Vitamin E and adiponectin: proposed mechanism for vitaminE-induced improvement in insulin sensitivitynure_377 155..161

Brianna Gray, Jennifer Swick, and Alayne G Ronnenberg

Insulin resistance and type 2 diabetes have been treated with the PPARg agoniststhiazolidinediones, or TZDs, since the 1990s. One mechanism by which these drugsmay work is through PPARg-mediated upregulation of adiponectin, an endogenousadipokine that has been shown to increase insulin sensitivity. Interestingly, a- andg-tocopherol, two vitamin E vitamers, have structural similarities to the TZDs andhave also been linked to enhanced insulin sensitivity. A recent study identified anovel function of a- and g-tocopherol in 3T3-L1 preadipocytes: upregulation of anendogenous ligand involved in activating PPARg. This study also found thattocopherols dramatically enhanced adiponectin expression and that this effect wasmediated through a PPARg-dependent process. These findings illustrate a possiblemechanistic link between vitamin E and insulin sensitivity.© 2011 International Life Sciences Institute

INTRODUCTION

Vitamin E is a fat-soluble vitamin known for its antioxi-dant capacity. Of the eight naturally occurring vitamerforms, a- and g-tocopherol are the predominant com-pounds found in the diet and in plasma. In addition to itsantioxidant capacity, a-tocopherol regulates expressionof genes involved in a wide range of cell functions, includ-ing cell cycle regulation, inflammation and cell adhesion,cell signaling, and lipid uptake.1

Over 15 years ago, Paolisso et al.2 reported thatvitamin E supplementation improves insulin sensitivity.They found that fasting plasma glucose and HbA1c weresignificantly lower in diabetic, but not control, subjectsfollowing daily supplementation with 900 mg vitamin E.They later reported a positive effect of supplementalvitamin E on insulin action in older, non-obese subjects.3

Additionally, in an epidemiologic study of 944 Finnishmen, low plasma vitamin E was associated with a nearlyfourfold increase in the risk of developing diabetes over a4-year period, thus providing additional evidence of alink between circulating vitamin E and insulin sensitiv-ity.4 Recent studies further support this connection. For

instance, Costacou et al.5 found a positive associationbetween plasma a-tocopherol levels and insulin sensitiv-ity in non-supplemented adults. In addition, Mayer-Daviset al.6 observed a protective effect of plasma a-tocopherollevels in preventing type 2 diabetes; however, in thisstudy, supplemental vitamin E conferred no additionalprotection beyond that observed from vitamin E derivedsolely from diet.

While there is strong evidence of a positive connec-tion between vitamin E and increased insulin sensitivity,several studies have found conflicting results. Sanchez-Lugo et al.7 failed to find an association between dietaryvitamin E intake and parameters of insulin sensitivity.Additionally, a placebo-controlled supplementation trialfollowing 38,716 initially healthy women over a 10-yearperiod found no difference in risk of developing T2DMbetween supplemented (alternate day 600 IU doses ofa-tocopherol) and placebo groups.8 Although a compre-hensive review of the literature connecting vitamin E andinsulin sensitivity is beyond the scope of this paper, thereports cited here provide an overview of the key findingsin the field to date, which have been discussed in greaterdetail by Bartlett and Eperjesi.9

Affiliations: B Gray, J Swick, and AG Ronnenberg are with the Department of Nutrition, University of Massachusetts, Amherst,Massachusetts, USA.

Correspondence: A Ronnenberg, 211 Chenoweth Laboratory, 100 Holdsworth Way, Amherst, MA 01003, USA. E-mail:alayne.ronnenberg@gmail.com, Phone: +1-413-545-1076, Fax: +1-413-545-1074.

Key words: adiponectin, insulin sensitivity, PPAR-gamma, vitamin E

Emerging Science

doi:10.1111/j.1753-4887.2011.00377.xNutrition Reviews® Vol. 69(3):155–161 155

While epidemiologic studies suggest that vitamin Estatus influences insulin sensitivity, its mechanism ofaction remains unclear. For many years, vitamin E hasbeen thought to exert insulin-sensitizing effects throughits antioxidant capacity.10–12 Oxidative stress has beenshown to alter cellular serine/threonine kinase pathways,specifically insulin receptor substrate-1, which becomesphosphorylated under oxidative conditions and dimin-ishes insulin signaling.13–15 Thus, it is conceivable thatantioxidant agents are capable of improving insulinsignaling.

