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The enigma of adiponectin
Atherosclerosis 227 (2013) 226e227
Contents lists available at SciVerse ScienceDirect
Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis
Invited commentary
The enigma of adiponectin Mogens Fenger* University Hospital of Copenhagen, Medical Biochemistry, Genetics, and Molecular Biology, Kettegaard Alle 30, 2650 Hvidovre, Denmark
a r t i c l e i n f o Article history: Received 16 November 2012 Accepted 17 November 2012 Available online 23 November 2012 Keywords: Adiponectin Diabetes mellitus type 2 Clinical trial
Adiponectin was discovered in the mid-nineties and known by various names [1e4], but the name adiponectin has finally been adopted as it is solely secreted from the adipocytes. Soon it became clear that this adipokine has a major impact on insulin resistance, diabetes and vascular injury although some controversy about its physiological functions are prevalent [5]. The consensus is however based on meta-analysis that adiponectin counteract the insulin resistance and is antiatherogenic, although the associations may not be as strong as previously reported [6], or may only be prevalent in subpopulations. In the case of hypertension it has been shown that study populations are a mixture of homogenous (as far as one can take this concept) subpopulations where the physiology and genetics differs between the subpopulations [7]. The paper published in this issue of Atherosclerosis by Ji-Hyun Kim et al. [8] underscores the complexity of adiponectins involvement in insulin resistance and diabetes mellitus type 2 in women. In fact, the study displays our lack of understanding of the role of adiponectin and its regulation. In contrast to some but not all previous studies statins (pravastatin) did not influence the levels of high molecular weight adiponectin or total adiponectin levels. Also, insulin sensitivity was not improved by pravastatin in these subjects. It is tempting to causally link the lack of change in adiponectin levels to status quo of insulin resistance. However, as pointed out by Kim et al. insulin resistance in diabetics may be physiological different from insulin resistance in non-diabetics, which may be one reason for the somewhat contradictory results obtained in the various studies referred by Kim et al. In addition,
* Tel.: þ45 351 46239; fax: þ45 367 50977. E-mail address: [email protected]. 0021-9150/$ e see front matter Ó 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.atherosclerosis.2012.11.018
there seems to be a gender difference in the levels and regulation of the adiponectin levels, which might explain some of the existing controversies. The differences in this study populations must certainly be taken in consideration as the so-called “genetic background” of the subjects, although a rather loose term essentially means that the genetic network in which adiponectin is a part of varies in expression due to variations in the not just the genes but certainly in non-genic regulatory structures. In all, Kim et al. hinted to this diversity, but the question remains: is insulin resistance graded on a continuous scale eventually resulting in diabetes mellitus type 2 or is the population a mixture disparate subpopulation defined by their genetic set-up? If latter is the case then the subpopulations will exhibit differences in the propensity to develop diabetes, (and in fact some will never develop diabetes despite their insulin resistance), and will this propensity simply set the limit for the influence of adiponectin? Importantly, and also pointed out by Kim et al., the effect of adiponectin has to be evaluated in the context of the “inflammatory” response, which is set by interactions of a plethora of -kines, hormones etc. No regulatory compounds as adiponectin function in a vacuum, but are influenced by other compounds in its physiological network either by interacting with its functionality and/or by its regulation. The state of the physiological process in the study population used by Kim et al. may simply be “locked” in its basis as genetically defined. Adiponectin is still an enigma despite some progress in understanding the mechanism and functionality. What sets adiponectin somewhat apart from e.g. insulin or leptin, is that it like other members of the complement factor C1q family multimerizes i.e. forms homotrimers and homohexamers and even higher order complexes, while monomeric adiponectin has not been detected. These complexes have different affinities for the two known
M. Fenger / Atherosclerosis 227 (2013) 226e227
adiponectin receptors [9], but this may be an artefact as hexameric and higher order complexes are sensitive to the thiol status in their environment, which has been suggested to play a role in cellular contact inhibition [10]. In addition, although adiponectin may have direct actions through defined receptors the physiological effects has to be put in context with the plethora of compounds like leptin and insulin with influence e.g. insulin resistance [11] not to mention genetic variability related to adiponectin and its receptors [12], much of which are not explored yet. Recently, adiponectin has been linked to the sphingolipid metabolism by activating ceramidase [13]. Ceramide impairs insulin signalling by inhibition of protein kinase B (PKB) [14], and the stimulation of ceramidase by adiponectin improves the insulin signalling e which just does not happen in fulminant diabetic mellitus type 2 because of the low levels of adiponectin. Certainly, still many questions remains to be addressed. References [1] Scherer PE, Williams S, Fogliano M, Baldini G, Lodish HF. A novel serum protein similar to C1q, produced exclusively in adipocytes. J Biol Chem 1995; 270:26746e9. [2] Maeda K, Okubo K, Shimomura I, Funahashi T, Matsuzawa Y, Matsubara K. cDNA cloning and expression of a novel adipose specific collagen-like factor, apM1 (AdiPose most abundant Gene transcript 1). Biochem Biophys Res Commun 1996;221:286e9.
