scholarly journals Chronically increased glucose uptake by adipose tissue leads to lactate production and improved insulin sensitivity rather than obesity in the mouse

Diabetologia ◽  
2010 ◽  
Vol 53 (11) ◽  
pp. 2417-2430 ◽  
Author(s):  
S. Muñoz ◽  
S. Franckhauser ◽  
I. Elias ◽  
T. Ferré ◽  
A. Hidalgo ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Glucose Uptake ◽  
Lactate Production

scholarly journals LMO3 reprograms visceral adipocyte metabolism during obesity

2021 ◽  
Author(s):  
Gabriel Wagner ◽  
Anna Fenzl ◽  
Josefine Lindroos-Christensen ◽  
Elisa Einwallner ◽  
Julia Husa ◽  
...  
Keyword(s):  
Gene Expression ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Glucose Uptake ◽  
Visceral Adipose Tissue ◽  
Tissue Expansion ◽  
Oxidative Capacity ◽  
Glut4 Translocation ◽  
Mitochondrial Oxidative Capacity ◽  
Visceral Adipose

Abstract Obesity and body fat distribution are important risk factors for the development of type 2 diabetes and metabolic syndrome. Evidence has accumulated that this risk is related to intrinsic differences in behavior of adipocytes in different fat depots. We recently identified LIM domain only 3 (LMO3) in human mature visceral adipocytes; however, its function in these cells is currently unknown. The aim of this study was to determine the potential involvement of LMO3-dependent pathways in the modulation of key functions of mature adipocytes during obesity. Based on a recently engineered hybrid rAAV serotype Rec2 shown to efficiently transduce both brown adipose tissue (BAT) and white adipose tissue (WAT), we delivered YFP or Lmo3 to epididymal WAT (eWAT) of C57Bl6/J mice on a high-fat diet (HFD). The effects of eWAT transduction on metabolic parameters were evaluated 10 weeks later. To further define the role of LMO3 in insulin-stimulated glucose uptake, insulin signaling, adipocyte bioenergetics, as well as endocrine function, experiments were conducted in 3T3-L1 adipocytes and newly differentiated human primary mature adipocytes, engineered for transient gain or loss of LMO3 expression, respectively. AAV transduction of eWAT results in strong and stable Lmo3 expression specifically in the adipocyte fraction over a course of 10 weeks with HFD feeding. LMO3 expression in eWAT significantly improved insulin sensitivity and healthy visceral adipose tissue expansion in diet-induced obesity, paralleled by increased serum adiponectin. In vitro, LMO3 expression in 3T3-L1 adipocytes increased PPARγ transcriptional activity, insulin-stimulated GLUT4 translocation and glucose uptake, as well as mitochondrial oxidative capacity in addition to fatty acid oxidation. Mechanistically, LMO3 induced the PPARγ coregulator Ncoa1, which was required for LMO3 to enhance glucose uptake and mitochondrial oxidative gene expression. In human mature adipocytes, LMO3 overexpression promoted, while silencing of LMO3 suppressed mitochondrial oxidative capacity. LMO3 expression in visceral adipose tissue regulates multiple genes that preserve adipose tissue functionality during obesity, such as glucose metabolism, insulin sensitivity, mitochondrial function, and adiponectin secretion. Together with increased PPARγ activity and Ncoa1 expression, these gene expression changes promote insulin-induced GLUT4 translocation, glucose uptake in addition to increased mitochondrial oxidative capacity, limiting HFD-induced adipose dysfunction. These data add LMO3 as a novel regulator improving visceral adipose tissue function during obesity. Key messages LMO3 increases beneficial visceral adipose tissue expansion and insulin sensitivity in vivo. LMO3 increases glucose uptake and oxidative mitochondrial activity in adipocytes. LMO3 increases nuclear coactivator 1 (Ncoa1). LMO3-enhanced glucose uptake and mitochondrial gene expression requires Ncoa1.

α1-Antitrypsin A treatment attenuates neutrophil elastase accumulation and enhances insulin sensitivity in adipose tissue of mice fed a high-fat diet.

