| 1. |
- Ek, I, et al.
(författare)
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A unique defect in the regulation of visceral fat cell lipolysis in the polycystic ovary syndrome as an early link to insulin resistance
- 2002
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 51:2, s. 484-492
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Tidskriftsartikel (refereegranskat)abstract
- The etiology of polycystic ovary syndrome (PCOS) is unknown. However, PCOS has a strong resemblance to the insulin resistance (metabolic) syndrome, where an increased rate of visceral fat cell lipolysis is believed to play a pathophysiological role. We hypothesized that primary defects in visceral lipolysis might also exist in PCOS. Ten young, nonobese, and otherwise healthy PCOS women were compared with 13 matched control women. In vitro lipolysis regulation and stoichiometric properties of the final step in lipolysis activation, namely the protein kinase A (PKA)-hormone sensitive lipase (HSL) complex, were investigated in isolated visceral (i.e., omental) fat cells. Body fat distribution and circulating levels of insulin, glucose, and lipids were normal in PCOS women. However, in vivo insulin sensitivity was slightly decreased (P = 0.03). Catecholamine-induced adipocyte lipolysis was markedly (i.e., about twofold) increased in PCOS women due to changes at the postreceptor level, although there was no change in the antilipolytic properties of visceral fat cells. Western blot analyses of visceral adipose tissue showed twofold increased levels of the catalytic and the regulatory la components of PKA. In contrast, the regulatory RIIbeta component of PKA was almost 50% decreased in visceral adipose tissue in PCOS women. Recent studies on genetically modified mice have shown that a similar transition in the regulatory PKA units induces an increased lipolytic response to catecholamines. Further analysis showed that the level of HSL-short, an enzymatically inactive splice form of HSL, was decreased in PCOS (P < 0.01). The altered lipolysis in PCOS is different from that observed in visceral fat cells in the insulin resistance syndrome that occurs at the level of adrenergic receptors. We concluded that increased catecholamine-induced lipolysis in visceral fat cells may be due to unique alterations in the stoichiometric properties of the adipose PKA-HSL holoenzymes. This could be an early and possibly primary lipolysis defect in PCOS.
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| 2. |
- Hagstrom-Toft, E, et al.
(författare)
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Marked heterogeneity of human skeletal muscle lipolysis at rest
- 2002
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 51:12, s. 3376-3383
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Tidskriftsartikel (refereegranskat)abstract
- In this study, variations in lipolysis among different muscle groups were examined by measuring local net glycerol release in vivo in healthy, normal-weight subjects (n = 11) during rested, postabsorptive conditions. Microdialysis of the gastrocnemius, deltoid, and vastus lateralis muscle regions revealed that extracellular glycerol concentrations of these three muscle regions were 84.7 ± 6.7, 59.7 + 7.3, and 56.4 ± 7.5 μmol/l, respectively, and the arterial plasma glycerol concentration was 44.8 ± 2.3 μmol/l (P = 0.0003–0.006, gastrocnemius vs. others). Local tissue blood flow, as measured by Xe clearance, did not differ among the regions. Net glycerol release was significantly higher in gastrocnemius muscle than in the two other regions. There were no regional differences in glycerol uptake when studied during glycerol infusion. Gastrocnemius muscle showed a dominance of type 1 fibers (70%), whereas the vastus lateralis muscle had equal distribution of fiber types (P = 0.02). No differences in intramuscular triaclyceride content, perimuscular fat, or the adipocyte-specific protein perilipin were observed among the muscle regions. Triglyceride turnover in the gastrocnemius muscle was 3.3 + 1.4% over 24 h, which is about 10 times more rapid than the turnover rate in subcutaneous adipose tissue (P < 0.01). Thus there were marked differences in lipolytic activity among skeletal muscle groups at rest, possibly reflecting variations in fiber type.
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| 3. |
- Lofgren, P, et al.
