Insulin Action and Its Disturbances in Disease - part 5 pptx

232 RELATIONSHIP BETWEEN FAT DISTRIBUTION AND INSULIN RESISTANCE 130. Tomlinson, J. W., Sinha, B., Bujalska, I., Hewison, M. and Stewart, P. M. (2002) Expression of 11beta-hydroxysteroid dehydrogenase type 1 in adipose tissue is not increased in human obesity. J Clin Endocrinol Metab 87 (12), 5630–5635. 131. Moore, J. S., Monson, J. P., Kaltsas, G., Putignano, P., Wood, P. J., Sheppard, M. C., Besser, G. M., Taylor, N. F. and Stewart, P. M. (1999) Modulation of 11beta- hydroxysteroid dehydrogenase isozymes by growth hormone and insulin-like growth factor: in vivo and in vitro studies. J Clin Endocrinol Metab 84 (11), 4172–4177. 132. Tomlinson, J. W., Moore, J., Cooper, M. S., Bujalska, I., Shahmanesh, M., Burt, C., Strain, A., Hewison, M. and Stewart, P. M. (2001) Regulation of expression of 11beta- hydroxysteroid dehydrogenase type 1 in adipose tissue: tissue-specific induction by cytokines. Endocrinology 142 (5), 1982–1989. 133. Bujalska, I. J., Kumar, S., Hewison, M. and Stewart, P. M. (1999) Differentiation of adipose stromal cells: The roles of glucocorticoids and 11β hydroxysteroid dehydroge- nase. Endocrinology 140 (7), 3188–3196. 134. Palermo, M., Shackleton, C. H. L., Mantero, F. and Stewart, P. M. (1996) Urinary free cortisone and the assessment of 11β hydroxysteroid dehydrogenase activity in man. Clin Endocrinol (Oxf) 45, 605–611. 135. Stewart, P. M. and Krozowski, Z. S. (1999) 11 beta-hydroxysteroid dehydrogenase. Vit Horm 57, 249–324. 136. Rask, E., Olsson, T., Soderberg, S., Andrew, R., Livingstone, D. E., Johnson, O. and Walker, B. R. (2001) Tissue-specific dysregulation of cortisol metabolism in human obesity. J Clin Endocrinol Metab 86 (3), 1418–1421. 137. Rask, E., Walker, B. R., Soderberg, S., Livingstone, D. E., Eliasson, M., Johnson, O., Andrew, R. and Olsson, T. (2002) Tissue-specific changes in peripheral cortisol meta- bolism in obese women: increased adipose 11beta-hydroxysteroid dehydrogenase type 1 activity. J Clin Endocrinol Metab 87 (7), 3330–3336. 138. Weaver, J. U., Taylor, N. F., Monson, J. P., Wood, P. J. and Kelly, W. F. (1998) Sex- ual dimorphism in 11 beta hydroxysteroid dehydrogenase activity and its relation to fat distribution and insulin sensitivity; a study in hypopituitary subjects. Clin Endocrinol (Oxf) 49 (1), 13–20. 139. Livingstone, D. E., Jones, G. C., Smith, K., Jamieson, P. M., Andrew, R., Kenyon, C. J. and Walker, B. R. (2000) Understanding the role of glucocorticoids in obesity: tissue- specific alterations of corticosterone metabolism in obese Zucker rats. Endocrinology 141 (2), 560–563. 140. Kotelevtsev, Y., Brown, R. W., Fleming, S., Kenyon, C., Edwards, C. R., Seckl, J. R. and Mullins, J. J. (1999) Hypertension in mice lacking 11beta-hydroxysteroid dehydro- genase type 2. J Clin Invest 103 (5), 683–689. 141. 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(1995) Oes- trogen biosynthesis, oestrogen metabolism and functional oestrogen receptors in bovine aortic endothelial cells. Ciba Foundation Symp 191, 122–132. 146. Labrie, F. (1991) Intracrinology. Mol Cell Endocrinol 78, 113–118. 147. Labrie, F., Belanger, A., Cusan, L. and Candas, B. (1997) Physiological changes in dehydroepiandrosterone are not reflected by serum levels of active androgens and estro- gens but their metabolites: intracrinology. J Clin Endocrinol Metab 82, 2403–2409. 148. Deslypere, J. P., Verdonck, L. and Vermeulen, A. (1985) Fat tissue: a steroid reservoir and site of steroid metabolism. J Clin Endocrinol Metab 61 (3), 564–570. 149. Simpson, E. R., Merrill, J. C., Hollub, A. J., Lorence, S. G. and Mendelson, C. R. (1989) Regulation of oestrogen biosynthesis by human adipose cells. Endo Rev 10, 136–148. 150. Simpson, E. R., Mahendroo, M. S., Means, G. D., Kilgore, M. W., Hinselwood, M. M., Graham-Lorence, S., Amarneh, B., Ito, Y., Fisher, C. R., Micheal, M. D., Mendelson, C. R. and Bulun, S. E. (1994) Aromatase cytochrome P450, the enzyme responsible for estrogen biosynthesis. Endo Rev 15, 352–354. 151. Bulun, S. E. and Simpson, E. R. (1994) Competitive reverse transcription-polymerase chain reaction analysis indicates that levels of aromatase cytochrome P450 transcripts in adipose tissue of buttocks, thighs, and abdomen of women increase with advancing age. J Clin Endocrinol Metab 78 (2), 428–432. 152. Zhao, Y., Nichols, J. E., Valdez, R., Mendelson, C. R. and Simpson, E. R. (1996) Tumor necrosis factor-alpha stimulates aromatase gene expression in human adipose stromal cells through use of an activating protein-1 binding site upstream of promoter 1.4. Mol Endocrinol 10 (11), 1350–1357. 