2021 ◽  
Author(s):  
Randall F. D'Souza ◽  
Stewart W.C. Masson ◽  
Jonathan S. T. Woodhead ◽  
Samuel L James ◽  
Caitlin MacRae ◽  
...  
Keyword(s):  
Body Weight ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Glucose Uptake ◽  
Neutrophil Elastase ◽  
High Fat Diet ◽  
Tolerance Test ◽  
Metabolic Dysfunction ◽  
High Fat ◽  
Insulin Tolerance

Neutrophils accumulate in insulin sensitive tissues during obesity and may play a role in impairing insulin sensitivity. The major serine protease expressed by neutrophils is neutrophil elastase (NE), which is inhibited endogenously by α1-antitrypsin A (A1AT). We investigated the effect of exogenous (A1AT) treatment on diet induced metabolic dysfunction. Male C57Bl/6j mice fed a chow or a high fat diet (HFD) were randomized to receive 3x weekly i.p injections of either Prolastin (human A1AT; 2mg) or vehicle (PBS) for 10 weeks. Prolastin treatment did not affect plasma NE concentration, body weight, glucose tolerance or insulin sensitivity in chow fed mice. In contrast, Prolastin treatment attenuated HFD induced increases in plasma and white adipose tissue (WAT) NE without affecting circulatory neutrophil levels or increases in body weight. Prolastin-treated mice fed a HFD had improved insulin sensitivity, as assessed by insulin tolerance test, and this was associated with higher insulin-dependent IRS-1 (insulin receptor substrate) and AktSer473phosphorylation, and reduced inflammation markers in WAT but not liver or muscle. In 3T3-L1 adipocytes, Prolastin reversed recombinant NE-induced impairment of insulin-stimulated glucose uptake and IRS-1 phosphorylation. Furthermore, PDGF mediated p-AktSer473 activation and glucose uptake (which is independent of IRS-1) was not affected by recombinant NE treatment. Collectively, our findings suggest that NE infiltration of WAT during metabolic overload contributes to insulin-resistance by impairing insulin-induced IRS-1 signaling.

Specific adaptations in muscle and adipose tissue in response to chronic systemic glucose oversupply in rats

1997 ◽  
Vol 273 (1) ◽  
pp. E1-E9 ◽  
Author(s):  
D. R. Laybutt ◽  
D. J. Chisholm ◽  
E. W. Kraegen
Keyword(s):  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Glucose Uptake ◽  
Glucose Infusion ◽  
Whole Body ◽  
Glucose Disposal ◽  
Saline Control ◽  
Slow Increase ◽  
Glucose Clearance

Rats minimize hyperglycemia during chronic glucose infusion, but the metabolic processes are unclear. We investigated the tissues involved and the role of altered insulin sensitivity. Cannulated rats were infused with glucose (40 mg.kg-1.min-1) for 1 or 4 days or with saline (control). Hyperglycemia at 1 day (15.3 +/- 1.0 mM) was absent at 4 days (7.5 +/- 0.3 mM), but hyperinsulinemia persisted. Whole body glucose disposal was similarly elevated at 1 and 4 days, implying increased glucose clearance at 4 days (2-fold, P < 0.001). Muscle glucose uptake and glycogen content declined in glucose-infused rats from 1 to 4 days, whereas white adipose tissue (WAT) glucose uptake (6-fold, P < 0.001) and lipogenesis (3-fold, P < 0.001) increased. Muscle and liver triglyceride were doubled at both 1 and 4 days (P < 0.05 vs. control). Insulin sensitivity (assessed during euglycemic clamps) decreased in muscle to 34% of control at 1 and 4 days (P < 0.001 vs. control) and increased fivefold in WAT from 1 to 4 days (P < 0.05). Thus chronic glucose infusion results in a slow increase in efficiency of glucose clearance with enhanced WAT glucose uptake, lipogenesis, and insulin action. In contrast, the adaptation reduces glucose oversupply to muscle. Muscle shows sustained insulin resistance, with lipid accumulation a possible contributing factor.

scholarly journals PET imaging reveals distinctive roles for different regional adipose tissue depots in systemic glucose metabolism in nonobese humans

2012 ◽  
Vol 303 (9) ◽  
pp. E1134-E1141 ◽  
Author(s):  
Jason M. Ng ◽  
Koichiro Azuma ◽  
Carol Kelley ◽  
Richard Pencek ◽  
Zofia Radikova ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Glucose Metabolism ◽  
Glucose Uptake ◽  
Pet Imaging ◽  
Normal Weight ◽  
Dynamic Pet ◽  
Imaging Studies ◽  
Systemic Insulin Resistance

