Clinical Study Metabolic Risk Susceptibility in Men Is Partially Related to Adiponectin/Leptin Ratio

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1 Journl of Obesity Volume 213, Article ID 49679, 9 pges Clinicl Study Metbolic Risk Susceptibility in Men Is Prtilly Relted to Adiponectin/Leptin Rtio Glori Len Veg nd Scott M. Grundy Center for Humn Nutrition nd Deprtments of Clinicl Nutrition, Internl Medicine nd The Metbolic Unit of the Veterns Administrtion North Helth Science Center t Dlls, 5323 Hrry Hines Boulevrd, Dlls, TX , USA Correspondence should be ddressed to Glori Len Veg; glori.veg@utsouthwestern.edu nd Scott M. Grundy; scott.grundy@utsouthwestern.edu Received 5 December 212; Revised 1 Februry 213; Accepted 1 Februry 213 Acdemic Editor: Anne E. Sumner Copyright 213 G. L. Veg nd S. M. Grundy. This is n open ccess rticle distributed under the Cretive Commons Attribution License, which permits unrestricted use, distribution, nd reproduction in ny medium, provided the originl work is properly cited. Bckground. High diponectin/leptin rtio my be protective from metbolic risks imprted by high triglyceride, low HDL, nd insulin resistnce. Methods. This cross-sectionl study exmines plsm dipokine levels in 428 dult men who were subgrouped ccording to low (<6.5 μg/ml)nd high ( 6.5 μg/ml)diponectin levels or low or high rtio of diponectin/leptin. Results.Men with high diponectin/leptin rtio hd lower plsm triglyceride nd higher HDL cholesterol thn those with low rtio. Similrly, those with high diponectin/leptin rtio hd lower TG/HDL cholesterol rtio nd HOMA2-IR thn those with low rtio. In contrst, levels of diponectin or the rtio of diponectin/leptin did not ssocite with systolic blood pressure. But the rtio of diponectin/leptin decresed progressively with the increse in the number of risk fctors for metbolic syndrome. Conclusion. Adipokine levels my reflect dipose tissue triglyceride storge cpcity nd insulin sensitivity. Leptin is n index of ft mss, nd diponectin is biomrker of triglyceride metbolism nd insulin sensitivity. Men with high diponectin/leptin rtios hve better triglyceride profile nd insulin sensitivity thn men with low rtio regrdless of wist girth. 1. Introduction Excess bdominl body ft is implicted in the etiology of the metbolic syndrome, cluster of risk fctors for crdiovsculr disese nd for type 2 dibetes mellitus. The risk fctors include dyslipidemi (high triglyceride nd/or low HDL cholesterol), insulin resistnce, nd hypertension [1]. Abdominl obesity is ssessed by wist girth, nd severl cut points of high-risk wist girth hve been recommended to identify t-risk individuls bsed on gender nd ethnicity [2]. Reching consensus on sex-specific, globl definition of high-risk wist girth hs proved to be chllenging [3]. However, globl cut point my be imprcticl becuse individuls vry in susceptibility to obesity-induced risk for metbolic syndrome. An lterntive to using wist girth is to identify biomrkers tht re cuslly relted to the metbolic risks nd tht reflect function of dipose tissue. Two dipokines, leptin nd diponectin, my be risk mrkers of ft-induced dyslipidemi nd insulin resistnce. Both dipokines re reportedly ssocited with risk for type 2 dibetes nd with crdiovsculr disese. Plsm levels of leptin correlte positively with totl body ft [4 6] ndwith dipocyte number in men [7]. In ddition, individuls t high risk seemingly hve high levels of plsm leptin [8]. The levels re directly proportionl to secretion rtes of the dipokine by dipose tissue [9], which is primrilyproduced in subcutneous tissue [1]. Adiponectin, in turn, is n insulin-sensitizing dipokine s well s n nti-inflmmtory nd ntitherogenic hormone. In obese subjects, levels of plsm diponectin re reduced suggesting n bnormlity in dipose tissue function. Furthermore, muttions in the gene encoding for diponectin re ssocited with type 2 dibetes mellitus nd fetures of metbolic syndrome including hypertension, dyslipidemi, nd therosclerosis [11]. It is still uncler whether diponectin production differs between subcutneous nd viscerl dipose tissue. However, it hs been suggested tht diponectin levels in plsm re inversely