(författare)
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Secretion of tumor necrosis factor-alpha shows a strong relationship to insulin-stimulated glucose transport in human adipose tissue
- 2000
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 49:5, s. 688-692
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 4. |
- Ryden, M, et al.
(författare)
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Effect of the (C825T) Gbeta(3) polymorphism on adrenoceptor-mediated lipolysis in human fat cells
- 2002
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 51:5, s. 1601-1608
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Tidskriftsartikel (refereegranskat)abstract
- A common Gβ3 gene polymorphism (C825T) influences G protein receptor-mediated signal transduction. We investigated whether this polymorphism influences lipolysis in isolated subcutaneous fat cells from 114 healthy obese subjects. The Gβ3 protein content was markedly decreased in adipocytes of TT carriers, but the alternatively spliced short form of Gβ3 previously shown in platelets of 825T carriers was not detected. Fat cells of TT carriers showed a significant 10-fold decrease in the half-maximum effective concentration of agonists selective for lipolytic β1- and β2-adrenoceptors as well as for the antilipolytic α2A-adrenoceptor. In TT carriers, maximum β-adrenoceptor agonist-stimulated lipolysis was decreased, but the maximum antilipolytic effect of α2-adrenoceptors was less marked. Norepinephrine induced adipocyte lipolysis and circulating fasting levels of free fatty acids and glycerol were reduced by half in TT carriers. The polymorphism did not influence the adipocyte content of α2A-adrenoceptors, β2-adrenoceptors, Gαi, or Gαs. In conclusion, the C825T variant of Gβ3 influences lipolysis. Adipocytes of TT carriers have a lower Gβ3 protein content and a decreased function of native Gs- as well as Gi-coupled adrenoceptors, which reduces the lipolytic effect of catecholamines. These data differ from those obtained in other cell systems that have shown increased expression of an alternative spliced Gβ3 variant and enhanced G protein signaling in 825T carriers, indicating that the polymorphism has cell type-specific effects that may be of importance for type 2 diabetes and other insulin-resistant conditions.
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| 5. |
- van Harmelen, V, et al.
(författare)
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Increased lipolysis and decreased leptin production by human omental as compared with subcutaneous preadipocytes
- 2002
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 51:7, s. 2029-2036
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Tidskriftsartikel (refereegranskat)abstract
- Site differences in adipose tissue function may have implications for insulin-resistant conditions. In mature adipose tissue, subcutaneous adipocytes have higher leptin secretion, similar tumor necrosis factor (TNF)-α secretion, and lower catecholamine-stimulated lipolysis as compared with omental adipocytes. In this study, lipolysis and leptin and TNF-α secretion were compared between human omental and subcutaneous preadipocytes. After 16 days of incubation in a minimal differentiation medium, leptin mRNA and secretion were found to be two to eight times higher in subcutaneous than omental preadipocytes (P < 0.05). On the other hand, norepinephrine-induced lipolysis was about two times higher in the omental than in the subcutaneous preadipocytes, whereas basal lipolysis did not differ between the two regions. TNF-α secretion was marginally but significantly higher in the omental than in the subcutaneous preadipocytes. Preadipocyte differentiation was equal in both regions and was augmented to the same extent by different thiazolidinediones (rosiglitazone, pioglitazone, or troglitazone) in the two depots. In the presence of rosiglitazone, leptin secretion remained about three times higher and norepinephrine-induced lipolysis about six times lower in subcutaneous as compared with omental preadipocytes (P < 0.05), whereas TNF-α secretion and basal lipolysis were similar in preadipocytes from the two regions. These findings remained unaltered even if rosiglitazone was removed from the medium. However, leptin mRNA showed no regional differences in rosiglitazone-treated cells. Thus, regional differences in adipocyte leptin secretion as well as in norepinephrine-induced lipolysis are marked and present during different stages of preadipocyte differentiation and seem to be determined by intrinsic (i.e., primary) factors.
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