Excess amounts of abdominal subcutaneous (SAT) and visceral (VAT) adipose tissue (AT) are associated with insulin resistance, even in normal-weight subjects. In contrast, gluteal-femoral AT (GFAT) is hypothesized to offer protection against insulin resistance. Dynamic PET imaging studies were undertaken to examine the contributions of both metabolic activity and size (volume) of these depots in systemic glucose metabolism. Nonobese, healthy volunteers ( n = 15) underwent dynamic PET imaging uptake of [18F]FDG at a steady-state (20 mU·m−2·min−1) insulin infusion. PET images of tissue [18F]FDG activity were coregistered with MRI to derive K values for insulin-stimulated rates of fractional glucose uptake within tissue. Adipose tissue volume was calculated from DEXA and MRI. VAT had significantly higher rates of fractional glucose uptake per volume than SAT ( P < 0.05) or GFAT ( P < 0.01). KGFAT correlated positively ( r = 0.67, P < 0.01) with systemic insulin sensitivity [glucose disappearance rate (Rd)] and negatively with insulin-suppressed FFA ( r = −0.71, P < 0.01). SAT ( r = −0.70, P < 0.01) and VAT mass ( r = −0.55, P < 0.05) correlated negatively with Rd, but GFAT mass did not. We conclude that rates of fractional glucose uptake within GFAT and VAT are significantly and positively associated with systemic insulin sensitivity in nonobese subjects. Furthermore, whereas SAT and VAT amounts are confirmed to relate to systemic insulin resistance, GFAT amount is not associated with insulin resistance. These dynamic PET imaging studies indicate that both quantity and quality of specific AT depots have distinct roles in systemic insulin resistance and may help explain the metabolically obese but normal-weight phenotype.

scholarly journals Stimulation of glucose uptake in murine soleus muscle and adipocytes by 5-(4-phenoxybutoxy)psoralen (PAP-1) may be mediated by Kv1.5 rather than Kv1.3

2014 ◽  
Author(s):  
Robert A Ngala ◽  
Mohamed S Zaibi ◽  
Kenneth Langlands ◽  
Claire J Stocker ◽  
Jonathan RS Arch ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Glucose Uptake ◽  
Soleus Muscle ◽  
White Adipose Tissue ◽  
Gastrocnemius Muscle ◽  
Obese Mice ◽  
Wild Type ◽  
High Concentration ◽  
White Adipocytes

Kv1 channels are shaker-related potassium channels that influence insulin sensitivity. Kv1.3 -/- mice are protected from diet-induced insulin resistance and some studies suggest that Kv1.3 inhibitors provide similar protection. However, it is unclear whether blockade of Kv1.3 in adipocytes or skeletal muscle increases glucose uptake. There is no evidence that the related channel Kv1.5 has any influence on insulin sensitivity and its expression in adipose tissue has not been reported. PAP-1 is a selective inhibitor of Kv1.3, with 23-fold, 32-fold and 125-fold lower potencies as an inhibitor of Kv1.5, Kv1.1 and Kv1.2 respectively. Soleus muscles from wild-type and genetically obese ob/ob mice were incubated with 2-deoxy[1-14C]-glucose for 45 min and formation of 2-deoxy[1-14C]-glucose-6-phosphate was measured. White adipocytes were incubated with D-[U-14C]-glucose for 1h. TNFalpha and Il-6 secretion from white adipose tissue pieces were measured by enzyme-linked-immunoassay. In the absence of insulin, a high concentration (3 μM) of PAP-1 stimulated 2-deoxy[1-14C]-glucose uptake in soleus muscle of wild-type and obese mice by 30% and 40% respectively, and in adipocytes by 20% and 50% respectively. PAP-1 also stimulated glucose uptake by adipocytes at the lower concentration of 1 μM, but at 300 nM, which is still 150-fold higher than its EC50 value for inhibition of the Kv1.3 channel, it had no effect. In the presence of insulin, PAP-1 (3 μM) had a significant effect only in adipocytes from obese mice. PAP-1 (3 μM) reduced the secretion of TNFalpha by adipose tissue but had no effect on the secretion of IL-6. Expression of Kv1.1, Kv1.2, Kv1.3 and Kv1.5 was determined by RT-PCR. Kv1.3 and Kv1.5 mRNA were detected in liver, gastrocnemius muscle, soleus muscle and white adipose tissue from wild-type and ob/ob mice, except that Kv1.3 could not be detected in gastrocnemius muscle, nor Kv1.5 in liver, of wild-type mice. Expression of both genes was generally higher in liver and muscle of ob/ob mice compared to wild-type mice. Kv1.5 appeared to be expressed more highly than Kv1.3 in soleus muscle, adipose tissue and adipocytes of wild-type mice. Expression of Kv1.2 appeared to be similar to that of Kv1.3 in soleus muscle and adipose tissue, but Kv1.2 was undetectable in adipocytes. Kv1.1 could not be detected in soleus muscle, adipose tissue or adipocytes. We conclude that inhibition of Kv1 channels by PAP-1 stimulates glucose uptake by adipocytes and soleus muscle of wild-type and ob/ob mice, and reduces the secretion of TNFalpha by adipose tissue. However, these effects are more likely due to inhibition of Kv1.5 than to inhibition of Kv1.3 channels.

