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

Zierath, Juleen R.; Livingston, James N.; Thörne, A.; Bolinder, Jan; Reynisdottir, Signy; Lönnqvist, Fredrik; Arner, Peter

doi:10.1007/s001250051075

Cited by 189 publications

(147 citation statements)

References 33 publications

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“…However, this was not the case, indeed, not even at the highest concentration of rosiglitazone did the PPRE activity in omental fat cells reach basal levels in subcutaneous fat cells. Since increased PPARG activity through treatment with synthetic PPARG activators leads to reduced adipose tissue lipolytic activity and lowered levels of NEFA in plasma, this novel finding of low PPARG activity is in line with the high lipolytic activity in intra-abdominal fat tissue [8].…”

Section: Discussionmentioning

confidence: 53%

“…Our study also shows that the difference cannot be compensated even by the potent synthetic PPARG agonist rosiglitazone. Further studies into the molecular mechanisms behind the large difference in PPARG signalling in the two adipose tissue depots could lead to the development of drugs that reduce the adverse metabolic effect of abdominal obesity and the poor cardiovascular prognosis linked to this condition [2,8,24].…”

Section: Discussionmentioning

confidence: 99%

“…It is generally considered that the unfavourable prognosis in subjects with abdominal obesity is due to large amounts of intra-abdominal fat [3][4][5][6]. Human omental fat cells display a high number of beta-adrenergic receptors and reduced antilipolytic effect of insulin, compared with subcutaneous fat cells, resulting in a high release of fatty acids from this fat cell depot [7,8]. Fatty acids from fat tissue within the abdominal cavity are drained to the hepatic vein resulting in delivery of venous blood with high concentrations of fatty acids directly to the liver, which can affect liver metabolism to cause dyslipidaemia and increased production of glucose.…”

Section: Introductionmentioning

confidence: 99%

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Peroxisome proliferator activated receptor gamma activity is low in mature primary human visceral adipocytes

et al. 2006

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Aims/hypothesis The amount of visceral fat mass strongly relates to insulin resistance in humans. The transcription factor peroxisome proliferator activated receptor gamma (PPARG) is abundant in adipocytes and regulates genes of importance for insulin sensitivity. Our objective was to study PPARG activity in human visceral and subcutaneous adipocytes and to compare this with the most common model for human disease, the mouse. Materials and methods We transfected primary human adipocytes with a plasmid encoding firefly luciferase controlled by PPARG response element (PPRE) from the acyl-CoA-oxidase gene and measured PPRE activity by emission of light.Results We found that PPRE activity was 6.6-fold higher (median) in adipocytes from subcutaneous than from omental fat from the same subjects (n=23). The activity was also 6.2-fold higher in subcutaneous than in intraabdominal fat cells when we used a PPARG ligand-binding domain-GAL4 fusion protein as reporter, demonstrating that the difference in PPRE activity was due to different levels of activity of the PPARG receptor in the two fat depots. Stimulation with 5 μmol/l rosiglitazone did not induce a PPRE activity in visceral adipocytes that was as high as basal levels in subcutaneous adipocytes. Interestingly, in mice of two different strains the PPRE activity was similar in visceral and subcutaneous fat cells. Conclusions/interpretation We found considerably lower PPARG activity in visceral than in subcutaneous primary human adipocytes. Further studies of the molecular mechanisms behind this difference could lead to development of drugs that target the adverse effects of visceral obesity.

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Section: Discussionmentioning

confidence: 53%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Peroxisome proliferator activated receptor gamma activity is low in mature primary human visceral adipocytes

et al. 2006

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“…In our study the A allele of SNP-43 was associated with intraabdominal fat area even after the adjustment for insulin sensitivity. The GG genotype has been associated with improved insulin action in isolated subcutaneous adipocytes [31], which could explain the preferential storage of fat in subcutaneous depots, in contrast to intra-abdominal fat that is less sensitive to insulin action [32]. Lower accumulation of intra-abdominal fat could then explain better whole-body insulin sensitivity in subjects with the GG genotype in this study.…”