More recently, however, research has implicateda-tocopherol in the direct regulation of gene expression.1

In fact, both a- and g-tocopherol have been shown toenhance PPARg expression in various cell types,11,16–18 andPPARg plays an important role in insulin sensitivity.Vitamin E may influence insulin sensitivity by regulatingan insulin-sensitizing protein. Emerging evidence sug-gests that adiponectin, an adipokine regulated by PPARg,may be one such protein.19

PPARg: regulation of adiponectin expression

Discovered in 1996, adiponectin was first identified as aprotein selectively produced by adipose tissue.20 Soonafter, an enzyme-linked immunosorbent assay wasdesigned to detect adiponectin levels in circulatingplasma.21 These same researchers found a negative corre-lation between adiponectin and BMI, which led to theidea that adiponectin secretion does not increase withaccumulated fat, but actually decreases.21 Several epide-miologic studies followed that examined associationsbetween adiponectin levels and chronic disease. Low adi-ponectin levels have subsequently been associated withincreased risk of cardiovascular disease,22 insulin resis-tance,23,24 hypertension25 and dyslipidemia.26

Thiazolidinediones (TZDs), a major class of insulin-sensitizing drugs, are synthetic PPARg ligands thatpromote the transcriptional activity of this nuclear recep-tor. PPARg has a wide range of functions, but for thepurpose of insulin sensitivity, it is known to promotelipogenesis and adipocyte differentiation and to reducethe level of circulating free fatty acids.27 In 2003, Iwakiet al.28 discovered that adiponectin expression wasinduced by nuclear receptors, specifically PPARg, andthey identified a PPARg response element (PPRE) in thepromoter region of the human adiponectin gene.

Around the same time, Combs et al.29 found thathuman subjects given rosiglitazone, a TZD, for 14 daysexperienced a 130% increase in circulating adiponectinlevels. In addition, ob/ob mice treated with a low dose ofthe TZD pioglitazone exhibited improved skeletalmuscle and liver insulin sensitivity, whereas adiponectinknockout ob/ob mice did not. Tripling the pioglitazone

dose ameliorated skeletal muscle insulin resistance inboth models yet still failed to decrease liver glucose pro-duction in the knockout model.30 These findings suggestthat TZDs can work through both adiponectin-dependent and -independent pathways to enhanceglucose tolerance.

Endogenous PPARg ligand: 15-deoxy-delta-12,14-prostaglandin J2

In search of natural PPARg ligands, Forman et al.31 exam-ined several arachidonate metabolites for their ability toenhance PPARg binding activity, and identified 15-deoxy-delta-12,14-prostaglandin J2 (15d-PGJ2) as one suchmetabolite. They found that 15d-PGJ2 uniquely activatesthe PPRE when PPARg and the 9-cis retinoic acid recep-tor are present, suggesting that their formation of a het-erodimer is essential for 15d-PGJ2 activity. The in vivoexistence of 15d-PGJ2 was confirmed by Hirata et al.32 in1988 using a specific enzyme immunoassay to detectlevels in urine. However, recent reports33–35 have sug-gested that 15d-PGJ2 may be a minor urinary metabolitethat is produced in vivo at levels too low to be biologicallysignificant.

All prostaglandin production begins with the cleav-age of arachidonic acid from phospholipids in the cellmembrane by A2 phospholipase (Figure 1). Cyclooxyge-nase then converts arachidonic acid into prostaglandinH2, which can be further metabolized into variousprostaglandins, including prostaglandin D2 (PGD2),depending on the cell type and the enzymes present.Although the mechanism is not fully understood, PGD2has been identified as the precursor prostaglandin for thesynthesis of 15d-PGJ2.32 The PPARg ligand activityof 15d-PGJ2 appears to possess an overall anti-inflammatory role in the body.36 Although it has beenestablished that 15d-PGJ2, like synthetic PPARg ago-nists,37 has adipogenic properties and can modulateglucose and lipid metabolism within the cell, it is veryprobable that 15d-PGJ2 exerts its effects through otherpathways, as it is known to bind to extracellular PGD2receptors, DP1 and DP2, which signal anti-inflammatoryand pro-inflammatory pathways, respectively.36 As notedin Figure 1, vitamin E acts in other ways to influencearachidonic acid metabolism,38,39 and its influenceappears to depend on tissue type.40

Adiponectin and insulin sensitivity

Recently, studies have begun to elucidate adiponectin’srole in various chronic diseases, especially diabetes.Receptors for adiponectin, AdipoR1 and AdipoR2, aremost abundantly expressed in liver and muscle tissue,respectively,41 suggesting that adiponectin targets these

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two tissues. In fact, adiponectin has been shown to stimu-late AMP-activated protein kinase, increasing fatty acidoxidation in skeletal muscle while inhibiting glucose pro-duction in the liver.42 Furthermore, Yamauchi et al.43

found that in lipoatrophic mice, which are characterizedby insulin resistance and hyperlipidemia, treatment withadiponectin significantly improved hyperglycemia, andadministration of adiponectin with leptin was more effec-tive than either treatment alone. In addition, Iwabu et al.44

found that in muscle cells, binding of adiponectin toAdipoR1 elicits an increase in intracellular calcium levelsthat activates calmodulin-dependent protein kinasekinase, AMP-activated protein kinase, and sirtuin-1, all ofwhich play roles in increasing the cell’s need for glucoseand thus enhance skeletal muscle glucose uptake. Thesefindings collectively support adiponectin’s insulin-sensitizing properties.