Effect of training on insulin sensitivity of glucose uptake and lipolysis in human adipose tissue

2000 ◽  
Vol 279 (2) ◽  
pp. E376-E385 ◽  
Author(s):  
Bente Stallknecht ◽  
Jens J. Larsen ◽  
Kari J. Mikines ◽  
Lene Simonsen ◽  
Jens Bülow ◽  
...  
Keyword(s):  
Blood Flow ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Glucose Uptake ◽  
Subcutaneous Adipose Tissue ◽  
Whole Body ◽  
Tissue Blood Flow ◽  
Glycerol Concentration ◽  
Adipose Tissue Blood Flow ◽  
Subcutaneous Adipose

Training increases insulin sensitivity of both whole body and muscle in humans. To investigate whether training also increases insulin sensitivity of adipose tissue, we performed a three-step hyperinsulinemic, euglycemic clamp in eight endurance-trained (T) and eight sedentary (S) young men [insulin infusion rates: 10,000 ( step I), 20,000 ( step II), and 150,000 ( step III) μU · min−1 · m−2]. Glucose and glycerol concentrations were measured in arterial blood and also by microdialysis in interstitial fluid in periumbilical, subcutaneous adipose tissue and in quadriceps femoris muscle (glucose only). Adipose tissue blood flow was measured by 133Xe washout. In the basal state, adipose tissue blood flow tended to be higher in T compared with S subjects, and in both groups blood flow was constant during the clamp. The change from basal in arterial-interstitial glucose concentration difference was increased in T during the clamp but not in S subjects in both adipose tissue and muscle [adipose tissue: step I ( n = 8), 0.48 ± 0.18 mM (T), 0.23 ± 0.11 mM (S); step II ( n = 8), 0.19 ± 0.09 (T), −0.09 ± 0.24 (S); step III( n = 5), 0.47 ± 0.24 (T), 0.06 ± 0.28 (S); (T: P < 0.001, S: P > 0.05); muscle: step I ( n = 4), 1.40 ± 0.46 (T), 0.31 ± 0.21 (S); step II ( n = 4), 1.14 ± 0.54 (T), −0.08 ± 0.14 (S); step III( n = 4), 1.23 ± 0.34 (T), 0.24 ± 0.09 (S); (T: P < 0.01, S: P > 0.05)]. Interstitial glycerol concentration decreased faster in T than in S subjects [half-time: T, 44 ± 9 min ( n = 7); S, 102 ± 23 min ( n = 5); P < 0.05]. In conclusion, training enhances insulin sensitivity of glucose uptake in subcutaneous adipose tissue and in skeletal muscle. Furthermore, interstitial glycerol data suggest that training also increases insulin sensitivity of lipolysis in subcutaneous adipose tissue. Insulin per se does not influence subcutaneous adipose tissue blood flow.

scholarly journals Minireview: Obesity and LipOdystrophy—Where Do the Circles Intersect?