153. Simpson, E. R., Zhao, Y., Agarwal, V. R., Michael, M. D., Bulun, S. E., Hinshelwood, M. M., Graham-Lorence, S., Sun, T., Fisher, C. R., Qin, K. and Mendelson, C. R. (1997) Aromatase expression in health and disease. 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J Clin Endocrinol Metab 82, 2198–2203. 9 PPARγ and Glucose Homeostasis Robert K. Semple and Stephen O’Rahilly It has long been known that various xenobiotic compounds, when adminis- tered to mice, give rise to exuberant proliferation of hepatic peroxisomes, and ultimately to tumour development. In 1990 the mediator of this response was cloned and identified as a nuclear hormone receptor subsequently called per- oxisome proliferator-activated receptor (PPAR). 1 When two homologues were later cloned in Xenopus 2 and then in all mammalian species studied, the three receptors were designated PPARα,PPARγ and PPARδ. Independently of these developments, large scale chemical screening in the 1980s identified thiazo- lidinediones as potent agents for lowering blood glucose and improving lipid profiles in animal models of diabetes and obesity. 3 The convergence of these two lines of investigation with the realization that the molecular target of the thiazolidinediones was PPARγ 4 placed this receptor right at the centre of the interplay between lipid and glucose metabolism. This occurred at a time in the early 1990s when the ‘glucocentric’ view of type 2 diabetes as a disease princi- pally of glucose metabolism (perhaps, in part, a historical accident) 5 was being usurped by the resurgent appreciation that it is a complex metabolic disease in which abnormal lipid and glucose homeostasis are intimately and inextricably linked. In the decade since then, a wealth of experimental data has confirmed the importance of PPARγ as a central regulator of the metabolic cross-talk between insulin-sensitive tissues, and thiazolidinediones have proved beneficial therapeu- tically as the first new class of insulin-sensitizing agents for several decades. While PPARγ has afforded investigators a valuable handle on the intractable pathophysiology of this most prevalent condition, many questions remain about Insulin Resistance. Edited by Sudhesh Kumar and Stephen O’Rahilly  2005 John Wiley & Sons, Ltd ISBN: 0-470-85008-6 238 PPARγ AND GLUCOSE HOMEOSTASIS its biology. Here the progress of investigation to date and the outstanding issues will briefly be reviewed. 9.1 Evidence from cell and rodent models PPARγ binds to specific promoter response elements as a heterodimer with the retinoic acid receptor (RXR). In the presence of ligand it recruits co- activator molecules, which target chromatin-decondensing complexes to the promoter region and render it accessible for the initiation of transcription. Con- versely, in the presence of an antagonist, and perhaps in the unliganded state, PPARγ recruits co-repressor molecules, which lead to the condensation of chro- matin and sequestration of promoter elements. In addition, there is an evolving appreciation that PPARγ may influence gene expression indirectly, and usu- ally negatively, through competition with other transcription factors for such accessory molecules. Although thiazolidinediones have been identified as potent synthetic ligands of PPARγ, it is not clear whether any physiologically relevant, potent endogenous ligands exist. The most widely studied candidate has been 15 deoxy- 12,14 -prostaglandin J2, identified as a potent activator in in vitro studies, but a more recent reanalysis has suggested not only that in vivo concentrations are too low for it to be a relevant ligand, but also that levels fail to correlate with PPARγ activity. 6 Furthermore, a large number of unsaturated fatty acids, eicosanoids and prostaglandins have also been shown in vitro to activate the receptor. The binding affinities of these agents tend to be rather low, leading to the suggestion that, instead of conforming to the paradigm of receptors with single, very high affinity ligands, PPARγ functions as a more generic sensor of fatty acid flux, a property which might help subserve a role as a nutritional sensor and co-ordinator of metabolic responses. Further complexity is attested to by the ability of RXR ligands, too, to stimulate the transactivational activity of the PPARγ–RXR heterodimer, and the further modulation of this activity by phosphorylation of PPARγ. 