Swedish Twin Registry was used in order to estimate the genetic and environmental effects in the variation of body mass index by means of structural equation modeling. A selection of those, 51 concordant and 155 discordant for obesity, was used for the linkage analysis by implementing the 'combined' Haseman-Elston approach. Heritability of body mass index ranged from 59-70%, implying that genetic effects were of importance for the variation of obesity, and there were significant sex and age differences. Linkage could not be verified in candidate regions of chromosomes 2 and 10, indicating that these genetic variants have a significant effect in extreme obese populations rather than in moderately obese Caucasians. However, the results were sensitive to issues related to power, minor effects of the genes, ethnic differences and the complex mechanism underlying obesity.