Endocrinology ◽  
2008 ◽  
Vol 149 (3) ◽  
pp. 925-934 ◽  
Author(s):  
Farid F. Chehab
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Glucose Uptake ◽  
Binding Protein ◽  
Retinol Binding Protein ◽  
Retinol Binding Protein 4 ◽  
Secreted Factors ◽  
Survival And Reproduction

Adipose tissue is unique in that it can undergo significant hypertrophy and atrophy, resulting in wide ranges of obesities and lipodystrophies. At the base of this elasticity is the lipid-filled adipocyte, which can either overfill by storing large amounts of triglycerides or shrink to a tiny cell by depleting its lipids and as such is remarkable in sustaining insults. As a major energy reservoir, the adipocyte may hold considerable calories necessary for survival and reproduction, two functions that are essential for the survival of the species. This review will summarize some of the recent studies that have advanced our understanding of the central and peripheral mechanisms that are initiated by adipocyte-secreted factors such as leptin, adiponectin, resistin, and retinol-binding protein 4. The intersection of obesity and lipodystrophy results in insulin resistance, which may be unlocked by elucidating the roles of these factors in pathways that control insulin sensitivity and glucose uptake.

Influence of TNF-α and IL-6 infusions on insulin sensitivity and expression of IL-18 in humans

2006 ◽  
Vol 291 (1) ◽  
pp. E108-E114 ◽  
Author(s):  
Rikke Krogh-Madsen ◽  
Peter Plomgaard ◽  
Kirsten Møller ◽  
Bettina Mittendorfer ◽  
Bente K. Pedersen
Keyword(s):  
Gene Expression ◽  
Insulin Resistance ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Glucose Uptake ◽  
Muscle Tissue ◽  
Plasma Concentrations ◽  
Whole Body ◽  
Euglycemic Hyperinsulinemic Clamp ◽  
Tnf Α

Inflammation is associated with insulin resistance, and both tumor necrosis factor (TNF)-α and interleukin (IL)-6 may affect glucose uptake. TNF induces insulin resistance, whereas the role of IL-6 is controversial. High plasma levels of IL-18 are associated with insulin resistance in epidemiological studies. We investigated the effects of TNF and IL-6 on IL-18 gene expression in skeletal muscle and adipose tissue. Nine human volunteers underwent three consecutive interventions, receiving an infusion of recombinant human (rh)IL-6, rhTNF, and saline. Insulin sensitivity was assessed by measurement of whole body glucose uptake with the stable isotope tracer method during a euglycemic hyperinsulinemic clamp (20 mU·min−1·kg−1), which was initiated 1 h after the IL-6-TNF-saline infusion. Cytokine responses were measured in plasma, muscle, and fat biopsies. Plasma concentrations of TNF and IL-6 increased 10- and 38-fold, respectively, during the cytokine infusions. Whole body insulin-mediated glucose uptake was significantly reduced during TNF infusion but remained unchanged during IL-6 infusion. TNF induced IL-18 gene expression in muscle tissue, but not in adipose tissue, whereas IL-6 infusion had no effect on IL-18 gene expression in either tissue. We conclude that TNF-induced insulin resistance of whole body glucose uptake is associated with increased IL-18 gene expression in muscle tissue, indicating that TNF and IL-18 interact, and both may have important regulatory roles in the pathogenesis of insulin resistance.

Maternal protein restriction during early lactation induces GLUT4 translocation and mTOR/Akt activation in adipocytes of adult rats

2008 ◽  
Vol 295 (3) ◽  
pp. E626-E636 ◽  
Author(s):  
Érica Patrícia Garcia-Souza ◽  
Simone Vargas da Silva ◽  
Gisele Barreto Félix ◽  
Ananda Lages Rodrigues ◽  
Marta Sampaio de Freitas ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Glucose Uptake ◽  
Glucose Homeostasis ◽  
Insulin Signaling ◽  
Molecular Mechanisms ◽  
Experimental Studies ◽  
Male Rats ◽  
Early Lactation ◽  
Peripheral Tissues

Epidemiological and experimental studies have demonstrated that early postnatal nutrition has been associated with long-term effects on glucose homeostasis in adulthood. Recently, our group demonstrated that undernutrition during early lactation affects the expression and activation of key proteins of the insulin signaling cascade in rat skeletal muscle during postnatal development. To elucidate the molecular mechanisms by which undernutrition during early life leads to changes in insulin sensitivity in peripheral tissues, we investigated the insulin signaling in adipose tissue. Adipocytes were isolated from epididymal fat pads of adult male rats that were the offspring of dams fed either a normal or a protein-free diet during the first 10 days of lactation. The cells were incubated with 100 nM insulin before the assays for immunoblotting analysis, 2-deoxyglucose uptake, immunocytochemistry for GLUT4, and/or actin filaments. Following insulin stimulation, adipocytes isolated from undernourished rats presented reduced tyrosine phosphorylation of IR and IRS-1 and increased basal phosphorylation of IRS-2, Akt, and mTOR compared with controls. Basal glucose uptake was increased in adipocytes from the undernourished group, and the treatment with LY294002 induced only a partial inhibition both in basal and in insulin-stimulated glucose uptake, suggesting an involvement of phosphoinositide 3-kinase activity. These alterations were accompanied by higher GLUT4 content in the plasma membrane and alterations in the actin cytoskeleton dynamics. These data suggest that early postnatal undernutrition impairs insulin sensitivity in adulthood by promoting changes in critical steps of insulin signaling in adipose tissue, which may contribute to permanent changes in glucose homeostasis.