2 2 Journl of Obesity Tble 1: Subject demogrphy nd bseline chrcteristics. Nonobese Overweight Obese Wist girth ctegory <9cm 9 11cm cm Number of men (% of totl) 55 (13) 147 (34) 226 (53) Age (±SD) (yers) 53. (8.9) 54.1 (1.2) 55.4 (9.6) Body mss index (kg/m 2 ) 24.1 (2.3) 27.9 (2.5) b 33.6 (4.1) Wist girth (cm) 85.3 (3.6) 95.9 (2.9) b (9.3) Systolic blood pressure (Hg mm) (17.9) c (16.7) (16.7) Distolic blood pressure (Hg mm) 79.1 (12.9) c 82.3 (9.7) 83. (8.9) Hemoglobin A1c (%), Medin (IQ) 5.4 (.4) 5.4 (.5) 5.5 (.6) Glucose (mg/dl) 93.3 (9.3) d 94.9 (1.) 97. (11.3) HOMA2-IR medin (IQ) 1.16 (.98) 1.57 (.77) 2.13 (1.53) HOMA2%β, medin (IQ) 97.5 (51.9) (47.4) (7.6) HOMA2%S, medin (IQ) 86.5 (11.7) 63.7 (33.3) b 46.9 (36.4) Adiponectin μg/ml, medin (IQ) 8.9 (87.6) c 7.7 (4.8) 7.5 (4.7) Leptin ng/ml, medin (IQ) 2.3 (2.2) 5.2 (3.9) b 1.4 (7.5) Triglyceride, medin (IQ) 11 (68) 153 (14) b 186 (92) HDL cholesterol mg/dl 47 (15) 39 (15) b 37 (9) Non-HDL cholesterol mg/dl 147 (44) 166 (43) 165 (47) Totl Apo B mg/dl 116 (29) 126 (28) b 129 (26) Hypertension (%) Smokers (%) Significntly different from non-obese nd overweight (P <.2); b significntly different from non-obese (P <.2); c significntly different from overweight nd from obese (P <.2); d significntly different from obese (P <.2); IQ: interqurtile. correlted with viscerl diposity [12] nd re positively correlted with lower extremity ft [13]. In the current study, levels of plsm diponectin nd leptin were exmined in men with vrying degrees of obesity tht hd mrked interindividul vrition in plsm triglycerides nd insulin sensitivity. The question ddressed ws whether diponectin lone or in combintion with leptin hd n effect on dyslipidemi nd insulin resistnce. 2. Mterils nd Methods Four hundred nd seventy-two dult men from the Veterns Affirs Medicl Center (VAMC) t Dlls were recruited into cross-sectionl study designed to quntify risk fctors forcrdiovsculrdisese[14]. Severl individuls tht were enrolledhdstblehypertension,few(9%oftotl)lso hd type 2 dibetes mellitus treted with hypoglycemic gents consisting mostly of metformin nd/or glyburide, nd very few subjects (4%) hd history of coronry hert disese (CHD). For the current nlyses, men with type 2 dibetes mellitus were excluded. Dt from 428 subjects ws nlyzed, nd summries re shown in Tble 1 nd Figures 2, 3,nd4. The rcil composition of enrolled individuls ws representtive of reserch prticipnts t the VAMC; tht is, 72% were non-hispnic White, 21% were non-hispnic Blck, 6% were Hispnic, nd 1% comprised other groups. Subjects were seen in the clinicl reserch unit, nd they hd clinicl ssessment nd nthropometry. Fsting blood ws drwn for mesurement of plsm lipids, lipoproteins, glucose, hemoglobin A1c, polipoprotein B, nd dipokines. All study volunteers gve written informed consent to prticipte in the study tht hd been pproved by the Institutionl Reserch Bord for Investigtion in Humns. 3. Lbortory Mesurements Plsm totl cholesterol, triglyceride, lipoprotein cholesterol, nd polipoprotein B were mesured s previously described [14]. Levels of plsm insulin, leptin, nd totl diponectin were mesured by rdioimmunossy s detiled before [15]. 4. Biosttistics Dt re summrized s mens + SD or medins (interqurtiles (IQ)), nd comprisons of mens were done by nlysis of vrince (ANOVA) with the Bonferroni djustments for multiplicity of testing s needed. Some vribles were positively skewed nd were log trnsformed before prmetric nlyses (triglyceride, leptin, diponectin, nd HOMA2-IR). The Kruskl-Wllis rnk test ws crried out for comprisons of men rnk diponectin/leptin rtios s function of number of risk fctors for metbolic syndrome. Adiponectin nd the rtio of diponectin to leptin were lso employed to crete dichotomous groups of insulin resistnce nd dyslipidemi risk fctors. The cut points were the medin for diponectin s previously detiled [13] nd the medin for the diponectin/leptin rtios for ech wist girth ctegory. Accordingly, wist girth ctegory <9cm hd medin rtio of 3.7, wist girth 9 11 cm hd medin rtio of 1.39, nd wist girth >9 cm ctegory hd medin rtio of.69. An SAS

