Hormone-sensitive lipase is reduced in the adipose tissue of patients with type 2 diabetes mellitus: influence of IL-6 infusion

Watt, Matthew James; Carey, Andrew L.; Wolsk-Petersen, E.; Kraemer, Fredric B.; Pedersen, Bente Klarlund; Febbraio, Mark A.

doi:10.1007/s00125-004-1598-x

Cited by 46 publications

(40 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The factors underpinning this apparent mismatch are presently unclear but may involve proteasome degradation via a ubiquitination pathway, as has been described previously for other proteins important for lipolytic regulation including perilipin and adipose differentiation-related protein (47,48). HSL content was previously shown to be associated with total neutral lipase activity (23,42), and, given the central role of ATGL in murine TG lipolysis (10, 15, 52), we hypothesized that ATGL content would also be positively related to TG lipase activity in humans. Surprisingly, we found no correlation between ATGL content and in vitro TG lipase activity despite finding that total TG lipase activity was reduced by 70 -85% after ATGL immunoprecipitation, indicating that ATGL is essential for efficient TG lipase activity.…”

Section: Discussionmentioning

confidence: 93%

“…Adipose tissue TG lipase activity was determined using an emulsified substrate consisting of 5 mmol/l triolein, 6.7 ϫ 10 6 counts/min [9,10-3 H]triolein, 0.6 mg of phospholipid (phosphatidylcholine-phosphatidylinositol, 3:1, wt/wt), 0.1 M potassium phosphate, and 20% BSA. Procedures for this assay have been described previously (42).…”

Section: Methodsmentioning

confidence: 99%

“…HSL expression is reduced in obesity (23,29,42), which is inconsistent with the elevated basal lipolysis observed in these individuals, implying that other TG lipases may be upregulated. Two recent reports (22,29) suggest that ATGL mRNA is not regulated in human obesity, whereas the same group reports that ATGL mRNA and protein expression are negatively associated with insulin resistance and not obesity per se (13).…”

mentioning

confidence: 94%

See 2 more Smart Citations

Adipocyte triglyceride lipase expression in human obesity

Steinberg¹,

Kemp²,

Watt³

2007

American Journal of Physiology-Endocrinology and Metabolism

145

117

View full text Add to dashboard Cite

We have investigated the gene and protein expression of adipose triglyceride lipase (ATGL) and triglyceride (TG) lipase activity from subcutaneous and visceral adipose tissue of lean and obese subjects. Visceral and subcutaneous adipose tissue was obtained from 16 age-matched lean and obese subjects during abdominal surgery. Tissues were analyzed for mRNA expression of lipolytic enzymes by real-time quantitative PCR. ATGL protein content was assessed by Western blot and TG lipase activity by radiometric assessment. Subcutaneous and visceral adipose tissue of obese subjects had elevated mRNA expression of PNPLA2 (ATGL) and other lipases including PNPLA3, PNPLA4, CES1, and LYPLAL1 (P Ͻ 0.05). Surprisingly, ATGL protein expression and TG lipase activity were reduced in subcutaneous adipose tissue of obese subjects. Immunoprecipitation of ATGL reduced total TG lipase activity in adipose lysates by 70% in obese and 83% in lean subjects. No significant differences in the ATGL activator CGI-58 mRNA levels (ABHD5) were associated with obesity. These data demonstrate that ATGL is important for efficient TG lipase activity in humans. They also demonstrate reduced ATGL protein expression and TG lipase activity despite increased mRNA expression of ATGL and other novel lipolytic enzymes in obesity. The lack of correlation between ATGL protein content and in vitro TG lipase activity indicates that small decrements in ATGL protein expression are not responsible for the reduction in TG lipase activity observed here in obesity, and that posttranslational modifications may be important. triglyceride metabolism; adipose triglyceride lipase; triglyceride hydrolase activity THE ABILITY TO EFFICIENTLY regulate the storage and release of fatty acids contained in adipose triglyceride (TG) requires tight coupling between hydrolysis and esterification. Fat stored in subcutaneous and visceral depots is mobilized by activation of lipolytic enzymes, which degrade TGs and release free fatty acids (FFAs) into the circulation for use as an energy substrate. Obesity is characterized by excessive adipose tissue deposition and increased FFA release that exceeds metabolic demands (17). Elevated postprandial FFAs are a hallmark of obesity (33) and contribute to metabolic disturbances including insulin resistance in skeletal muscle and liver (4, 44), pancreatic ␤-cell dysfunction (51), and increased VLDL triglyceride production (27).Until recently, hormone-sensitive lipase (HSL) was considered the rate-limiting enzyme for lipolysis, but recent evidence suggests that adipose triglyceride lipase (ATGL) may also be important. HSL Ϫ/Ϫ mice have residual TG lipase activity (11, 31, 32) indicative of the presence of other TG lipases and maintain partial basal and catecholamine-stimulated lipolysis (41). Recent studies have identified the molecular lipolytic (and esterolytic) proteome in mouse adipose tissue (3) and 23 proteins that are incompletely characterized. Many of these proteins are predicted to contain an ␣/␤-hydrolase fold that accommodates catal...

