Depot-Specific Variation in Protein-Tyrosine Phosphatase Activities in Human Omental and Subcutaneous Adipose Tissue: A Potential Contribution to Differential Insulin Sensitivity

Abstract Context Exercise training improves glycemic control and increases mitochondrial content and respiration capacity in skeletal muscle. Rodent studies suggest that training increases mitochondrial respiration in adipose tissue. Objective To assess the effects of endurance training on respiratory capacities of human skeletal muscle and abdominal subcutaneous adipose tissue and to study the correlation with improvement in insulin sensitivity. Design Using high-resolution respirometry, we analyzed biopsies from 25 sedentary (VO2 peak 25.1 ± 4.0 VO2 mL/[kg*min]) subjects (16 female, 9 male; 29.8 ± 8.4 years) with obesity (body mass index [BMI] 31.5 ± 4.3 kg/m2), who did not have diabetes. They performed a supervised endurance training over 8 weeks (3 × 1 hour/week at 80% VO2 peak). Results Based on change in insulin sensitivity after intervention (using the Matsuda insulin sensitivity index [ISIMats]), subjects were grouped in subgroups as responders (>15% increase in ISIMats) and low-responders. The response in ISIMats was correlated to a reduction of subcutaneous and visceral adipose tissue volume. Both groups exhibited similar increases in fitness, respiratory capacity, and abundance of mitochondrial enzymes in skeletal muscle fibers. Respiratory capacities in subcutaneous adipose tissue were not altered by the intervention. Compared with muscle fibers, adipose tissue respiration showed a preference for β-oxidation and complex II substrates. Respiratory capacities were higher in adipose tissue from female participants. Conclusion Our data show that the improvement of peripheral insulin sensitivity after endurance training is not directly related to an increase in mitochondrial respiratory capacities in skeletal muscle and occurs without an increase in the respiratory capacity of subcutaneous adipose tissue.

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Adiponectin expression in adipose tissue is reduced in first-degree relatives of type 2 diabetic patients

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00358.2002 ◽

2003 ◽

Vol 284 (2) ◽

pp. E443-E448 ◽

Cited By ~ 43

Author(s):

A. S. Lihn ◽

T. Østergård ◽

B. Nyholm ◽

S. B. Pedersen ◽

B. Richelsen ◽

...

Keyword(s):

Adipose Tissue ◽

Insulin Sensitivity ◽

Subcutaneous Adipose Tissue ◽

Diabetic Patients ◽

Mrna Levels ◽

Type 2 Diabetic Patients ◽

Adiponectin Mrna ◽

Subcutaneous Adipose ◽

Type 2 Diabetic

Adiponectin is suggested to be an important mediator of insulin resistance. Therefore, we investigated the association between adiponectin and insulin sensitivity in 22 healthy first-degree relatives (FDR) to type 2 diabetic patients and 13 matched control subjects. Subcutaneous adipose tissue biopsies were taken before and after a hyperinsulinemic euglycemic clamp. FDR subjects were insulin resistant, as indicated by a reduced Mvalue (4.44 vs. 6.09 mg · kg−1· min−1, P < 0.05). Adiponectin mRNA expression was 45% lower in adipose tissue from FDR compared with controls ( P < 0.01), whereas serum adiponectin was similar in the two groups (6.4 vs. 6.6 μg/ml, not significant). Insulin infusion reduced circulating levels of adiponectin moderately (11–13%) but significantly in both groups ( P < 0.05). In the control group, adiponectin mRNA levels were negatively correlated with fasting insulin ( P < 0.05) and positively correlated with insulin sensitivity ( P < 0.05). In contrast, these associations were not found in the FDR group. In conclusion, FDR have reduced adiponectin mRNA in subcutaneous adipose tissue but normal levels of circulating adiponectin. Adiponectin mRNA levels are positively correlated with insulin sensitivity in control subjects but not in FDR. These findings indicate dysregulation of adiponectin gene expression in FDR.