3 Journl of Obesity Leptin (ng/ml) Wist girth (cm) () Wist girth (cm) (b) Figure 1: Scttered plots of leptin () nd diponectin (b) s function of wist girth. There ws trend for liner ssocition of leptin to wist girth (R 2 =.56; P <.1). Subjects with wist girths below 9 cm consistently hd the lowest leptin levels. More interindividul vritions were noted in the leptin levels of subjects in wist girth in the rnge of 9 to 11 cm. In contrst to leptin, diponectin ws not linerly ssocited with wist girth (b). There ws striking interindividul vrition in diponectin levels t ech wist girth subctegory, tht is, nonobese, overweight, nd obese. version of Stt View ws employed. HOMA2-IR clcultor described by Levy et l. [16]wsused. ws high mong the three subgroups; smoking prevlence ws reltively low (Tble 1). 5. Results 5.1. Chrcteristics of Study Subgroups. Men were subgrouped ccording to wist girth becuse this nthropometric mesure is recommended for ssessment of metbolic risk imprted by centrl obesity [1 3]. The wist girth cut points coincide with BMI cut points for nonobese (BMI <25 kg/m 2 or wist girth <9 cm), overweight (BMI 25 to 29.9 kg/m 2 or wist girth 9 to 11 cm), nd obese men (BMI 3 kg/m 2 or wist girth cm) [17]. Accordingly, 13% of the men were nonobese, 34% were overweight, nd 53% were obese. The men were of similr ge cross the wist girth subgroups (Tble 1). Severl mesures of insulin resistnce were different mong the subgroups. First, overweight nd obese men hd higher fsting glucose concentrtions nd tended to be more insulin resistnt compred to the nonobese group s shown by the HOMA2-IR levels (Tble 1). Overweight nd obese men hd lower insulin sensitivity (HOMA2%S) compred with nonobese, but there were no significnt differences in the stedy-stte bet-cell function estimted by HOMA2%β. Levels of hemoglobin A1c were similr mong the subgroups. Overweight nd obese men hd higher triglyceride levels, reduced HDL cholesterol, nd incresed polipoprotein B levels. However, levels of non-hdl cholesterol (i.e., VLDL + LDL) were not significntly different. Nonobese men hd lower blood pressure thn overweight or obese men. The prevlence of hypertension ( 13/85 Hgmm or stble on ntihypertensive mediction) 5.2. Interindividul Vrition in Adipokines. Scttered plots of leptin versus wist girth (Figure 1()) nd diponectin versus wist girth (Figure 1(b)) were exmined. There ws liner ssocition of leptin to wist girth (Ln leptin = (wist girth); R 2 =.56; P <.1). Len men consistently hd the lowest leptin levels (<5ng/mL). More interindividul vritions were noted in the leptin levels of overweight nd obese men. In contrst to leptin, diponectin ws not linerly ssocited with wist girth (Figure 1(b)). Insted, there ws striking interindividul vrition in diponectin levels rnging from very low to high levels t ech wist girth subctegory (nonobese, overweight, nd obese individuls) Adipokine Rtios nd Metbolic Risk Fctors. Levels of plsm triglyceride, HDL cholesterol, rtio of triglyceride/hdl cholesterol (C), HOMA2-IR, nd systolic blood pressure were exmined ccording to cut-off points for diponectin (<6.5 ng/ml designted s low levels of diponectin nd 6.5 ng/ml designted s high levels) nd ccording to diponectin/leptin ctegories. The cut-off point for the rtio of diponectin/leptin ws the medin rtio for ech wist girth ctegory s indicted in the sttisticl section. Levels of plsm triglyceride in nonobese, overweight, nd obese men grouped ccording to low or high diponectin levels were compred (Figure 2()). Overweight men with high diponectin levels hd significntly lower levels of plsm triglyceride ( P <.2) compred with those men with