Interestingly,DL-a-tocopherol (a synthetic form) at aconcentration of 1 mmol/L has been shown to enhance

adiponectin mRNA expression in 3T3-L1 preadipocytes.45

In addition, obese rats treated with a-tocopherol(350 mg/kg DL- a-tocopherol acetate) had significantlyelevated adiponectin levels both in adipose tissue (mRNAand protein) and in circulation when compared withuntreated obese rats.46 These findings, and those pointingto PPARg as a potentiator of adiponectin expression,28,29

suggest a possible relationship between tocopherol intake,PPARg activity, and adiponectin levels and support thenotion that a-tocopherol’s action in enhancing adiponec-tin expression may be via upregulation of PPARg.

VITAMIN E AND ADIPONECTIN: RECENT FINDINGS

A recent study by Landrier et al.19 explored vitamin E’sinfluence on adiponectin synthesis and PPARg expressionand elucidated a potential mechanism through which a-and g-tocopherol may enhance adiponectin expression.

Figure 1 Illustration of prostaglandin J2 synthesis. Phospholipase A2 (PL A2) catalyzes hydrolytic release of arachidonic acid(AA) from membrane phospholipids. Cyclooxygenases (COX-1 and COX-2) catalyze oxidative conversion of AA to prostaglandinH2 (PGH2). PGD2 is generated by the action of hematopoietic and/or lipocaline PGD2 synthases (H-PGDS, L-PDGS); otherprostaglandin synthases produce PGI2, PGD2, PGE2, PGF2a, and thromboxanes (not shown). PGD2 undergoes chemicaldehydration, losing water to form the cyclopentenone prostaglandin PGJ2, which can undergo further conversion to PGJ2derivatives.

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Role of vitamin E in inducing adiponectin expressionthrough an antioxidant-independent mechanism

To test the hypothesis that supplementation withg-tocopherol induces adiponectin expression in vivo,Lan-drier et al.19 fed mice 4 mg g-tocopherol per day, whichthey equated to a human“supranutritional” dose of 70 mga-tocopherol equivalents per day. Both plasma adiponec-tin protein levels and epididymal fat pad adiponectinmRNA expression increased after 4 days’ treatment.

Although vitamin E has previously been thought toinfluence insulin sensitivity through its antioxidantcapacity,11 the findings by Landrier et al.19 suggest thatother mechanisms may also be involved. When 3T3-L1preadipocytes were treated with varying concentrationsof a- and g-tocopherol, both compounds significantlyand dose-dependently induced adiponectin expression(mRNA). However, neither N-acetylcysteine (NAC) norTrolox, which are known antioxidants, were effective atinducing adiponectin expression. These results indicatethat induction of adiponectin expression by a- andg-tocopherol is likely independent of their antioxidantcapacities.

Role of alpha- and gamma-tocopherol in inducingPPARg expression in vitro and in vivo

Since a- and g-tocopherol induce adiponectin expressionindependent of their antioxidant capacity, Landier et al.19

hypothesized that tocopherol induction of adiponectinexpression occurs through direct gene regulation. Asmentioned previously, PPARg plays an important role inenhancing insulin sensitivity, and the human adiponectinpromoter contains a PPRE.

Therefore, the researchers tested the effect of toco-pherol treatment on PPARg expression and foundincreased mRNA levels in vitro, using 3T3-L1 cells, and invivo, using epididymal fat pads of C57BL/6J mice.Tocopherol-mediated induction of PPARg could increasethe available amount of PPARg for binding to the PPRE inthe adiponectin promoter region. However, once bound,PPARg must be activated for transcription of the adi-ponectin gene product to occur.29 Thus, in addition tohaving increased levels of PPARg available for binding,ligand-dependent activation of PPARg must also occur toinduce transcription of PPARg-dependent target genes,such as adiponectin.