show abstract

Section: Discussionmentioning

confidence: 93%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 94%

See 1 more Smart Citation

Adipocyte triglyceride lipase expression in human obesity

Steinberg¹,

Kemp²,

Watt³

2007

American Journal of Physiology-Endocrinology and Metabolism

145

117

View full text Add to dashboard Cite

show abstract

“…TG lipase activity was determined as described previously (39,42). Briefly, an aliquot of powdered skeletal muscle (ϳ30 mg) was homogenized for 10 s on ice in 20 vol of homogenizing buffer using a Polytron homogenizer at full speed.…”

Section: Methodsmentioning

confidence: 99%

Dysregulation of muscle lipid metabolism in rats selectively bred for low aerobic running capacity

Spargo¹,

McGee²,

Dzamko³

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

View full text Add to dashboard Cite

Spargo FJ, McGee SL, Dzamko N, Watt MJ, Kemp BE, Britton SL, Koch LG, Hargreaves M, Hawley JA. Dysregulation of muscle lipid metabolism in rats selectively bred for low aerobic running capacity. Am J Physiol Endocrinol Metab 292: E1631-E1636, 2007. First published February 6, 2007 doi:10.1152/ajpendo.00702.2006.-As substrate for evaluation of metabolic diseases, we developed novel rat models that contrast for endurance exercise capacity. Through twoway artificial selection, we created rodent phenotypes of intrinsically low-capacity runners (LCR) and high-capacity runners (HCR) that also differed markedly for cardiovascular and metabolic disease risk factors. Here, we determined skeletal muscle proteins with putative roles in lipid and carbohydrate metabolism to better understand the mechanisms underlying differences in whole body substrate handling between phenotypes. Animals (generation 16) differed for endurance running capacity by 295%. LCR animals had higher resting plasma glucose (6.58 Ϯ 0.45 vs. 6.09 Ϯ 0.45 mmol/l), insulin (0.48 Ϯ 0.03 vs. 0.32 Ϯ 0.02 ng/ml), nonesterified fatty acid (0.57 Ϯ 0.14 v 0.35 Ϯ 0.05 mM), and triglyceride (TG; 0.47 Ϯ 0.11 vs. 0.25 Ϯ 0.08 mmol/l) concentrations (all P Ͻ 0.05). Muscle TG (72.3 Ϯ 14.7 vs. 38.9 Ϯ 6.2 mmol/kg dry muscle wt; P Ͻ 0.05) and diacylglycerol (96 Ϯ 28 vs. 42 Ϯ 8 pmol/mg dry muscle wt; P Ͻ 0.05) contents were elevated in LCR vs. HCR rats. Accompanying the greater lipid accretion in LCR was increased fatty acid translocase/CD36 content (1,014 Ϯ 80 vs. 781 Ϯ 70 arbitrary units; P Ͻ 0.05) and reduced TG lipase activity (0.158 Ϯ 0.0125 vs. 0.274 Ϯ 0.018 mmol⅐min Ϫ1 ⅐kg dry muscle wt Ϫ1 ; P Ͻ 0.05). Muscle glycogen, GLUT4 protein, and basal phosphorylation states of AMP-activated protein kinase-␣1, AMP-activated protein kinase-␣2, and acetyl-CoA carboxylase were similar in LCR and HCR. In conclusion, rats with low intrinsic aerobic capacity demonstrate abnormalities in lipid-handling capacity. These disruptions may, in part, be responsible for the increased risk of metabolic disorders observed in this phenotype. exercise capacity; insulin resistance; mitochondrial biogenesis; lipids DURING THE PAST 50 YEARS, the prevalence of a cluster of interrelated chronic metabolic disease states including coronary heart disease, insulin resistance, type 2 diabetes mellitus, and obesity has reached epidemic proportions (5). The etiological basis of these disorders is both polygenic and dependent on environmental factors. However, because no new major human gene mutations have occurred in the latter half of the 20th century to cause this greater frequency of chronic metabolic diseases, the increased incidence must principally be due to alterations in environmental conditions. One contemporary environmental factor that changed and is strongly associated with chronic metabolic disorders is the decline in physical activity (8). Indeed, the increased prevalence of coronary heart disease, insulin resistance, type 2 diabetes mellitus, and obesity and their strong associations with i...