4 4 Journl of Obesity 25 Triglyceride (mg/dl) Triglyceride (mg/dl) Wist girth (cm) < Wist girth (cm) Adiponectin/leptin rtio Low High () (b) 6 6 HDL C (mg/dl) HDL C (mg/dl) Wist girth (cm) <6.5 2 Wist girth (cm) Adiponectin/leptin rtio Low 6.5 High (c) (d) Figure 2: Levels of plsm triglyceride in nonobese (wist girth <9 cm), overweight (wist girth 9 to 11 cm), nd obese ( cm) grouped ccording to low (<6.5 ng/ml) or high ( 6.5 ng/ml) diponectin. Overweight men with high diponectin levels hve significntly ( P <.2) lower levels of plsm triglyceride compred with those with low diponectin levels (). However, fter djustment of diponectin levels for leptin (rtio of diponectin/leptin), levels of plsm triglycerides were significntly ( P <.2) lower in those with high rtio of diponectin/leptin, regrdless of wist ctegory (nonobese, overweight, or obese) (b). Similr nlyses re shown for HDL C. Levels of plsm HDL C were significntly ( P <.2) higher in overweight nd obese men hving high diponectin level (c). However, HDL cholesterol levels were significntly higher ( P <.2) in nonobese men fter grouping the subjects ccording to low or high rtio of diponectin/leptin (d). low diponectin levels. Levels of plsm triglyceride for ech obesity ctegory lso were compred between men with low or high rtios of diponectin/leptin (Figure 2(b)). Levels of plsm triglycerides were significntly lower ( P <.2) in individuls with high rtio of diponectin/leptin, regrdless of wist ctegory (nonobese, overweight, or obese). HDL cholesterol (C) levels were significntly higher in overweight nd obese men ( P <.2) ththdhighlevel of diponectin compred with those tht hd low level of (Figure 2(c)). However, HDL cholesterol levels were significntly higher in nonobese men ( P <.2)ftergroupingthe subjects ccording to low or high rtio of diponectin/leptin (Figure 2(d)). Rtio of triglyceride/hdl cholesterol (C) ws lower in nonobese ( b P<.5)ndoverweight( P <.2)menwhohd high level of plsm diponectin (Figure 3()). In contrst, the rtio of plsm triglyceride/hdl C ws lower ( P<.2) in nonobese, overweight, nd obese subjects with high rtio

5 Journl of Obesity Triglyceride/HDL C rtio b Triglyceride/HDL C rtio b Wist girth (cm) < Wist girth (cm) Adiponectin/leptin rtio Low High () (b) 4 4 HOMA2-IR (medin) HOMA2-IR (medin) Wist girth (cm) <6.5 Wist girth (cm) Adiponectin/leptin rtio Low 6.5 High (c) (d) Figure 3: Rtio of triglyceride to HDL cholesterol (C) is lower in nonobese ( b P <.5) nd overweight ( P <.2) men who hve high level of plsm diponectin (). In contrst, the rtio of plsm triglyceride to HDL C is lower in nonobese, overweight, nd obese subjects with high rtio of diponectin/leptin compred to those with low rtio of diponectin to leptin (b). HOMA2-IR levels re significntly higher ( P <.2) in overweight nd obese men with high level of diponectin compred with those with low level of diponectin (c). However, the HOMA2-IR levels re significntly lower in nonobese, overweight, nd obese men who hve high rtio of diponectin to leptin compred withthoseththvelowrtio(d). of diponectin/leptin compred to those with low rtio of diponectin/leptin (Figure 3(b)). HOMA2-IR levels re significntly higher ( P <.2) in overweight nd obese men with high level of diponectin compred with those with low level of diponectin (Figure 3()). However, the HOMA2-IR levels re significntly lower in nonobese, overweight, nd obese men who hd high rtio of diponectin/leptin compred with those tht hve low rtio (Figure 3(b)). Systolic blood pressure in nonobese, overweight, nd obese men ws similr in those with low nd those with high level of diponectin (Figure 4())ndinthosewithhighor low rtio of diponectin/leptin (Figure 4(b)). The rtio of diponectin/leptin in subjects with nd without risks for metbolic syndrome tht excluded wist girth ws lso exmined using the Kruskl-Wllis rnk test (Figure 5). Subjects with 1risk fctors hve lower rtio thn those without ny risk fctor. In ddition, men with 2 risk fctors hve significntly lower rtio thn those with 1risk,ndthosewith 3 risks hve significntly lower rtio thn those with 1 or 2 risks.