Figure 2 Model of a Two-Plasmid Transfection. Landrier et al.19 transfected COS 1 cells with two plasmids to determinewhether the PPRE was necessary for Vitamin E’s action. The first plasmid (left) constitutively expressed PPARy, while the second(right) contained the human adiponectin promoter region with either a functional or mutated PPRE. This second plasmid alsocontained a reporter gene, luciferase, to quantify transcription. In the presence of a functional PPRE, Vitamin E was able toenhance transcriptional activity of the second plasmid.

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Upregulation of adiponectin by a- and g-tocopherol ismediated through PPARg

To test whether the PPRE in the human adiponectin pro-moter region is essential for enhanced transcriptionalactivation by vitamin E, Landrier et al.19 designed a two-plasmid transfection. One plasmid constitutivelyexpressed PPARg, and the other contained the adiponec-tin promoter region linked to a luciferase reporter gene(Figure 2). In the presence of a- and g-tocopherol,luciferase reporter gene activity increased, indicating thatboth vitamers were able to enhance PPARg activity.However, when the PPRE was mutated, treatment withtocopherols did not increase luciferase activity, whichsuggests the PPRE is essential for tocopherol induction ofadiponectin but is not critical for basal expression ofadiponectin.

To obtain additional evidence that tocopherol’saction is PPARg-mediated, Landrier et al.19 measured adi-ponectin levels (mRNA and media protein concentra-tion) in 3T3-L1 cells in the presence or absence of aknown PPARg antagonist, GW9662. With no antagonistpresent, both a- and g-tocopherol increased adiponectinexpression and concentration; however, in the presenceof GW9662, the vitamers had no enhancing effect.Although this observation suggests tocopherol’s activityrequires ligand binding to PPARg, it does not establishthat tocopherols are ligands for PPARg.

To determine if tocopherol binds to PPARg, Landrieret al.19 implemented a second two-plasmid transfection in

which the first plasmid produced a chimeric protein con-taining the ligand-binding domain of PPARg and aGAL4-binding site, allowing it to bind to the secondplasmid and report activity via luciferase expression.(This chimera design was first used by Forman et al.31 inthe identification of 15d-PGJ2 as an endogenous ligand.)Increasing concentrations of tocopherols did not increaseluciferase activity but the addition of a known PPARgagonist, GW347875, did. This finding indicates that toco-pherols do not have the same ligand-binding activity asthe known agonist and, therefore, most likely do not binddirectly to PPARg. Instead, tocopherols appear to exerttheir adiponectin-enhancing activity through anothermechanism. Landrier et al.19 further determined that inthe presence of a- and g-tocopherol, 3T3-L1 cellsexpressed increased amounts of 15d-PGJ2 in cell culturemedia. Taken together, these results suggest that vitaminE induces adiponectin expression indirectly throughupregulation of PPARg expression as well as increased15d-PGJ2 levels; these two elements appear to work syn-ergistically to enhance adiponectin expression (Figure 3).

CONCLUSION

The work by Landrier et al.19 brings us one step closer tounderstanding the mechanisms through which vitamin Emay exert its positive influence on insulin sensitivity.These findings suggest that vitamin E, at slightly supra-dietary doses, enhances adiponectin expression throughupregulation of PPARg and its endogenous ligand, 15d-

Figure 3 A model of vitamin E-induced adiponectin synthesis. Vitamin E may induce adiponectin synthesis byup-regulating expression of PPARg and its endogenous ligand, 15d-PGJ2.

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PGJ2. Interestingly, in a recent small study involving 40young healthy male participants, Ristow et al.47 showedthat vitamin E and vitamin C supplementation abolishedexercise-induced insulin sensitivity, and more specifi-cally, prevented exercise-induced increases in plasma adi-ponectin levels and PPARg mRNA. These findings appearto contradict the ideas that antioxidants improve insulinsignaling and that vitamin E enhances PPARg activity andthus adiponectin expression. However, a more likelyexplanation of the findings of Ristow et al.47 is that acutebouts of oxidative stress, resulting from exercise, affectinsulin sensitivity very differently than does the chronicoxidative stress characteristic of diabetic patients. Theirfindings also suggest that vitamin E’s role in insulin sen-sitivity likely includes both antioxidant-dependent and-independent actions. Given the complexity of theseobservations, additional in vivo studies are warranted.Particular emphasis should be placed on studies thatassess the binding affinity of a- and g-tocopherol forPPARg in vivo and the ability of a- and g-tocopherol toinduce expression of 15d-PGJ2, whose biological signifi-cance remains poorly understood. Nonetheless, the find-ings presented here underscore the importance of dietaryvitamin E and provide intriguing evidence suggestingthat vitamin E may have potential as a therapeutic agentfor type 2 diabetes.

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