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miR-30a Remodels Subcutaneous Adipose Tissue Inflammation to Improve Insulin Sensitivity in Obesity

Diabetes ◽

10.2337/db17-1378 ◽

2018 ◽

Vol 67 (12) ◽

pp. 2541-2553 ◽

Cited By ~ 24

Author(s):

Eun-Hee Koh ◽

Natasha Chernis ◽

Pradip K. Saha ◽

Liuling Xiao ◽

David A. Bader ◽

...

Keyword(s):

Adipose Tissue ◽

Insulin Sensitivity ◽

Subcutaneous Adipose Tissue ◽

Adipose Tissue Inflammation ◽

Improve Insulin Sensitivity ◽

Tissue Inflammation ◽

Subcutaneous Adipose

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Inhibition of Protein Tyrosine Phosphatase-1B with Antisense Oligonucleotides Improves Insulin Sensitivity and Increases Adiponectin Concentrations in Monkeys

Endocrinology ◽

10.1210/en.2008-0885 ◽

2009 ◽

Vol 150 (4) ◽

pp. 1670-1679 ◽

Cited By ~ 43

Author(s):

Michael M. Swarbrick ◽

Peter J. Havel ◽

Arthur A. Levin ◽

Andrew A. Bremer ◽

Kimber L. Stanhope ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Adipose Tissue ◽

Insulin Sensitivity ◽

Protein Tyrosine Phosphatase ◽

Antisense Oligonucleotides ◽

Tyrosine Phosphatase ◽

Ptp 1B ◽

Insulin Responses

Protein tyrosine phosphatase (PTP)-1B antagonizes insulin signaling and is a potential therapeutic target for insulin resistance associated with obesity and type 2 diabetes. To date, studies of PTP-1B have been limited by the availability of specific antagonists; however, treatment of rodents with antisense oligonucleotides (ASOs) directed against PTP-1B improves insulin sensitivity, inhibits lipogenic gene expression, and reduces triglyceride accumulation in liver and adipose tissue. Here we investigated ASO-mediated PTP-1B inhibition in primates. First, PTP-1B ASO (ISIS 113715) dose-dependently inhibited PTP-1B mRNA and protein expression in cultured monkey hepatocytes. Subcutaneous administration of ISIS 113715 reduced PTP-1B mRNA expression in liver and adipose tissue of normal-weight monkeys by 40–50% and improved insulin sensitivity during an iv glucose tolerance test (IVGTT). In obese, insulin-resistant rhesus monkeys, treatment with 20 mg/kg ISIS 113715 for 4 wk reduced fasting concentrations of insulin and glucose and reduced insulin responses during an IVGTT. In these animals, adiponectin concentrations were also increased by 70%, most of which was an increase of high-molecular-weight oligomers. These effects were not observed in monkeys on a lower, dose-escalation regimen (1–10 mg/kg over 9 wk). Overall, the increase of adiponectin concentrations during ISIS 113715 treatment was correlated with the lowering of insulin responses during IVGTT (r = −0.47, P = 0.042). These results indicate that inhibition of PTP-1B with ASOs such as ISIS 113715 may be a viable approach for the treatment and prevention of obesity-associated insulin resistance and type 2 diabetes because they potently increase adiponectin concentrations in addition to improving insulin sensitivity.

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Developmental Switch from Prolonged Insulin Action to Increased Insulin Sensitivity in Protein Tyrosine Phosphatase 1B-Deficient Hepatocytes

Endocrinology ◽

10.1210/en.2006-0644 ◽

2007 ◽

Vol 148 (2) ◽

pp. 594-608 ◽

Cited By ~ 35

Author(s):

Agueda Gonzalez-Rodriguez ◽

Jill E. Clampit ◽

Oscar Escribano ◽

Manuel Benito ◽

Cristina M. Rondinone ◽

...

Keyword(s):

Insulin Sensitivity ◽

Protein Tyrosine Phosphatase ◽

Insulin Action ◽

Tyrosine Phosphatase ◽

Protein Tyrosine Phosphatase 1B ◽

Protein Tyrosine ◽

Developmental Switch

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Catecholamine and insulin control of lipolysis in subcutaneous adipose tissue during long-term diet-induced weight loss in obese women

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00240.2011 ◽

2012 ◽

Vol 302 (2) ◽

pp. E226-E232 ◽

Cited By ~ 7

Author(s):

Katrien Koppo ◽

Michaela Siklová-Vitková ◽

Eva Klimčáková ◽

Jan Polák ◽

Marie A. Marques ◽

...

