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- Ryden, M, et al.
(author)
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Comparative studies of the role of hormone-sensitive lipase and adipose triglyceride lipase in human fat cell lipolysis
- 2007
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In: American journal of physiology. Endocrinology and metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 292:6, s. E1847-E1855
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Journal article (peer-reviewed)abstract
- Hormone-sensitive lipase (HSL) and adipose triglyceride lipase (ATGL) regulate adipocyte lipolysis in rodents. The purpose of this study was to compare the roles of these lipases for lipolysis in human adipocytes. Subcutaneous adipose tissue was investigated. HSL and ATGL protein expression were related to lipolysis in isolated mature fat cells. ATGL or HSL were knocked down by RNA interference (RNAi) or selectively inhibited, and effects on lipolysis were studied in differentiated preadipocytes or adipocytes derived from human mesenchymal stem cells (hMSC). Subjects were all women. There were 12 lean controls, 8 lean with polycystic ovary syndrome (PCOS), and 27 otherwise healthy obese subjects. We found that norepinephrine-induced lipolysis was positively correlated with HSL protein levels ( P < 0.0001) but not with ATGL protein. Women with PCOS or obesity had significantly decreased norepinephrine-induced lipolysis and HSL protein expression but no change in ATGL protein expression. HSL knock down by RNAi reduced basal and catecholamine-induced lipolysis. Knock down of ATGL decreased basal lipolysis but did not change catecholamine-stimulated lipolysis. Treatment of hMSC with a selective HSL inhibitor during and/or after differentiation in adipocytes reduced basal lipolysis by 50%, but stimulated lipolysis was inhibited completely. In contrast to findings in rodents, ATGL is of less importance than HSL in regulating catecholamine-induced lipolysis and cannot replace HSL when this enzyme is continuously inhibited. However, both lipases regulate basal lipolysis in human adipocytes. ATGL expression, unlike HSL, is not influenced by obesity or PCOS.
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- Spalding, KL, et al.
(author)
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Dynamics of fat cell turnover in humans
- 2008
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In: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 453:7196, s. 783-787
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Journal article (peer-reviewed)
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- Arner, P, et al.
(author)
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Adrenoceptor genes in human obesity
- 1999
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In: Journal of internal medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 245:6, s. 667-672
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Journal article (peer-reviewed)
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- Ek, I, et al.
(author)
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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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In: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 51:2, s. 484-492
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Journal article (peer-reviewed)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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- Hoffstedt, J, et al.
(author)
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A common hormone-sensitive lipase i6 gene polymorphism is associated with decreased human adipocyte lipolytic function
- 2001
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In: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 50:10, s. 2410-2413
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Journal article (peer-reviewed)abstract
- Hereditary factors may be involved in the pathogenesis of type 2 diabetes. A polymorphism in the hormone-sensitive lipase (HSL) gene (HSLi6) is associated with obesity and diabetes, although it is unknown whether the polymorphism is functional and thereby influences lipolysis. We genotyped 355 apparently healthy nonobese male and female subjects for the HSLi6 polymorphism. Allele 5 was found to be the most common allele (allele frequency 0.57). In 117 of the subjects, we measured abdominal subcutaneous fat cell lipolysis induced by drugs acting at various steps in the lipolytic cascade. The lipolysis rate induced by norepinephrine isoprenaline (acting on β-adrenoceptors), forskolin (acting on adenylyl cyclase), and dibutyryl cyclic AMP (acting on HSL) were all decreased by ∼50% in allele 5 homozygotes, as compared with noncarriers. Heterozygotes showed an intermediate lipolytic rate. The difference in lipolysis rate between genotypes was more pronounced in men than in women. We conclude that allele 5 of the HSLi6 polymorphism is associated with a marked decrease in the lipolytic rate of abdominal fat cells. This may in turn contribute to the development of obesity.
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| 30. |
- Hoffstedt, J, et al.
(author)
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Adipose tissue adiponectin production and adiponectin serum concentration in human obesity and insulin resistance
- 2004
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In: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 89:3, s. 1391-1396
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Journal article (peer-reviewed)abstract
- The role of adiponectin production for the circulating protein concentration in human obesity and insulin resistance is unclear. We measured serum concentration and sc adipose tissue secretion rate of adiponectin in 77 obese and 23 nonobese women with a varying degree of insulin sensitivity. The serum adiponectin concentration was similar in both groups. In obesity, adiponectin adipose tissue secretion rate per weight unit was reduced by 30% (P = 0.01), whereas total body fat secretion rate was increased by 100% (P < 0.0001). In the group being most insulin resistant (1/3), serum concentration (P < 0.001) and adipose tissue secretion rate per tissue weight (P < 0.05) were reduced, whereas total body fat secretion rate was increased (P < 0.01), by about 30%. The adipose tissue secretion rate of adiponectin was related to the serum concentration (P = 0.005) but explained only about 10% of the interindividual variation in circulating adiponectin and insulin sensitivity. The plasma adiponectin half life was long, 2.5 h. In conclusion, the role of protein secretion for the circulating concentration of adiponectin and insulin sensitivity under these conditions is minor because adiponectin turnover rate is slow. Although increased in obesity and insulin resistance, total body production of adiponectin is insufficient to raise the circulating concentration, may be due to reduced secretion rate per tissue unit.
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| 37. |
- Hoffstedt, J, et al.
