Decreased Activation Rate of Insulin-Stimulated Glucose Transport in Adipocytes From Obese Subjects

Molina, Joseph M.; Ciaraldi, Theodore P.; Brady, David M.; Olefsky, Jerrold M.

doi:10.2337/diab.38.8.991

Cited by 25 publications

(12 citation statements)

References 21 publications

(30 reference statements)

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“…Adipocytes from obese persons or animals compared with those from lean persons or animals are characterised by increased cell size and decreased insulin-stimulated glucose uptake [14,15]. It has therefore been speculated that larger adipocytes are more insulin resistant.…”

Section: Discussionmentioning

confidence: 99%

Basal lipolysis, not the degree of insulin resistance, differentiates large from small isolated adipocytes in high-fat fed mice

et al. 2008

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Aims/hypothesis Adipocytes in obesity are characterised by increased cell size and insulin resistance compared with adipocytes isolated from lean patients. However, it is not clear at present whether hypertrophy actually does drive adipocyte insulin resistance. Thus, the aim of the present study was to metabolically characterise small and large adipocytes isolated from epididymal fat pads of mice fed a high-fat diet (HFD). Methods C57BL/6J mice were fed normal chow or HFD for 8 weeks. Adipocytes from epididymal fat pads were isolated by collagenase digestion and, in HFD-fed mice, separated into two fractions according to their size by filtration through a nylon mesh. Viability was assessed by lactate dehydrogenase and 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium assays. Basal and insulin-stimulated d-[U-14 C]glucose incorporation and lipolysis were measured. Protein levels and mRNA expression were determined by western blot and real-time RT-PCR, respectively.14 C]glucose incorporation into adipocytes isolated from HFD-fed mice was reduced by 50% compared with adipocytes from chow-fed mice. However, it was similar between small (average diameter 60.9±3.1 μm) and large (average diameter 83.0±6.6 μm) adipocytes. Similarly, insulin-stimulated phosphorylation of protein kinase B and AS160 were reduced to the same extent in small and large adipocytes isolated from HFDmice. In addition, insulin failed to inhibit lipolysis in both adipocyte fractions, whereas it decreased lipolysis by 30% in adipocytes of chow-fed mice. In contrast, large and small adipocytes differed in basal lipolysis rate, which was twofold higher in the larger cells. The latter finding was associated with higher mRNA expression levels of Atgl (also known as Pnpla2) and Hsl (also known as Lipe) in larger adipocytes. Viability was not different between small and large adipocytes. Conclusions/interpretation Rate of basal lipolysis but not insulin responsiveness is different between small and large adipocytes isolated from epididymal fat pads of HFD-fed mice.

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Section: Discussionmentioning

confidence: 99%

Basal lipolysis, not the degree of insulin resistance, differentiates large from small isolated adipocytes in high-fat fed mice

et al. 2008

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“…9 In the second scenario, increased energy availability results in the hypertrophic expansion of the WAT. Evidence suggests that hypertrophic adipocytes are more insulin resistant 1,3 and display alterations in the repertoire of adipokines that enhance the progression of insulin resistance. 10 In the hypertrophic scenario, adipocytes may be unable to store all of the delivered FAs and incompletely suppress hormone-sensitive lipase-mediated FA output due to insulin resistance.…”

Section: Lipotoxicity and Interorgan Communicationmentioning

confidence: 99%

Lipotoxicity, an imbalance between lipogenesis de novo and fatty acid oxidation

2004

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Obesity and type 2 diabetes mellitus are the major noncommunicable public health problem of the 21st century. The best strategy to tackle this problem is to develop strategies to prevent/treat obesity. However, it is becoming clear that despite successful research identifying weight regulatory pathways, the development of the obesity epidemic is outpacing scientific progress. The lack of success controlling the obesity epidemic in an aging population will result in another subsequent uncontrolled epidemic of complications. Our research focuses on the mechanisms causing lipotoxicity aiming to identify suitable strategies to prevent or at least retard the development of the metabolic syndrome. Previous work using transgenic and knockout mouse models has shown an interplay between white adipose tissue and skeletal muscle linking fatty acid (FA) synthesis with reciprocal effects on FA oxidation. Work from our lab and others suggests that defective adipose tissue is a key link between obesity, insulin resistance and type 2 diabetes mellitus by promoting the development of lipotoxicity in peripheral tissues. We propose a series of models to describe the process by which the adipose tissue could react to an energy-rich environment and responds depending on genetic and physiological factors, impacting on the functions of other peripheral tissues. We suggest that by examining hypotheses that encompass multiple organs and the partitioning of energy between these organs, a suitable strategy can be devised for the treatment of chronic obesity.

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“…2b). Evidence suggests, that hypertrophic obesity is associated with insulin resistance [19], leptin resistance and a spectrum of clinical symptoms that recapitulates the symptomatology observed in lipodystrophy patients. The common link between both of them probably is the defective storage capacity in adipose tissue depots, in the case of lipodistrophy due to lack of proper adipose tissue, in the case of obesity due to saturation of storage capacity due to excessive fat load.…”

Section: Adipose Tissue Expand Ability and Lipotoxicitymentioning

confidence: 99%