7 PPARγ is expressed at the highest levels in brown and white adipose tissue, where around 30 per cent of its protein expression is accounted for by a splice variant known as PPARγ 2 . 8, 9 This variant has an additional 28 N-terminal amino acids, and appears to be specific to white adipose tissue. PPARγ is also expressed at high levels in large intestine and white blood cells of both the lymphoid and myeloid lineages, and at lower levels in kidney, liver, skeletal and smooth muscles, pancreas and small intestine. 9–11 The relative importance of PPARγ in each of these tissues from the point of view of glucose homeostasis is incompletely understood, and will form the remainder of this discussion. White adipose tissue Although obesity is robustly associated with impaired insulin sensitivity, the severe insulin resistance of both humans with lipodystrophy and of mice with EVIDENCE FROM CELL AND RODENT MODELS 239 genetically ablated white adipose tissue bears witness to the importance of normal amounts of this tissue in glucose homeostasis. 12 Murine models of complete 13 or near complete 14 lipoatrophy exhibit ectopic fat accumulation in liver and muscle with severe insulin resistance progressing to diabetes. 15 Importantly, transplantation of white adipose tissue into these mice dramatically improves insulin sensitivity and related parameters, 16 demonstrating that it is the absence of fat per se that leads to the abnormal metabolic phenotype. Human subjects with lipodystrophy exhibit a similar pattern of severe insulin resistance and dyslipidaemia, and are discussed in detail in Section 17.5. PPARγ is known to play a pivotal role in preadipocyte differentiation in well characterized in vitro models of adipogenesis, as detailed in Figure 9.1. Mouse embryo-derived preadipocyte cell lines such as 3T3-L1 have been key tools in establishing the transcriptional cascade of adipogenesis. Comparison of this data C/EBPβ C/EBPδ PPARγ C/EBPα dexamethasone cAMP IGF-1 ERKs P Adipocyte genes Proadipogenic factors Anti-adipogenic factors O/E-1, FGF10, FGF2, FBI GATA-2,3, TGFβ, wnt10b 10% serum Insulin Dexamethasone IBMX (raises cAMP) 10% serum Insulin 10% serum (a) (b) ERK C/EBPα PPARγ C/EBPδ C/EBPβ aP2, Glut4 etc. 48 h 96 h Figure 9.1 Role of PPARγ in adipogenesis in vitro 240 PPARγ AND GLUCOSE HOMEOSTASIS with adipose phenotypes of genetically modified animals suggests that they do, at least in part, model the in vivo situation, although it is also clear that many more influences on in vivo adipogenesis remain to be discovered. Figure 9.1(a) shows a typical pattern of expression of some of the key genes implicated in 3T3- L1 differentiation, showing details of the artificial differentiation medium used. Figure 9.1(b) shows a simplified model of the transcriptional cascade, showing a complex series of kindling reactions leading to a robust mutually sustaining expression of PPARγ and C/EBPα, which then drive the full programme of adipocyte gene expression. In view of the physiological importance of adipose tissue, the simplest inter- pretation of the role of PPARγ in modulating insulin sensitivity is that the beneficial effects of its activation derive solely from its ability to promote the expansion of adipose tissue. However, thiazolidinediones are not used in clinical practice principally as a means of inducing adipogenesis in lipodys- trophic subjects, but rather are used effectively in patients of normal or more commonly increased adiposity to enhance insulin sensitivity. Thus, apparently paradoxically, a pro-adipogenic agent is used to treat a condition that is often precipitated by the development of excessive adipose tissue. This paradox is at least partly resolved by consideration of the complex biology of adipose tis- sue in vivo, which cannot be replicated fully in vitro: far from the historical perception of adipose tissue as a relatively inert reservoir for excess dietary fat, it is now understood that white adipose tissue is a complex ‘organ’, which plays a key role in orchestrating numerous metabolic processes. It is constantly sensing the nutritional status of the whole organism, is in continuous commu- nication with other tissues such as liver and muscle and is moreover spatially heterogeneous, with fat depots at different anatomical sites exhibiting markedly different patterns of gene expression, presumably reflecting distinct metabolic functions. Thus, modifying the hypothesis by invoking depot-selective responses of adipose tissue to PPARγ activation is necessary. Support for the concept of such depot-selective PPARγ effects is provided by pharmacological studies in mice: administration of potent and selective thi- azolidinediones results in a preferential expansion of inguinal fat, analogous to human subcutaneous adipose tissue, at the expense of retroperitoneal and other depots. 