scholarly journals Stimulation of glucose uptake in murine soleus muscle and adipocytes by 5-(4-phenoxybutoxy)psoralen (PAP-1) may be mediated by Kv1.5 rather than Kv1.3

2014 ◽  
Author(s):  
Robert A Ngala ◽  
Mohamed S Zaibi ◽  
Kenneth Langlands ◽  
Claire J Stocker ◽  
Jonathan RS Arch ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Glucose Uptake ◽  
Soleus Muscle ◽  
White Adipose Tissue ◽  
Gastrocnemius Muscle ◽  
Obese Mice ◽  
Wild Type ◽  
High Concentration ◽  
White Adipocytes

Kv1 channels are shaker-related potassium channels that influence insulin sensitivity. Kv1.3 -/- mice are protected from diet-induced insulin resistance and some studies suggest that Kv1.3 inhibitors provide similar protection. However, it is unclear whether blockade of Kv1.3 in adipocytes or skeletal muscle increases glucose uptake. There is no evidence that the related channel Kv1.5 has any influence on insulin sensitivity and its expression in adipose tissue has not been reported. PAP-1 is a selective inhibitor of Kv1.3, with 23-fold, 32-fold and 125-fold lower potencies as an inhibitor of Kv1.5, Kv1.1 and Kv1.2 respectively. Soleus muscles from wild-type and genetically obese ob/ob mice were incubated with 2-deoxy[1-14C]-glucose for 45 min and formation of 2-deoxy[1-14C]-glucose-6-phosphate was measured. White adipocytes were incubated with D-[U-14C]-glucose for 1h. TNFalpha and Il-6 secretion from white adipose tissue pieces were measured by enzyme-linked-immunoassay. In the absence of insulin, a high concentration (3 μM) of PAP-1 stimulated 2-deoxy[1-14C]-glucose uptake in soleus muscle of wild-type and obese mice by 30% and 40% respectively, and in adipocytes by 20% and 50% respectively. PAP-1 also stimulated glucose uptake by adipocytes at the lower concentration of 1 μM, but at 300 nM, which is still 150-fold higher than its EC50 value for inhibition of the Kv1.3 channel, it had no effect. In the presence of insulin, PAP-1 (3 μM) had a significant effect only in adipocytes from obese mice. PAP-1 (3 μM) reduced the secretion of TNFalpha by adipose tissue but had no effect on the secretion of IL-6. Expression of Kv1.1, Kv1.2, Kv1.3 and Kv1.5 was determined by RT-PCR. Kv1.3 and Kv1.5 mRNA were detected in liver, gastrocnemius muscle, soleus muscle and white adipose tissue from wild-type and ob/ob mice, except that Kv1.3 could not be detected in gastrocnemius muscle, nor Kv1.5 in liver, of wild-type mice. Expression of both genes was generally higher in liver and muscle of ob/ob mice compared to wild-type mice. Kv1.5 appeared to be expressed more highly than Kv1.3 in soleus muscle, adipose tissue and adipocytes of wild-type mice. Expression of Kv1.2 appeared to be similar to that of Kv1.3 in soleus muscle and adipose tissue, but Kv1.2 was undetectable in adipocytes. Kv1.1 could not be detected in soleus muscle, adipose tissue or adipocytes. We conclude that inhibition of Kv1 channels by PAP-1 stimulates glucose uptake by adipocytes and soleus muscle of wild-type and ob/ob mice, and reduces the secretion of TNFalpha by adipose tissue. However, these effects are more likely due to inhibition of Kv1.5 than to inhibition of Kv1.3 channels.

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