Adiponectin Enhances Insulin Action by Decreasing Ectopic Fat Deposition

Adiponectin enhances insulin action E Ravussin 4

age. Older individuals have more sig- studies have confirmed GHB is a weak the opportunity to further clarify the nificant problems with behavioural agonist at native and recombinant role of GHB and its receptors in the disturbance and aggressive, agitated GABABR1/2 receptors and that it has mammalian central nervous system. behaviour. This change may correlate high affinity binding to a GHB recep- The facilitation of the development of with the reduction in GHB levels tor, the nature of which is not cur- pharmacological agents for the treat- observed in the CSF of patients with rently clear.6,7 ment of GHB abuse, SSADH and age. The irreversible GABA transamin- Hogema et al demonstrated that potentially other neurological dis- ase inhibitor, vigabatrin has been used their mice could be maximally rescued orders is evident. in the treatment of this disorder as it with vigabatrin treatment thus con- inhibits GABA breakdown thereby lim- firming that the observed pathology is iting accumulation of GHB. In clinical primarily due to the elevated GHB lev- DUALITY OF INTEREST use, vigabatrin is not affective in all els. They provide evidence to confirm None declared. patients and there are concerns sur- high levels of GHB act upon GABAB rounding its use following reports of receptors, as mice could also be res- Correspondence should be sent to visual field loss.3,4 cued to a lesser extent with the GABA B H Peters, Murdoch Childrens Research Hogema et al recently described a antagonist CPG 35348. The corre- Institute, Royal Children’s Hospital, knockout mouse model in which the lation of the onset of clinical disease Melbourne, Australia. SSADH gene (Aldh5a.1) had been tar- with weaning, in conjunction with Tel: 00 61 03 8341 6236 geted resulting in no detectable previous studies identifying taurine as Fax: 00 61 03 9348 1391 enzyme.5 These mice have elevated having effects on neurotransmission, E-mail: petershȰcryptic.rch.unimelb.edu.au levels of GABA and GHB in urine and led to the development of the hypoth- homogenates of liver and brain. esis that taurine may play a role in dis- 1 Chebib M, Johnston GAR. Clin Exp Pharma- Gliosis was observed in the hippocam- ease protection. Administration of col 1999; 26: 937–940. pus. They develop ataxia and seizures taurine alone to these mice resulted in 2 Gibson KM et al. Neuropediatrics 1998; 29: at around postnatal day 16 with death rescue, although the exact mechanism 14–22. by postnatal day 22. It appears this remains unclear. The authors postulate 3 Gibson KM et al. J Inherit Metab Dis 1995; 18 model is an accurate model for the that affected mice may be taurine : 143–146. 4 Peters H et al. J Inherit Metab Dis 1999; 22: human disease SSADH and GHB inges- depleted which is rectified by dietary 198–199. tion. To date studies of the supplement. 5 Hogema BM et al. Nat Genet 2001; 29: affects/action of GHB have relied on This unique mouse model represents 212–216. the intermittent administration of a more physiologically accurate 6 Lingenhoehl K. et al. Neuropharmacology 1999; 38: 1667–1673. GHB to rats/mice. Based on these there model, which should enable a better 7 Snead OC. J Neurochem 2000; 75: 1986– is accumulating evidence to support understanding of the neurophysiolog- 1996. GHB as a neurotransmitter. Numerous ical effects of elevated GHB. It provides