(author)
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Polymorphism in the Calpain 10 gene influences glucose metabolism in human fat cells
- 2002
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In: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 45:2, s. 276-282
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Journal article (peer-reviewed)abstract
- Aims/hypothesis. A common G to A polymorphism (UCSNP-43) in the Calpain 10 gene was recently found to be associated with Type 11 (non-insulin-dependent) diabetes mellitus and variations in post-absorptive and insulin stimulated glucose metabolism in vivo. We aimed to study the influence of Calpain 10 polymorphism on insulin action in fat cells. Methods. Calpain 10 polymorphism (UCSNP-19, -43 or -63) were set in relation to lipolysis and lipogenesis in isolated subcutaneous adipocytes of 46 apparently healthy non-obese subjects. Results. For UCSNP-43 the GIG genotype had twofold higher basal and insulin stimulated rates as compared with AA/AG genotypes. However, there was no genotype effect on basal or insulin inhibited lipolysis rates in fat cells. The protein amount of GLUT 4 in adipocytes was not influenced by the polymorphism. Fat cells expressed mRNA for the Calpain 10 gene at a relatively high concentration, about 4 amol/mug RNA, which is similar to that of uncoupling protein-2. Neither a UCSNP-19 nor a UCSNP-63 polymorphism in the Calpain 10 gene was found to be associated with basal or insulin-induced adipocyte lipolysis and lipogenesis. None of the polymorphisms influenced body mass index or fasting plasma concentrations of insulin and glucose in 693 non-obese healthy subjects. Conclusion/interpretation. The Calpain 10 gene could be involved in the regulation of glucose metabolism but not lipolysis in human fat cells, although it does not involve adipocyte GLUT-4 protein content. It is possible that the Calpain 10 gene predisposes to diabetes by influencing the glucose metabolism.
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| 47. |
- Langin, D, et al.
(author)
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Adipocyte lipases and defect of lipolysis in human obesity
- 2005
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In: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 54:11, s. 3190-3197
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Journal article (peer-reviewed)abstract
- The mobilization of fat stored in adipose tissue is mediated by hormone-sensitive lipase (HSL) and the recently characterized adipose triglyceride lipase (ATGL), yet their relative importance in lipolysis is unknown. We show that a novel potent inhibitor of HSL does not inhibit other lipases. The compound counteracted catecholamine-stimulated lipolysis in mouse adipocytes and had no effect on residual triglyceride hydrolysis and lipolysis in HSL-null mice. In human adipocytes, catecholamine- and natriuretic peptide-induced lipolysis were completely blunted by the HSL inhibitor. When fat cells were not stimulated, glycerol but not fatty acid release was inhibited. HSL and ATGL mRNA levels increased concomitantly during adipocyte differentiation. Abundance of the two transcripts in human adipose tissue was highly correlated in habitual dietary conditions and during a hypocaloric diet, suggesting common regulatory mechanisms for the two genes. Comparison of obese and nonobese subjects showed that obesity was associated with a decrease in catecholamine-induced lipolysis and HSL expression in mature fat cells and in differentiated preadipocytes. In conclusion, HSL is the major lipase for catecholamine- and natriuretic peptide-stimulated lipolysis, whereas ATGL mediates the hydrolysis of triglycerides during basal lipolysis. Decreased catecholamine-induced lipolysis and low HSL expression constitute a possibly primary defect in obesity.
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| 49. |
- Lavebratt, C., et al.
(author)
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Association study between chromosome 10q26.11 and obesity among Swedish men
- 2005
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In: International Journal of Obesity. - : Springer Science and Business Media LLC. - 0307-0565 .- 1476-5497. ; 29:12, s. 1422-1428
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Journal article (peer-reviewed)abstract
- OBJECTIVE: Proximal chromosome 10q26 was recently linked to waist/hip ratio in European and African-American families. The objective was to investigate whether genomic variation in chromosome 10q26.11 reflects variation in obesity-related clinical parameters in a Swedish population. DESIGN: Genetic association study of single-nucleotide polymorphisms (SNPs) in chromosome 10q26.11 and obesity-related clinical parameters was performed. Obesity was defined as body mass index (BMI)≥30 kg/m2. SUBJECTS: Swedish Caucasians comprising 276 obese and 480 nonobese men, 313 obese and 494 nonobese women, 177 obese and 163 nonobese patients with type 2 diabetes mellitus (T2DM), and 106 obese and 201 nonobese subjects with impaired glucose tolerance (IGT) patients. MEASUREMENTS: Genotypes of 11 SNPs at chromosome 10q26.11, and various obesity-related clinical parameters. RESULTS: Homozygosity of a common haplotype constructed by three SNPs, rs2185937, rs1797 and hCV1402327, covering an interval of 2.7 kb, was suggested to confer an increased risk for obesity of 1.5 among men (P=0.043). The C allele frequency and homozygous genotype frequency of the rs1797 tended to be higher among obese compared to among nonobese men (P=0.017 and 0.020, respectively). The distribution of BMI and diastolic blood pressure was higher among those with the C/C genotype (P=0.022 and 0.0061, respectively). The obese and the nonobese groups were homogeneous over BMI subgroups with regard to rs1797 risk genotype distribution. There was no tendency for association between rs1797 and obesity among neither women nor T2DM nor IGT patients. CONCLUSION: We show support for association between proximal chromosome 10q26.11 and obesity among Swedish men but not women through the analysis of a haplotype encompassing 2.7 kb. © 2005 Nature Publishing Group All rights reserved.
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