Keyword(s):

Adipose Tissue ◽

Insulin Sensitivity ◽

Subcutaneous Adipose Tissue ◽

Dietary Intervention ◽

Glycerol Concentration ◽

Obese Women ◽

Low Calorie ◽

Low Calorie Diet ◽

Calorie Diet ◽

Subcutaneous Adipose

The aim of this study was to investigate the evolution of the adrenergic and insulin-mediated regulation of lipolysis during different phases of a 6-mo dietary intervention. Eight obese women underwent a 6-mo dietary intervention consisting of a 1-mo very low-calorie diet (VLCD) followed by a 2-mo low-calorie diet (LCD) and 3-mo weight maintenance (WM) diet. At each phase of the dietary intervention, microdialysis of subcutaneous adipose tissue (SCAT) was performed at rest and during a 3-h hyperinsulinemic euglycemic clamp. Responses of dialysate glycerol concentration (DGC) were determined at baseline and during local perfusions with adrenaline or adrenaline and phentolamine before and during the last 30 min of the clamp. Dietary intervention induced a body weight reduction and an improved insulin sensitivity. DGC progressively decreased during the clamp, and this decrease was similar during the different phases of the diet. The adrenaline-induced increase in DGC was higher at VLCD and LCD compared with baseline condition and returned to prediet levels at WM. In the probe with adrenaline and phentolamine, the increase in DGC was higher than that in the adrenaline probe at baseline and WM, but it was not different at VLCD and LCD. The results suggest that the responsiveness of SCAT to adrenaline-stimulated lipolysis increases during the calorie-restricted phases due to a reduction of the α2-adrenoceptor-mediated antilipolytic action of adrenaline. At WM, adrenaline-stimulated lipolysis returned to the prediet levels. Furthermore, no direct relationship between insulin sensitivity and the diet-induced changes in the regulation of lipolysis was found.

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Increased Energy Expenditure, Decreased Adiposity, and Tissue-Specific Insulin Sensitivity in Protein-Tyrosine Phosphatase 1B-Deficient Mice

Molecular and Cellular Biology ◽

10.1128/mcb.20.15.5479-5489.2000 ◽

2000 ◽

Vol 20 (15) ◽

pp. 5479-5489 ◽

Cited By ~ 894

Author(s):

Lori D. Klaman ◽

Olivier Boss ◽

Odile D. Peroni ◽

Jason K. Kim ◽

Jennifer L. Martino ◽

...

Keyword(s):

Insulin Sensitivity ◽

Energy Expenditure ◽

Protein Tyrosine Phosphatase ◽

Tyrosine Phosphatase ◽

Protein Tyrosine Phosphatase 1B ◽

Tissue Specific ◽

Protein Tyrosine ◽

Ptp 1B ◽

Deficient Mice

ABSTRACT Protein-tyrosine phosphatase 1B (PTP-1B) is a major protein-tyrosine phosphatase that has been implicated in the regulation of insulin action, as well as in other signal transduction pathways. To investigate the role of PTP-1B in vivo, we generated homozygotic PTP-1B-null mice by targeted gene disruption. PTP-1B-deficient mice have remarkably low adiposity and are protected from diet-induced obesity. Decreased adiposity is due to a marked reduction in fat cell mass without a decrease in adipocyte number. Leanness in PTP-1B-deficient mice is accompanied by increased basal metabolic rate and total energy expenditure, without marked alteration of uncoupling protein mRNA expression. In addition, insulin-stimulated whole-body glucose disposal is enhanced significantly in PTP-1B-deficient animals, as shown by hyperinsulinemic-euglycemic clamp studies. Remarkably, increased insulin sensitivity in PTP-1B-deficient mice is tissue specific, as insulin-stimulated glucose uptake is elevated in skeletal muscle, whereas adipose tissue is unaffected. Our results identify PTP-1B as a major regulator of energy balance, insulin sensitivity, and body fat stores in vivo.

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