17 Possibly because this remodelling favours the accretion of lipid in depots that are less hormonally sensitive, and that do not have direct access to the portal circulation and hence the liver, insulin sensitivity is enhanced. However, the increased mass of inguinal fat pads is not simply due to accu- mulation of more tissue of the same morphology: analysis of the distribution of adipocyte size reveals that, while the total number of cells does increase, these cells are of smaller size due to a combination of hyperplasia of precursor cells and apoptosis of larger, hypertrophic adipocytes. 18–22 Correlational studies in different genetic and dietary models of obesity have consistently revealed a positive relationship between adipocyte size and insulin resistance, 23–28 and so EVIDENCE FROM CELL AND RODENT MODELS 241 PPARγ is instrumental not only in modulating the amount and distribution of adipose tissue, but also in regulating the function of that mature tissue. A further experimental approach to the question of PPARγ and glucose sen- sitivity has been to manipulate mice genetically in order to look at the effects of altering PPARγ expression. Attempts to generate homozygous knockout animals foundered due to the embryonic lethality of the deficiency, 22 but study of het- erozygous knockout mice has been instructive, and has revealed some surprising results. Two groups have determined independently that PPARγ heterozygote knockout mice are more insulin sensitive than their wild type counterparts at baseline, 22, 29 but only one of these groups found these animals to be protected from high-fat-induced insulin resistance. 22 Further analysis of the mechanism underlying this showed that, as in thiazolidinedione-treated wild type animals, the mean size of the adipocytes decreased, though in this case they also declined in number, so that body weight and fat mass of the heterozygotes was reduced. However, when these heterozygous knockout mice were treated with antagonists of PPARγ and/or RXR they did indeed become insulin resistant, 30 consistent with data from humans harbouring rare loss-of-function mutations in PPARγ, discussed later. The other group generating PPARγ heterozygote knockout mice found no difference in adipocyte hypertrophy and insulin resistance between het- erozygous knockout and wild type animals, but did find the heterozygous animals to be relatively protected from the age-related decline in insulin sensitivity. 31 A second, and complementary, genetic approach involved generation of mice with homozygous PPARγ alleles which have a point mutation preventing serine phosphorylation at position 112. 32 Phosphorylation at this site has been shown in vitro to reduce PPARγ transactivational activity, and so loss of the poten- tial for phosphorylation would be expected to result in a more active PPARγ, at least intermittently. The homozygous mice had no more adipose tissue than wild type counterparts, and were protected from high-fat-diet-induced insulin resistance and adipocyte hypertrophy. Thus the relationship between the level of PPARγ activity and insulin sensi- tivity is more complex than first imagined, with either stimulation or a moderate reduction in its action apparently leading to metabolic benefits. These metabolic benefits are lost when PPARγ activity drops below a certain critical thresh- old. It appears that the unifying feature of the two situations is a change in adipocyte morphology, such that the cells are predominantly smaller and less lipid laden. The possible functional connections between these adipocyte mor- phological changes and enhanced insulin sensitivity may broadly be classified into three groups: first, PPARγ may influence glucose tolerance through direct effects on the insulin sensitivity of the adipocytes, thus augmenting the rate of glucose disposal in adipose tissue. Second, the trapping of fatty acids in adipose tissue in the fed state may be rendered more efficient, and finally the change in adipocyte phenotype may result in an altered profile of secretory factors, which have remote effects on other insulin-sensitive tissues. [...]