6 6 Journl of Obesity Systolic blood pressure (mmhg) Systolic blood pressure (mmhg) Wist girth (cm) <6.5 9 Wist girth (cm) Adiponectin/leptin rtio Low High 6.5 () (b) Figure 4: Systolic blood pressure in nonobese, overweight, nd obese men ws similr in those with low nd those with high level of diponectin (). There were no significnt differences in systolic blood pressure when the men were subgrouped ccording to the rtio of diponectin/leptin (b). 6. Discussion This study exmined the reltion of diponectin levels lone or normlized by leptin to metbolic risk fctors for crdiovsculr disese including mrkers of therogenic dyslipidemi (levels of plsm triglyceride nd HDL cholesterol nd rtios of plsm triglyceride/hdl cholesterol) nd insulin resistnce (levels of HOMA2-IR) in men. The key observtions mde in this study were tht high levels of diponectin were ssocited with lower plsm triglycerides, higher HDL cholesterol, reduced rtios of triglyceride/hdl cholesterol, nd reduced HOMA2-IR compred to lower levels of diponectin in men regrdless of wist girth. Normlizing diponectin levels by leptin enhnced the ssocitions of diponectin to the metbolic risk fctors. Tht is, subjects with high rtio of diponectin/leptin hd lower triglycerides nd triglyceride/hdl cholesterol rtios nd higher HDL cholesterol nd insulin sensitivity thn those with low rtios of diponectin/leptin regrdless of wist girth. Thus, the diponectin/leptin rtio ws useful index for identifiction of overweight nd obese subjects with lower susceptibility to metbolic risk compred to individuls with higher susceptibility. Both diponectin nd leptin hve been implicted in the custion of dyslipidemi nd insulin resistnce. For exmple, leptin deficiency is ssocited with hypertriglyceridemi, low HDL C, nd low insulin sensitivity in cses of cquired or congenitl lipodystrophies [18]; leptin therpy reverses the metbolic dysfunction [19].But in obese subjects,leptin does not hve n effect [2]. Insted, leptin correltes with ft mss nd it cn be viewed s biomrker of ft cell mss. Plsm levels of leptin generlly reflect secretion rtes by subcutneous dipose tissue, principlly by lrge dipocytes [9]. Omentl ft lso secretes leptin, but the subcutneous ft is thought to be mjor source of leptin. This hormone is known to modulte energy homeostsis through its ction on hypothlmic receptors where it inhibits ppetite [21]. Muttions in the humn leptin gene re ssocited with hypogondism nd morbid obesity [22], nd muttions in the humn leptin receptor gene cuses obesity nd pituitry dysfunction [23]. Leptin replcement in obese subjects with leptin deficiency reverses the metbolic consequences of the deficiency in the hypothlmus [24]. In the current study, the liner ssocition between plsm levels of leptin nd wist girth provided rtionle for using leptin s surrogte of ft mss. Moreover, overweight ndobesemenshowedconsiderbleinterindividulvrition in leptin levels despite the high correltion with wist girth. The interindividul vrition lso suggested tht leptin levels re probbly more specific mesure of ft mss thn wist girth. For these resons, leptin ws used to normlize levels of diponectin. In contrst to leptin levels, plsm levels of diponectin were not strongly correlted with wist girth. Others hve shownninversessocitionofdiponectinwithtotlbody ft [25]. However, the current study popultion showed mrked heterogeneity in plsm diponectin level nd this proved to be instructive. At ny wist girth ctegory, it ws cler tht there were men with high nd low diponectin levels. Thus, two questions could be ddressed redily: (1) re there differences in levels of metbolic risk fctors between men with high nd low diponectin levels regrdless of wist girth? (2) If diponectin levels re normlized for leptin levels, re the differences in metbolic risk fctors better defined by the rtio of diponectin/leptin thn diponectin lone? The levels of plsm triglyceride were lower in men with high diponectin thn in those with low diponectin.