that a proteolytic cleavage product of Adiponectin enhances insulin action adiponectin causes increased fatty acid oxidation and weight loss in murine by decreasing ectopic fat deposition models of dietary induced obesity.7 In the August issue of Nature Medi- E Ravussin cine, two studies published side-by-side now show that acute treatment of Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA mice with adiponectin dramatically improves insulin sensitivity in both skeletal muscle and liver tissues.8,9 The Pharmacogenomics Journal (2002) 2, therefore, represents the only source of More specifically, in models of obesity 4–7. DOI: 10.1038/sj/tpj/6500068 the circulating protein. However, and diabetes, adiponectin improved unlike leptin, its tissue expression and insulin-mediated glucose uptake by Adiponectin (also known as Acrp30, its plasma concentration are decreased the skeletal muscle and insulin- AdipoQ, Apm1 and GBP28) is an (not increased) in obesity and/or type mediated suppression of hepatic adipocyte-derived hormone disco- 2 diabetes. Further work provided evi- glucose production, both mechanisms vered almost simultaneously by four dence that adiponectin may prevent leading towards normalization of different groups using diverse metho- atherogenesis by suppressing endo- serum glucose concentration. The dological approaches.1–4 Very early thelial adhesion molecules via inhi- effect of adiponectin on skeletal after its discovery, it was found that bition of the NF-KappaB signaling muscle in obese or lipoatrophic mice the adiponectin gene is exclusively pathway.5,6 Last year, Fruebis et al pub- is mediated by increased expression of expressed in adipose tissue, which, lished exciting novel data showing genes involved in fatty acid transport

The Pharmacogenomics Journal Adiponectin enhances insulin action E Ravussin 5

and ␤-oxidation and probably of storage of excess calories in skeletal plasma adiponectin and body fat is genes increasing energy expenditure muscle, liver, pancreas and blood, all most intriguing.13 Why do animals or (indicated by an increase in rectal precipitating insulin resistance.10 The individuals with larger adipose depots temperature).8 Enhanced thermogen- major culprit in insulin resistance secrete less of a protein made by the esis and fat oxidation then result in may, therefore, be an ectopic fat stor- adipose tissue itself? Such observations decreased muscle triglyceride content age in tissues not meant to store fat.11 may argue in favor of an autocrine and improved glucose uptake and Three lines of evidence support the or paracrine effect of adipocytes insulin signaling. In the second study, above hypothesis. First, failure to inhibiting their own production and acute injections of adiponectin to develop adipose tissue mass in either secretion of the hormone. An initial wild-type, ob/ob and non-obese dia- mice or man—known as lipodystro- clue towards the regulation of betic (NOD) mice resulted in a signifi- phy—results in severe insulin resist- adiponectin secretion is provided by cant drop in serum glucose concen- ance and diabetes probably because of the increased production of the pro- tration in these three animal models.9 excess storage of lipids into tissues tein in white adipocytes (and 3T3L1 Adiponectin decreased glucose output other than adipose. Secondly, most adipocytes grown in vitro) and from isolated primary hepatocytes, obese patients shunt part of dietary fat increased serum concentration in consistent with the hypothesis that into skeletal muscle and liver, and the response to treatment with an insulin this adipocytokine normalizes serum degree of their insulin resistance corre- sensitizing PPAR-␥ activator such as glucose concentration by suppressing lates closely with lipid infiltration into rosiglitazone.8 Furthermore, high-fat hepatic glucose production. these tissues. Thirdly, large fat cells are feeding of mice caused a reduction in Together with previously published predictive of the development of type adiponectin mRNA and circulating data, these studies strongly suggest 2 diabetes,12 probably as a conse- levels, whereas caloric restriction that adiponectin may represent a new quence of the failure of the adipose increased the level of the protein. molecular target for the treatment of tissue to expand (impaired fat cell Thus, adiponectin expression and different disorders of the metabolic proliferation/differentiation) and, secretion correlate with insulin sensi- syndrome including obesity, insulin therefore, to accommodate excess tivity and these preliminary data indi- resistance, and atheroscelerosis. Like energy intake. As a result, dietary fat is cate that hormones such as leptin leptin, adiponectin seems to prevent deposited in excess in tissues not and/or insulin may down-regulate its the deposition of fat in insulin-sensi- designed for fat storage. In support of production. However, adiponectin lev- tive tissues by increasing fat oxidation. the ‘ectopic fat storage hypothesis,’ els seem relatively constant in humans Unlike leptin (which acts both directly treatment with thiazolidinediones and do not change after a meal, which or via CNS mechanisms), adiponectin improves insulin sensitivity in part by seems to exclude insulin as a regulator seems to act exclusively at peripheral activation of PPAR-␥, which promotes of its production.13 Another issue to be tissues, although its effects on the the differentiation and proliferation of resolved is what part of the adiponec- brain have not yet been tested. There- new fat cells, therefore increasing the tin protein is biologically active? fore, there are at least two hormones capacity to store the excess dietary fat. Adiponectin is a 247-amino acid pro- secreted by the adipocyte that play a As a consequence, less unwanted fat is tein consisting of an N-terminal col- role in counteracting the ectopic fat deposited in insulin-sensitive tissues lagenous domain and a C-terminal storage syndrome by increasing fat and insulin sensitivity is improved. globular domain.7 Intriguingly, crys- oxidation. Interestingly, in Yamau- The two new studies on the insulin- tallography studies revealed that the chi’s study, insulin resistance was sensitizing role of adiponectin leave us globular domain of adiponectin has almost totally reversed when the two now with many unanswered questions significant homology with the tumor- adipocytokines were combined in regarding the physiological role and necrosis factor family,14 other cyto- physiological dose.8 importance of adiponectin in health kines involved in insulin resistance. It Insulin resistance is clearly recog- and disease. How is the secretion of is unclear whether the whole protein nized to be one—if not the most— adiponectin controlled? What is the is necessary for the insulin-sensitizing important predictor of the develop- importance of post-translational pro- effect since, in some studies, only the ment of type 2 diabetes. However, cessing of adiponectin for its physio- intact protein caused biological even if the molecular mechanisms of logical activity? Through which effects,9 whereas in others the globular insulin resistance are not totally receptor(s) does adiponectin or its domain was sufficient.7 It is conceiv- understood, there is evidence that part fragments act? How does adiponectin able that different post-translational of the resistance is related to cellular and other adipocyte-derived proteins modifications (multimerization, pro- and intracellular molecular defects interact to modulate insulin resist- teolytic processing events) may be whereas the other part may be the ance? What are the post-receptors sig- required for different biological activi- consequence of impaired transport of naling pathways involved in the insu- ties in different tissues. In a genome- insulin to insulin-dependent tissues. lin-sensitizing effect of adiponectin? wide scan for the discovery of genetic Danforth recently proposed that a fail- What other physiological mechanisms loci underlying the susceptibility to ure of adipocyte differentiation pre- are regulated by adiponectin? traits of the metabolic syndrome, Kis- cipitates type 2 diabetes by causing The inverse correlation between sebah et al identified a ‘hot’ area on