227
[3] Nakano Y, Tobe T, Choi-Miura NH, Mazda T, Tomita M. Isolation and characterization of GBP28, a novel gelatin-binding protein purified from human plasma. J Biochem 1996;120:803e12. [4] Hu E, Liang P, Spiegelman BM. AdipoQ is a novel adipose-specific gene dysregulated in obesity. J Biol Chem 1996;271:10697e703. [5] Gu W, Li Y. The therapeutic potential of the adiponectin pathway. BioDrugs 2012;26. [6] Sattar N, Wannamethee G, Sarwar N, et al. Adiponectin and coronary heart disease. Circulation 2006;114:623e9. [7] Fenger M, Linneberg A, Jorgensen T, et al. Genetics of the ceramide/ sphingosine-1-phosphate rheostat in blood pressure regulation and hypertension. BMC Genet 2011;12:44. [8] Kim J-H. Effects of pravastatin on serum adiponectin levels in patients with type 2 diabetes mellitus. Atherosclerosis 2013;227(2):355e9. [9] Tsao TS, Tomas E, Murrey HE, et al. Role of disulfide bonds in Acrp30/Adiponectin structure and signaling specificity: different oligomers activate different signal transduction pathways. J Biol Chem 2003;278:50810e7. [10] Spassieva SD, Rahmaniyan M, Bielawski J, Clarke CJ, Kraveka JM, Obeid LM. Cell density-dependent reduction of dihydroceramide desaturase activity in neuroblastoma cells. J Lipid Res 2012;53:918e28. [11] Peterson JM, Wei Z, Wong GW. C1q/TNF-related protein-3 (CTRP3), a novel adipokine that regulates hepatic glucose output. J Biol Chem 2010;285: 39691e701. [12] Menzaghi C, Trischitta V, Doria A. Genetic influences of adiponectin on insulin resistance, type 2 diabetes, and cardiovascular disease. Diabetes 2007;56: 1198e209. [13] Holland WL, Miller RA, Wang ZV, et al. Receptor-mediated activation of ceramidase activity initiates the pleiotropic actions of adiponectin. Nat Med 2011;17:55e63. [14] Stratford S, Hoehn KL, Liu F, Summers SA. Regulation of insulin action by ceramide: dual mechanisms linking ceramide accumulation to the inhibition of Akt/protein kinase B. J Biol Chem 2004;279:36608e15.
Contents lists available at SciVerse ScienceDirect
Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis
Invited commentary
The enigma of adiponectin Mogens Fenger* University Hospital of Copenhagen, Medical Biochemistry, Genetics, and Molecular Biology, Kettegaard Alle 30, 2650 Hvidovre, Denmark
a r t i c l e i n f o Article history: Received 16 November 2012 Accepted 17 November 2012 Available online 23 November 2012 Keywords: Adiponectin Diabetes mellitus type 2 Clinical trial
Adiponectin was discovered in the mid-nineties and known by various names [1e4], but the name adiponectin has finally been adopted as it is solely secreted from the adipocytes. Soon it became clear that this adipokine has a major impact on insulin resistance, diabetes and vascular injury although some controversy about its physiological functions are prevalent [5]. The consensus is however based on meta-analysis that adiponectin counteract the insulin resistance and is antiatherogenic, although the associations may not be as strong as previously reported [6], or may only be prevalent in subpopulations. In the case of hypertension it has been shown that study populations are a mixture of homogenous (as far as one can take this concept) subpopulations where the physiology and genetics differs between the subpopulations [7]. The paper published in this issue of Atherosclerosis by Ji-Hyun Kim et al. [8] underscores the complexity of adiponectins involvement in insulin resistance and diabetes mellitus type 2 in women. In fact, the study displays our lack of understanding of the role of adiponectin and its regulation. In contrast to some but not all previous studies statins (pravastatin) did not influence the levels of high molecular weight adiponectin or total adiponectin levels. Also, insulin sensitivity was not improved by pravastatin in these subjects. It is tempting to causally link the lack of change in adiponectin levels to status quo of insulin resistance. However, as pointed out by Kim et al. insulin resistance in diabetics may be physiological different from insulin resistance in non-diabetics, which may be one reason for the somewhat contradictory results obtained in the various studies referred by Kim et al. In addition,
* Tel.: þ45 351 46239; fax: þ45 367 50977. E-mail address: [email protected]. 0021-9150/$ e see front matter Ó 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.atherosclerosis.2012.11.018