7 Journl of Obesity 7 In contrst, HDL C, levels were higher in men who hd high diponectin compred with those with low diponectin. Similrly, low rtios of plsm triglyceride/hdl C were lower in men with high diponectin compred with those with low diponectin. After normlizing diponectin levels by leptin, the impct of the rtio of diponectin/leptin on triglyceride, HDL C, nd the rtio of triglyceride to HDL C ws more pprent. The rtio segregted overweight nd obese subjects into those with reltively helthier metbolic profile nd those with higher-risk profile. Still the verge plsm triglyceride levels of overweight nd obese men with high rtio of diponectin/leptin were somewht higher thn the cut point of t-risk triglyceride (15 mg/dl). Perhps higher diponectin/leptin rtio is needed to optimize triglyceride levels. In contrst to leptin, diponectin levels my be indictive of protective effect of the dipokine on triglyceride metbolism even in the presence of excess body ft. Studies in nimls suggest tht diponectin reduces levels of plsm triglyceride by incresing VLDL-triglyceride hydrolysis medited by lipoprotein lipse [26]. Trnsgenic mice overexpressing diponectin show reduction in plsm triglycerides compred to wildtype [27 29] while diponectinknockoutmicehveincresedplsmtriglycerides. These dt suggest tht diponectin hs direct effect on triglyceride hydrolysis [3]. Other studies lso suggest tht diponectin is n insulin sensitizer nd it could exert hypotriglyceridemic effect under such conditions. The ssocition of diponectin with HDL cholesterol my result from its hypotriglyceridemiceffectoritcouldbetheresultoftheeffect of diponectin on either po A-I frctionl ctbolic rte [31, 32] or direct effect of diponectin on heptic lipse [33, 34]. In the current study, high diponectin levels lso were generlly ssocited with higher insulin sensitivity mesured by HOMA2-IR thn low diponectin levels. This effect is supportive of the view tht diponectin is n insulin sensitizer [35, 36].Assuchthedipokinecnmodultethemetbolism of triglycerides, HDL, nd glucose. The exct mechnisms of the insulin sensitizing effect of diponectin re not clerly understood. But in this study, it ws cler tht diponectin nd, more specificlly, the rtio of diponectin/leptin were good indictor of insulin sensitivity in overweight nd obese men. The diponectin/leptin rtio lso ws shown to decrese with the incresing number of metbolic risk fctors for crdiovsculr disese (Figure 5). This rtio my be useful to identify subjects susceptible to metbolic risk, nd diponectin/leptin rtios my reflect the functionlity of dipose tissue. Accordingly, two metbolic phenotypes were identified in overweight nd obese subjects in the current study. It hs been suggested tht subjects re heterogeneous in the prevlence of metbolic risk fctors. Some nonobese subjects hve metbolic obesity [37]. Other investigtors hve identified obese subjects with low prevlence of metbolic ltertions which they hve designted s metboliclly helthy or unhelthy [38 4]. In the current study, the individuls with the high rtio of diponectin/leptin hd less dyslipidemi nd insulin resistnce thn those with the low rtio, but they were not free of other risk fctors. The rtio, Adiponectin/leptin rtio P < Number of risk fctors Figure 5: Plot of rtios of diponectin/leptin versus number of risk fctors. Subjects with 1 risk fctors hve lower rtio thn those without ny risk fctor. In ddition, men with 2 risk fctors hve significntly lower rtio thn those with 1 risk, nd those with 3 risks hve significntly lower rtio thn those with 1 or 2 risks. however, suggested tht diponectin levels reltive to leptin my be indices of susceptibility to metbolic risk. 7. Conclusion The current study shows tht overweight nd obese individuls with high rtio of diponectin/leptin hve lower levels of plsm triglyceride, triglyceride/hdl C rtios nd higher insulin sensitivity thn those with lower diponectin/leptin rtios.itisverylikelythtdiponectincontributestothe regultion of plsm triglyceride levels. The dt lso suggests tht interindividul vrition in dyslipidemi nd insulin sensitivity is ssocited with the rtio of the dipokines. The study provides supportive evidence for the contention tht some overweight nd obese subjects hve better dipokine profile thn others nd tht metbolic heterogeneity mong overweight nd obese subjects my depend on the bility of dipocytes to mintin secretion of the dipokines s the cells become filled with triglyceride. Conflict of Interests The uthors hve no conflict of interests to report for the submitted pper. Acknowledgments The uthors express their pprecition to Lur Cldwell, PAC; Regin Strowd, RN, nd her clinicl stff; Rit Nemons, RN, nd the stff of the Clinicl Reserch Unit nd Reserch Service of the Veterns Administrtion North Helth Center t Dlls. The work of Bimn Prmnik, Anh Nguyen, nd the reserch stff t the Center for Humn Nutrition nd the Nutrition nd Metbolism Lbortory is lso gretly pprecited.