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insulin resistance so common in obes- ity. Some or all of these hormones seem to play a role in important bio- logical functions such as feeding behavior, energy and fat balance, insu- lin sensitivity, and atherogenesis. Dynamic interactions between these proteins probably dictate the fine-tun- ing of the above mechanisms. The two recent papers on the role of adiponec- tin in insulin sensitivity represent an important step towards an under- standing of the regulation of such important survival mechanisms and may shed some light on why the prevalence of disorders of the meta- bolic syndrome is so high in our ‘obesigenic’ environment. Most of the work remains to be done to elucidate what part of the insulin signaling cas- Figure 1 Adipose tissue is much more complex than previously thought and operates as cade is influenced by the activity of an endocrine organ with many secreted proteins. It is now well recognized that cytokines these new adipocytokines. such as TNF-␣, interleukins, leptin, resistin andadiponectinplay an important role in The findings on adiponectin are still whole-body carbohydrate metabolism and therefore insulin sensitivity. Adiponectin seems to play a role as an insulin sensitizer, both at the level of the skeletal muscle tissue and preliminary; we need to fully under- the liver. More specifically, it improves muscle insulin sensitivity by increasing fat oxidation stand the importance of this hormone and, therefore, decreasing muscle triglyceride, a major inhibitor of insulin signaling. The in health and disease. However, with picture is not so clear at the hepatic level, but the new data discussed in this comment only preliminary data, there is cre- show that adiponectin may have a direct effect on the hepatocyte to suppress glucose dence to the idea that adiponectin and production (in vitro data) or indirectly via a lowering of plasma free-fatty acids. The new its receptor(s) may represent an excit- exciting data about the importance of adiponectin in the development of insulin resistance ing target for the development of now raise many questions. How is adiponectin secretion controlled? What is the impor- drugs to treat facets of the metabolic tance of post-translational processing for adiponectin biological activity? How do syndrome. First, the protein itself or an adiponectin and other adipocyte-derived proteins interact to modulate insulin resistance? What are the post-receptor(s) signaling pathways involvedin the insulin sensitizing effect analog (or a fragment of it) can be used of adiponectin? What other physiological mechanisms are regulated by adiponectin? All to target insulin resistance in type 2 these questions are likely to be at least partially answeredwithin the next year or so. diabetic patients. These patients will probably be sensitive to the action of adiponectin since their body is rela- chromosome 3q27 overlapping the many research groups are actively tively depleted in this hormone. This region where adiponectin maps on the working on the identification of the is in marked contrast to the use of lep- human genome. More intriguingly, adiponectin receptor(s). tin, which has been proven mostly another ‘hot’ locus (LOD = 5.0) was Our notion of the adipocyte as being inefficacious in obese patients because found on 17p12 working in an epis- a storage tank for fat has undergone a of resistance to its action. If the tatic way with the chromosome 3 dramatic change over the past 6 or 7 biology continues to support the locus to determine the susceptibility to years.16 It is now well accepted that importance of adiponectin in the eti- the development of the metabolic syn- the adipose tissue plays a complex role ology of traits of the metabolic syn- drome.15 The locus on chromosome 17 as an endocrine organ releasing many drome, pharmaceutical companies will harbors a gene for the receptor protein important hormones in response to identify small molecules as oral drugs. known to bind the globular ‘heads’ of acute or chronic changes in metabolic Such molecules may act at different the complement factor C1q. This status. Figure 1 presents many of the steps of the adiponectin pathway, ie to receptor is highly expressed in endo- hormones and proteins secreted by the increase the synthesis and secretion of thelium, smooth muscle and hepato- adipose tissue including some of the the hormone, to mimic its activity at cytes. Since the globular domain of key players for the link between obes- the level of the receptor or, finally, to adiponectin shares significant hom- ity and insulin resistance such as lep- enhance in an allosteric manner the ology with the globular domain of tin, TNF-␣, resistin and adiponectin. activity of the endogenous hormone. C1q, it is conceivable that the C1q Now, the challenging task is to under- New breakthroughs in our under- receptor may be the, or one of the stand at the physiological and molecu- standing of the regulation of the hor- receptors for adiponectin or its biologi- lar levels the interaction between these mone may also lead to intervention cally active fragment. It is likely that messengers of the obese state and the and prevention strategies (such as diet)