show abstract

“…[11][12][13][14][15][16] Reducing the availability of FFAs from the AT to liver and muscles is a pivotal component of the insulinsensitizing mechanism of PPAR agonists in the AT. The improved insulin sensitivity in agonist-treated DKO mice can thus result from a decrease in circulating FFAs by increased uptake in the AT, supported by increased expression of FATP-4 and FABP-4.…”

Section: Effect Of the Agonist On Ffas Glucose Tolerance And Insulimentioning

confidence: 99%

Peroxisome Proliferator-Activated Receptor-α,γ-Agonist Improves Insulin Sensitivity and Prevents Loss of Left Ventricular Function in Obese Dyslipidemic Mice

Verreth

Gáname

Mertens

et al. 2006

ATVB

View full text Add to dashboard Cite

Objective-We investigated the effect of a dual peroxisome proliferator-activated receptor (PPAR)␣,␥-agonist on atherosclerosis and cardiac function in mice with combined leptin and low-density lipoprotein receptor deficiency (DKO). In these mice, obesity, diabetes, and hyperlipidemia are associated with accelerated atherosclerosis and loss of cardiac function. Methods and Results-We treated 12-week-old DKO mice with the PPAR␣,␥-agonist (S)-3-(4-(2-carbazol-9-yl-ethoxy) phenyl-2-ethoxy-propionic-acid) for 12 weeks. The agonist lowered free fatty acids with 42% and increased insulin sensitivity with 76%. It had no effect on plasma cholesterol and triglycerides. RT-PCR analysis showed that the agonist increased the expression of fatty acid transport protein-4, fatty acid binding protein-4, glucose transporter-4, hormone-sensitive lipase, and adiponectin in white adipose tissue that was associated with the increase in insulin sensitivity. At 24 weeks, the shortening fraction (SF) of placebo DKO mice was 30% lower than that of C57BL6 mice. The PPAR agonist increased PPAR␥ but not PPAR␣ expression in the heart and prevented loss of left ventricular function. Adiponectin correlated positively with PPAR␥ in the heart and with SF. The agonist had no effect on atherosclerosis in the aortic arch of DKO mice. Key Words: cardiovascular disease prevention Ⅲ echocardiography Ⅲ insulin resistance Ⅲ obesity Ⅲ gene expression C ardiovascular diseases remain the leading cause of mortality in the Western societies. Several risk factors predispose to cardiovascular diseases, including the metabolic syndrome components diabetes, obesity, insulin resistance, dyslipidemia, and hypertension. It has been demonstrated that nuclear peroxisome proliferator-activated receptor (PPAR) deactivation (mainly obesity-related) is a key phase of metabolic syndrome initiation. [1][2][3] The identification of the nuclear receptors PPAR␥ and PPAR␣ as being the primary targets for the insulin-sensitizing thiazolidinediones and the lipid-lowering fibrates, respectively, has provided opportunities for the identification of novel compounds for the treatment of the metabolic syndrome. Conclusions-TheRecently, we demonstrated that several metabolic syndrome components (obesity, dyslipidemia, diabetes, and hypertension) in mice with combined leptin and low-density lipoprotein receptor deficiency (DKO) are associated with increased oxidative stress, accelerated atherosclerosis, and impaired cardiovascular function. 4,5 Compared with lean mice, PPAR␣ and PPAR␥ expression were downregulated in DKO mice. Diet restriction-induced weight loss resulted in increased expression of PPAR␣ and PPAR␥ in the adipose tissue (AT), the aortic arch, and the heart. These changes in expression were associated with increased insulin sensitivity, decreased hypertriglyceridemia, reduced mean 24-hour blood pressure and heart rate, restored circadian variations of blood pressure and heart rate, increased ejection fraction, and reduced atherosclerosis. To further study the role of PP...

show abstract

Hormone-sensitive lipase is reduced in the adipose tissue of patients with type 2 diabetes mellitus: influence of IL-6 infusion

Cited by 46 publications

References 50 publications

Adipocyte triglyceride lipase expression in human obesity

Adipocyte triglyceride lipase expression in human obesity

Dysregulation of muscle lipid metabolism in rats selectively bred for low aerobic running capacity

Peroxisome Proliferator-Activated Receptor-α,γ-Agonist Improves Insulin Sensitivity and Prevents Loss of Left Ventricular Function in Obese Dyslipidemic Mice

Contact Info

Product

Resources

About