Section: Subjects Inmentioning

confidence: 54%

Common polymorphisms of calpain-10 are associated with abdominal obesity in subjects at high risk of type 2 diabetes

et al. 2006

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Aims/hypothesis: The mechanisms by which the calpain-10 gene (CAPN10) affects the risk of type 2 diabetes are unclear. Therefore, we investigated the effects of four polymorphisms in CAPN10 (single nucleotide polymorphism [SNP]-43, SNP-44, Insertion/Deletion [Indel]-19 and SNP-63) on insulin secretion, insulin action and abdominal fat distribution in offspring of patients with type 2 diabetes. Subjects and methods: Insulin secretion was determined by an IVGTT, insulin action by the hyperinsulinaemic-euglycaemic clamp and abdominal fat distribution by computed tomography in 158 non-diabetic offspring (age 34.9±6.3 years [mean±SD], BMI 26.2± 4.9 kg/m 2 ) of type 2 diabetic patients. Results: SNP-43 (p=0.009 over the three genotypes, adjusted for age, sex, BMI and family relationship) and haplotypes carrying the A allele of SNP-43 were associated with intra-abdominal fat area. The A allele of SNP-43 was associated with intraabdominal fat area in men (p=0.014) but not in women. were not associated with intra-abdominal fat area or insulin action. Furthermore, we demonstrated in a separate sample of middle-aged men (n=234) who had a history of type 2 diabetes in firstdegree relatives that the A allele of SNP-43 was associated with a large waist circumference, and high insulin levels in an OGTT.Conclusions/interpretation: SNP-43 of CAPN10 may contribute to the risk of diabetes by regulating abdominal obesity in subjects with high risk of type 2 diabetes.

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“…Adipocytes were incubated [21]. An aliquot (2 ml) of adipocytes (15% cell suspension) was incubated for 10 min at 37°C in the absence or presence of 3 or 1000 nmol/l insulin.…”

Section: Subject Characteristics and Dietary Interventionmentioning

confidence: 99%

Insulin signal transduction and glucose transport in human adipocytes: effects of obesity and low calorie diet

et al. 2002

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Aim/hypothesis. We examined insulin signal transduction at the level of insulin receptor substrates (IRS) 1 and 2, phosphatidylinositol (PI) 3-kinase and glucose transport in isolated subcutaneous adipocytes from obese and lean women. Methods. Glucose transport and insulin signalling were investigated in isolated adipocytes from six obese women (BMI 36-43 kg/m 2 ) (before and after 11 days of very low calorie diet) and from six lean women (BMI 22-26 kg/m 2 ). Results. Insulin sensitivity of glucose transport was reduced in adipocytes from obese women (p<0.05), with further reductions in basal and maximal insulinstimulated glucose transport after a very low calorie diet (p<0.05). In obese women, IRS-1 associated PI 3-kinase activity was markedly impaired (p<0.05), whereas, IRS-2 associated PI 3-kinase activity was normal. IRS-1 associated PI 3-kinase activity remained blunted after a very low calorie diet, whereas IRS-2 associated PI 3-kinase activity was increased. GLUT4 protein was reduced by 37% in obese versus lean subjects (p<0.05), and decreased further after a very low calorie diet (from 19±4 to 14±4 arbitrary units; p<0.05). Conclusion/interpretation. IRS-1 signalling to PI 3-kinase is a site of insulin resistance in adipocytes from obese women, whereas insulin action on IRS-2 is normal. Thus, IRS-1 and IRS-2 undergo differential regulation in adipocytes from obese insulin resistant subjects. Finally, a very low calorie diet is associated with a further impairment in glucose transport in adipose tissue. The defect in glucose transport after a very low calorie diet occurs independent of further defects in insulin signalling at the level of the PI 3-kinase.

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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

Cited by 189 publications

References 33 publications

Peroxisome proliferator activated receptor gamma activity is low in mature primary human visceral adipocytes

Peroxisome proliferator activated receptor gamma activity is low in mature primary human visceral adipocytes

Common polymorphisms of calpain-10 are associated with abdominal obesity in subjects at high risk of type 2 diabetes

Insulin signal transduction and glucose transport in human adipocytes: effects of obesity and low calorie diet

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