there seems to be a gender difference in the levels and regulation of the adiponectin levels, which might explain some of the existing controversies. The differences in this study populations must certainly be taken in consideration as the so-called “genetic background” of the subjects, although a rather loose term essentially means that the genetic network in which adiponectin is a part of varies in expression due to variations in the not just the genes but certainly in non-genic regulatory structures. In all, Kim et al. hinted to this diversity, but the question remains: is insulin resistance graded on a continuous scale eventually resulting in diabetes mellitus type 2 or is the population a mixture disparate subpopulation defined by their genetic set-up? If latter is the case then the subpopulations will exhibit differences in the propensity to develop diabetes, (and in fact some will never develop diabetes despite their insulin resistance), and will this propensity simply set the limit for the influence of adiponectin? Importantly, and also pointed out by Kim et al., the effect of adiponectin has to be evaluated in the context of the “inflammatory” response, which is set by interactions of a plethora of -kines, hormones etc. No regulatory compounds as adiponectin function in a vacuum, but are influenced by other compounds in its physiological network either by interacting with its functionality and/or by its regulation. The state of the physiological process in the study population used by Kim et al. may simply be “locked” in its basis as genetically defined. Adiponectin is still an enigma despite some progress in understanding the mechanism and functionality. What sets adiponectin somewhat apart from e.g. insulin or leptin, is that it like other members of the complement factor C1q family multimerizes i.e. forms homotrimers and homohexamers and even higher order complexes, while monomeric adiponectin has not been detected. These complexes have different affinities for the two known
M. Fenger / Atherosclerosis 227 (2013) 226e227
adiponectin receptors [9], but this may be an artefact as hexameric and higher order complexes are sensitive to the thiol status in their environment, which has been suggested to play a role in cellular contact inhibition [10]. In addition, although adiponectin may have direct actions through defined receptors the physiological effects has to be put in context with the plethora of compounds like leptin and insulin with influence e.g. insulin resistance [11] not to mention genetic variability related to adiponectin and its receptors [12], much of which are not explored yet. Recently, adiponectin has been linked to the sphingolipid metabolism by activating ceramidase [13]. Ceramide impairs insulin signalling by inhibition of protein kinase B (PKB) [14], and the stimulation of ceramidase by adiponectin improves the insulin signalling e which just does not happen in fulminant diabetic mellitus type 2 because of the low levels of adiponectin. Certainly, still many questions remains to be addressed. References [1] Scherer PE, Williams S, Fogliano M, Baldini G, Lodish HF. A novel serum protein similar to C1q, produced exclusively in adipocytes. J Biol Chem 1995; 270:26746e9. [2] Maeda K, Okubo K, Shimomura I, Funahashi T, Matsuzawa Y, Matsubara K. cDNA cloning and expression of a novel adipose specific collagen-like factor, apM1 (AdiPose most abundant Gene transcript 1). Biochem Biophys Res Commun 1996;221:286e9.
227
[3] Nakano Y, Tobe T, Choi-Miura NH, Mazda T, Tomita M. Isolation and characterization of GBP28, a novel gelatin-binding protein purified from human plasma. J Biochem 1996;120:803e12. [4] Hu E, Liang P, Spiegelman BM. AdipoQ is a novel adipose-specific gene dysregulated in obesity. J Biol Chem 1996;271:10697e703. [5] Gu W, Li Y. The therapeutic potential of the adiponectin pathway. BioDrugs 2012;26. [6] Sattar N, Wannamethee G, Sarwar N, et al. Adiponectin and coronary heart disease. Circulation 2006;114:623e9. [7] Fenger M, Linneberg A, Jorgensen T, et al. Genetics of the ceramide/ sphingosine-1-phosphate rheostat in blood pressure regulation and hypertension. BMC Genet 2011;12:44. [8] Kim J-H. Effects of pravastatin on serum adiponectin levels in patients with type 2 diabetes mellitus. Atherosclerosis 2013;227(2):355e9. [9] Tsao TS, Tomas E, Murrey HE, et al. Role of disulfide bonds in Acrp30/Adiponectin structure and signaling specificity: different oligomers activate different signal transduction pathways. J Biol Chem 2003;278:50810e7. [10] Spassieva SD, Rahmaniyan M, Bielawski J, Clarke CJ, Kraveka JM, Obeid LM. Cell density-dependent reduction of dihydroceramide desaturase activity in neuroblastoma cells. J Lipid Res 2012;53:918e28. [11] Peterson JM, Wei Z, Wong GW. C1q/TNF-related protein-3 (CTRP3), a novel adipokine that regulates hepatic glucose output. J Biol Chem 2010;285: 39691e701. [12] Menzaghi C, Trischitta V, Doria A. Genetic influences of adiponectin on insulin resistance, type 2 diabetes, and cardiovascular disease. Diabetes 2007;56: 1198e209. [13] Holland WL, Miller RA, Wang ZV, et al. Receptor-mediated activation of ceramidase activity initiates the pleiotropic actions of adiponectin. Nat Med 2011;17:55e63. [14] Stratford S, Hoehn KL, Liu F, Summers SA. Regulation of insulin action by ceramide: dual mechanisms linking ceramide accumulation to the inhibition of Akt/protein kinase B. J Biol Chem 2004;279:36608e15.