The Pharmacogenomics Journal Metastatic medulloblastoma MC Fru¨hwald and C Plass 7

to improve its production and 1 Maeda K et al. Biochem Biophys Res Commun 10 Danforth E Jr. Nat Genet 2000; 26: 13. secretion. 1996; 221: 286–289. 11 Shulman GI. Cellular mechanisms of insulin 2 Scherer PE et al. J Biol Chem 1995; 270: resistance. J Clin Invest 2000; 106: 171– 26746–26749. 176. 3HuEet al. J Biol Chem 1996; 271: 10697– 12 Weyer C et al. Diabetologica 2000; 43: DUALITY OF INTEREST 10703. 1498–1506. None declared. 4 Nakano Y et al. J Biochem (Tokyo) 1996; 13 Hotta K et al. Arterioscler Thromb Vasc Biol 120: 803–812. 2000; 20: 1595–1599. 5 Ouchi N et al. Circulation 2000; 102: 14 Shapiro L, Scherer PE. Curr Biol 1998; 8: 1296–1301. 335–338. Correspondence should be sent to 6 Ouchi N et al. Circulation 1999; 100: 15 Kissebah AH. Proc Natl Acad Sci USA 2000; E Ravussin, Pennington Biomedical Research 2473–2476. 97: 14478–14483. Center, Health and Performance Enhancement 7 Fruebis J et al. Proc Natl Acad Sci USA 2001; 16 Spiegelman BM, Flier JS. Cell 2001; 104: Center, 6400 Perkins Rd, Baton Rouge, 98: 2005–2010. 531–543. Louisiana, LA 70808 4124, USA. 8 Yamauchi T et al. Nat Med 2001; 7: 941– Tel: +1 225 763 3186 946. 9 Berg AH et al. Nat Med 2001; 7: 947– E-mail: ravusseȰpbrc.edu 953.