8 8 Journl of Obesity References [1] Ntionl Cholesterol Eduction Progrm (NCEP) Expert Pnel on Detection, Evlution, nd tretment of high blood cholesterol in dults (Adult Tretment Pnel III). Third report of the ntionl cholesterol eduction progrm (NCEP) expert pnel on detection, evlution, nd tretment of high blood cholesterol in dults (Adult Tretment Pnel III) finl report, Circultion,vol.16,pp ,22. [2]Alberti,R.H.Eckel,S.M.Grundyetl., Hrmonizingthe metbolic syndrome: joint interim sttement of the interntionl dibetes federtion tsk force on epidemiology nd prevention; Ntionl hert, lung, nd blood institute; Americn hert ssocition; World hert federtion; Interntionl therosclerosis society; And interntionl ssocition for the study of obesity, Circultion, vol. 12, no. 16, pp , 29. [3] A. J. Cmeron, R. A. Sicree, P. Z. Zimmet et l., Cut-points for wist circumference in Europids nd South Asins, Obesity, vol. 18, no. 1, pp , 21. [4] R. V. Considine, M. K. Sinh, M. L. Heimn et l., Serum immunorective-leptin concentrtions in norml-weight nd obese humns, The New Englnd Journl of Medicine,vol.334, no. 5, pp , [5] C. E. Ruhl, J. E. Everhrt, J. Ding et l., Serum leptin concentrtions nd body dipose mesures in older blck nd white dults, Americn Journl of Clinicl Nutrition,vol.8,no.3,pp , 24. [6] Mpfei, Hls, Rvussin et l., Leptin levels in humn nd rodent: mesurement of plsm leptin nd ob RNA in obese nd weight-reduced subjects, Nture Medicine,vol.1,no.11,pp , [7] C. Couillrd, P. Muriège,P.Imbeult,D.Prud homme,a. Ndeu, nd A. Trembly, Hyperleptinemi is more closely ssocited with dipose cell hypertrophy thn with dipose tissue hyperplsi, Interntionl Journl of Obesity, vol. 24, no. 6, pp , 2. [8] Lilj, Rolndsson, Shw et l., Higher leptin levels in Asin Indins thn Creoles nd Europids: potentil explntion for incresed metbolic risk, Interntionl Journl of Obesity, vol. 34, no. 5, pp , 21. [9] Klein, Coppck, Mohmed-Ali, nd Lndt, Adipose tissue leptin production nd plsm leptin kinetics in humns, Dibetes, vol. 45, no. 3, pp , [1] V. Vn Hrmelen, S. Reynisdottir, P. Eriksson et l., Leptin secretion from subcutneous nd viscerl dipose tissue in women, Dibetes, vol. 47, no. 6, pp , [11] H. Kondo, L. Shimomur, Y. Mtsukw et l., Assocition of diponectin muttion with type 2 dibetes: cndidte gene for the insulin resistnce syndrome, Dibetes,vol.51,no.7,pp , 22. [12] Y. Mtsuzw, T. Funhshi, S. Kihr, nd I. Shimomur, Adiponectin nd metbolic syndrome, Arteriosclerosis, Thrombosis, nd Vsculr Biology, vol.24,no.1,pp.29 33, 24. [13] A.T.Turer,A.Kher,C.R.Ayersetl., Adiposetissuemssnd loction ffect circulting diponectin levels, Dibetologi,vol. 54, no. 1, pp , 211. [14] J. J. Clrenbch, S. M. Grundy, N. Plcio, nd G. L. Veg, Reltionship of polipoprotein B levels to the number of risk fctors for metbolic syndrome, Journl of Investigtive Medicine,vol.55,no.5,pp ,27. [15] G. L. Veg, M. Chndli, L. S. Szczepnik, nd S. M. Grundy, Metbolic correltes of nonlcoholic ftty liver in women nd men, Heptology, vol. 46, no. 3, pp , 27. [16]J.C.Levy,D.R.Mtthews,ndM.P.Hermns, Correct homeostsis model ssessment (HOMA) evlution uses the computer progrm, Dibetes Cre, vol. 21, no. 12, pp , [17] S. Zhu, S. B. Heymsfield, H. Toyoshim, Z. Wng, A. Pietrobelli, nd S. Heshk, Rce-ethnicity-specific wist circumference cutoffs for identifying crdiovsculr disese risk fctors, Americn Journl of Clinicl Nutrition, vol.81,no.2,pp , 25. [18] J.Y.Prk,A.Y.Chong,E.K.Cochrnetl., Type1dibetes ssocited with cquired generlized lipodystrophy nd insulin resistnce: the effect of long-term leptin therpy, Journl of Clinicl Endocrinology nd Metbolism,vol.93,no.1,pp.26 31, 28. [19] E. A. Orl, V. Simh, E. Ruiz et l., Leptin-replcement therpy for lipodystrophy, The New Englnd Journl of Medicine, vol. 346, no. 8, pp , 22. [2]P.M.Zelissen,K.Stenlof,M.E.Lenetl., Effectofthree tretment schedules of recombinnt methionyl humn leptin on body weight in obese dults: rndomized, plcebo-controlled tril, Dibetes, Obesity nd Metbolism, vol.7,no.6,pp , 