... decrease resistin expression in vivo in several different models of obesity and insulin resistance.84 A further possible link between PPARγ action in adipose tissue and insulin sensitization lies in its effects on nitric oxide (NO) production: in diet-induced obesity and insulin resistance it is known that NO is overproduced in adipose tissue and muscles by inducible nitric oxide synthase (iNOS), 85 and NO... pathway, involving interaction of the tyrosine kinase cCbl with the insulin receptor, is also thought to be involved This, too, has been implicated directly in the PPARγ-mediated sensitization of adipocytes to insulin: cCbl interacts with the insulin receptor only via the adaptor protein CAP, or cCbl-associated protein, and expression of CAP appears to be rate limiting for the recruitment of cCbl to the insulin. .. homeostasis, its beneficial metabolic effects are not proportional to its concentration over the higher part of its range, and in cases of insulin resistance in animals that have normal or increased adipose stores other factors override it in determining insulin sensitivity PPARγ activation, while decreasing leptin levels, enhances insulin sensitivity Unlike leptin, adiponectin, an adipocyte-derived multimeric... AMP-activated protein kinase,70 with resulting depletion of the ectopic triglyceride accumulated at these sites Interestingly, this protein kinase has also been suggested recently to mediate the insulin- sensitizing action of metformin.71 In conjunction with the observation that PPARγ activation increases adiponectin expression and production both in vitro and in vivo, these findings render adiponectin... markedly induces expression of IRS-233 and Glut4.34 Conversely, a decline in the expression of these genes and a reduction in cell size and triglyceride content are seen in the presence of a dominant negative PPARγ. 35 The induction of Glut4 expression and glucose transport in response to insulin is known to depend in part on activation of phosphatidyl inositol-3-kinase downstream from IRS1 and 2 However,... capacity and enhance insulin- mediated control of systemic FFA availability Diabetes 50 (5) , 1 158 –11 65 58 Zhang, Y., Proenca, R., Maffei, M., Barone, M., Leopold, L and Friedman, J M (1994) Positional cloning of the mouse obese gene and its human homologue Nature 372, 4 25 432 59 Margetic, S., Gazzola, C., Pegg, G G and Hill, R A (2002) Leptin: a review of its peripheral actions and interactions Int J Obes... Kahn, B B (2000) In vivo administration of leptin activates signal transduction directly in insulin- sensitive tissues: overlapping but distinct pathways from insulin Endocrinology 141, 2328–2339 61 Minokoshi, Y., Kim, Y B., Peroni, O D., Fryer, L G., Muller, C., Carling, D and Kahn, B B (2002) Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase Nature 4 15, 339–343 62 Shimomura,... E and Saltiel, A R (2001) Insulin- stimulated GLUT4 translocation requires the CAP-dependent activation of TC10 Nature 410, 944–948 REFERENCES 259 37 Baumann, C A., Brady, M J and Saltiel, A R (2001) Activation of glycogen synthase by insulin in 3T3-L1 adipocytes involves c-Cbl-associating protein (CAP)-dependent and CAP-independent signaling pathways J Biol Chem 276, 60 65 6068 38 Baumann, C A., Ribon,... levels that are inversely related to the amount of white adipose tissue Also unlike leptin, circulating levels of adiponectin have been shown to correlate with insulin sensitivity in both genetic and dietary models of murine insulin resistance and obesity, 65, 66 while infusion of adiponectin markedly improves hepatic insulin sensitivity.67 Furthermore, it has been shown that in a murine model of lipoatrophy... those adipocytokines discussed earlier, adiponectin appears to be the best candidate in humans: plasma levels correlate with insulin sensitivity,131 – 133 and are inversely proportional to fat mass,134, 1 35 and thiazolidinediones increase adiponectin gene expression.136, 137 Moreover, circulating adiponectin levels were found to be dramatically lower in three individuals harbouring loss-of-function PPARγ . adipocyte- derived signalling molecule that reduces insulin- stimulated glucose uptake 75 and is found in high concentrations in obese and insulin- resistant individuals. 76, 77 TNFα expression is inhibited. the insulin- sensitizing action of metformin. 71 In conjunction with the observation that PPARγ activation increases adiponectin expression and produc- tion both in vitro and in vivo, these findings. resistin expression in vivo in several different models of obesity and insulin resistance. 84 A further possible link between PPARγ action in adipose tissue and insulin sensitization lies in its