Even though promising, all of the Metastatic medulloblastoma— currently successful treatment options for high-risk medulloblastoma are therapeutic success through associated with neural and neuroen- docrine side effects. Many follow-up molecular target identification? studies demonstrate a tremendous decline in quality of life among sur- MC Fru¨hwald1 and C Plass2 vivors of medulloblastoma.8 To avoid toxicity to the developing 1Universita¨tsklinikum Mu¨nster, Klinik und Poliklinik fu¨r Kinderheilkunde, Pa¨diatrische brain, therapeutic avenues targeting Ha¨matologie/Onkologie, Mu¨nster, Germany; 2The Ohio State University, Division of the underlying molecular lesions have Human Cancer Genetics, Columbus, Ohio, USA to be explored. The search for the underlying genetic lesions in medullo- blastoma has been long, however, The Pharmacogenomics Journal (2002) 2, evance, the metastatic status is used knowledge has come only slowly.2 7–10. DOI: 10.1038/sj/tpj/6500077 for stratification of patients into risk Genomic changes, such as the forma- 3 groups. tion of an isochromosome 17q and a Metastatic medulloblastoma is a The treatment of patients with stan- loss of heterozygosity distal to 17p13.1 malignant tumor of the developing dard risk tumors, ie those without met- (distal to the TP53 locus) have been CNS with little hope for a permanent astases has been rather successful with known for over 10 years,9 however a cure. A report by McDonald et al offers survival rates of up to 78%.4,6 In con- proposed tumor suppressor gene in the alternatives by identifying potential trast, the cure of metastatic disease has region has not yet been identified. therapeutic targets using expression until recently been limited to single Table 1 recognizes some of the genes array analysis.1,2 cases. that have been identified in recent The last three decades have seen In metastatic medulloblastoma stan- impressive advances in the successful dard chemotherapy regimens com- years as showing genetic differences treatment of many common child- bined with neuraxis radiotherapy have between normal (cerebellar) and med- 2,9 hood malignancies such as acute lym- shown only temporary response. In ulloblastoma tissue. phoblastic leukemia. This success has younger children radiotherapy is asso- Recently medulloblastomas have unfortunately not been paralleled for ciated with unacceptable neurotoxic- been extensively analyzed by novel malignant brain tumors.3 The most ity and attempts at delaying the time genome-wide screening methodologies common of these, the cerebellar med- to radiotherapy are often futile. Sur- ranging from comparative genome ulloblastoma, exhibits a tremendous vival rates for this group of patients hybridization over methylation scans metastatic potential: up to 50% of have been close to zero and any to expression profiling.1,2,9,10 patients present with metastatic dis- relapse has been associated with an Expression profiling has stirred high ease at the time of diagnosis (see inevitably fatal outcome.4 hopes among clinicians and scientists Figure 1).4 While the spread of malig- This grim scenario has to some alike as it can rapidly identify nant brain tumors is usually limited extent changed with the introduction expression differences in multiple to the CNS, medulloblastomas can of high dose chemotherapy protocols genes, which then may serve as poten- aggressively metastasize into extraneu- supported by autologous stem cell tial therapeutic targets. ral tissues.5 Due to its prognostic rel- rescue.7 MacDonald et al compared

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