25. [21] C. S. Mntzoros, F. Mgkos, M. Brinkoetter et l., Leptin in humn physiology nd pthophysiology, Americn Journl of Physiology,vol.31,no.4,pp.E567 E584,211. [22] A. Strobel, T. Issd, L. Cmoin, M. Ozt, nd D. Strosberg, A leptin missense muttion ssocited with hypogondism nd morbid obesity, Nture Genetics,vol.18,no.3,pp ,1998. [23] K. Clément, C. Visse, N. Lhlou et l., A muttion in the humn leptin receptor gene cuses obesity nd pituitry dysfunction, Nture, vol. 392, no. 6674, pp , [24] I. S. Frooqi, S. A. Jebb, G. Lngmck et l., Effects of recombinnt leptin therpy in child with congenitl leptin deficiency, The New Englnd Journl of Medicine, vol. 341, no. 12, pp , [25] A. S. Ryn, D. M. Bermn, B. J. Nickls et l., Plsm diponectin nd leptin levels, body composition, nd glucose utiliztion in dult women with wide rnges of ge nd obesity, Dibetes Cre, vol. 26, no. 8, pp , 23. [26] L. Qio, C. Zou, D. R. vn der Westhuyzen, nd J. Sho, Adiponectin reduces plsm triglyceride by incresing VLDL triglyceride ctbolism, Dibetes, vol.57,no.7,pp , 28. [27] T. P. Combs, U. B. Pjvni, A. H. Berg et l., A trnsgenic mouse with deletion in the collgenous domin of diponectin displys elevted circulting diponectin nd improved insulin sensitivity, Endocrinology, vol. 145, pp , 24. [28] T. Ymuchi, J. Kmon, H. Wki et l., Globulr diponectin protected ob/ob mice from dibetes nd ApoE-deficient mice from therosclerosis, TheJournlofBiologiclChemistry, vol. 278,no.4,pp ,23. [29] I. B. Buche, S. A. El Mkdem, A. Pottier et l., Overexpression of diponectin trgeted to dipose tissue in trnsgenic mice: impired dipocyte differentition, Endocrinology,vol.148,no. 4, pp , 27. [3] R. Brtt, S. Amto, C. Degno et l., Adiponectin reltionship with lipid metbolism is independent of body ft mss: evidence from both cross-sectionl nd intervention studies, Journl of

9 Journl of Obesity 9 Clinicl Endocrinology nd Metbolism,vol.89,no.6,pp , 24. [31] B. Vergès,J.M.Petit,L.Duvillrdetl., Adiponectinisn importnt determinnt of ApoA-I ctbolism, Arteriosclerosis, Thrombosis, nd Vsculr Biology,vol.26,no.6,pp , 26. [32]D.C.Chn,P.H.R.Brrett,E.M.M.Ooi,J.Ji,D.T.Chn, nd G. F. Wtts, Very low density lipoprotein metbolism nd plsm diponectin s predictors of high-density lipoprotein polipoprotein -l kinetics in obese nd nonobese men, Journl of Clinicl Endocrinology nd Metbolism,vol.94,no.3,pp , 29. [33] J. G. Schneider, M. Von Eyntten, S. Schiekofer, P. P. Nwroth, nd K. A. Dugi, Low plsm diponectin levels re ssocited with incresed heptic lipse ctivity in vivo, Dibetes Cre,vol. 28,no.9,pp ,25. [34] J. J. Clrenbch, G. L. Veg, B. Adms-Huet, R. V. Considine, M. Ricks, nd A. E. Sumner, Vribility in postheprin heptic lipse ctivity is ssocited with plsm diponectin levels in Africn Americns, Journl of Investigtive Medicine, vol.55, no. 4, pp , 27. [35] F. M. Finucne, J. Lun, N. J. Wrehm et l., Correltion of the leptin: diponectin rtio with mesures of insulin resistnce in non-dibetic individuls, Dibetologi,vol.52,no.11,pp , 29. [36] N. Od, S. Immur, T. Fujit et l., The rtio of leptin to diponectin cn be used s n index of insulin resistnce, Metbolism,vol.57,no.2,pp ,28. [37] R. P. Wildmn, P. Muntner, K. Reynolds et l., The obese without crdiometbolic risk fctor clustering nd the norml weight with crdiometbolic risk fctor clustering: prevlence nd correltes of 2 phenotypes mong the US popultion (NHANES ), Archives of Internl Medicine,vol.168, no.15,pp ,28. [38] M. Blüher, The distinction of metboliclly helthy from unhelthy obese individuls, Current Opinion in Lipidology, vol. 21, pp , 21. [39] M. Brochu, A. Tchernof, I. J. Dionne et l., Wht re the physicl chrcteristics ssocited with norml metbolic profile despite high level of obesity in postmenopusl women? The JournlofCliniclEndocrinology&Metbolism,vol.86,pp , 21. [4] N. Stefn, K. Kntrtzis, J. Mchnn et l., Identifiction nd chrcteriztion of metboliclly benign obesity in humns, Archives of Internl Medicine, vol.168,no.15,pp , 28.

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