Higher body mass index (BMI) is associated with increased serum C-reactive protein (CRP) levels in HIV-infected individuals on antiretroviral therapy (ART), but the relationship of adipose tissue mass to systemic inflammation is not well described in this population. We hypothesized that serum adipokine levels (i.e., hormones produced by adipocytes) are a superior predictor of CRP compared to anthropometric or radiographic measures of body composition in patients on effective, stable ART. We evaluated the relationship of serum leptin, adiponectin, and resistin, BMI, and dual energy x-ray absorptiometry (DEXA) measurements with serum highly sensitive CRP (hsCRP) in a cross-sectional cohort of 106 predominantly virologically suppressed, HIV-infected adults on ART for ≥24 weeks using multivariable linear regression and formal criteria to assess statistical mediation. Median BMI, hsCRP, and leptin values were 25.2 kg/m2, 3.0 mg/liter, and 3.8 ng/ml, respectively. BMI and DEXA limb fat, body fat, and trunk fat measurements were significantly associated with both serum leptin and hsCRP levels (all p≤0.02). Leptin was also associated with hsCRP (p<0.01). The regression coefficient for the effect of BMI or DEXA measurements on hsCRP was reduced, and the relationship was no longer statistically significant, after adjusting for leptin, indicating leptin functioned as a mediating variable within these relationships. Adiponectin and resistin levels did not demonstrate similar effects. Serum leptin was a superior predictor of hsCRP compared to BMI and DEXA body fat measurements, which may reflect alterations in body composition in treated HIV infection and the important contribution of adipose tissue to inflammation in this population.
Get full access to this article
View all access options for this article.
References
1.
BrownTT, ColeSR, LiXet al.Antiretroviral therapy and the prevalence and incidence of diabetes mellitus in the multicenter AIDS cohort study. Arch Intern Med, 2005; 165,10:1179–1184.
2.
TriantVA, LeeH, HadiganC, GrinspoonSK. Increased acute myocardial infarction rates and cardiovascular risk factors among patients with human immunodeficiency virus disease. J Clin Endocrinol Metab, 2007; 92,7:2506–2512.
3.
WandH, CalmyA, CareyDLet al.Metabolic syndrome, cardiovascular disease and type 2 diabetes mellitus after initiation of antiretroviral therapy in HIV infection. AIDS, 2007; 21,18:2445–2453.
4.
WormSW, Friis-MollerN, BruyandMet al.High prevalence of the metabolic syndrome in HIV-infected patients: Impact of different definitions of the metabolic syndrome. AIDS, 2010; 24,3:427–435.
5.
SamarasK, GanSK, PeakePW, CarrA, CampbellLV. Proinflammatory markers, insulin sensitivity, and cardiometabolic risk factors in treated HIV infection. Obesity (Silver Spring), 2009; 17,1:53–59.
6.
AmorosaV, SynnestvedtM, GrossRet al.A tale of 2 epidemics: The intersection between obesity and HIV infection in Philadelphia. J Acquir Immune Defic Syndr, 2005; 39,5:557–561.
7.
Crum-CianfloneN, RoedigerMP, EberlyLet al.Increasing rates of obesity among HIV-infected persons during the HIV epidemic. PLoS One, 2010; 5,4:e10106.
8.
PradhanAD, MansonJE, RifaiN, BuringJE, RidkerPM. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA, 2001; 286,3:327–334.
9.
KullerLH, TracyR, BellosoWet al.Inflammatory and coagulation biomarkers and mortality in patients with HIV infection. PLoS Med, 2008; 5,10:e203.
10.
HenryK, KitchD, DubeMet al.C-Reactive protein levels over time and cardiovascular risk in HIV-infected individuals suppressed on an indinavir-based regimen: AIDS Clinical Trials Group 5056s. AIDS, 2004; 18,18:2434–2437.
11.
ShikumaCM, RibaudoHJ, ZhengYet al.Change in high-sensitivity C-reactive protein levels following initiation of efavirenz-based antiretroviral regimens in HIV-infected individuals. AIDS Res Hum Retroviruses, 2011; 27,5:461–468.
12.
FordES, GreenwaldJH, RichtermanAGet al.Traditional risk factors and D-dimer predict incident cardiovascular disease events in chronic HIV infection. AIDS, 2010; 24,10:1509–1517.
13.
BrownTT, TassiopoulosK, BoschRJ, ShikumaC, McComseyGA. Association between systemic inflammation and incident diabetes in HIV-infected patients after initiation of antiretroviral therapy. Diabetes Care, 2010; 33,10:2244–2249.
14.
TriantVA, MeigsJB, GrinspoonSK. Association of C-reactive protein and HIV infection with acute myocardial infarction. J Acquir Immune Defic Syndr, 2009; 51,3:268–273.
15.
ConsidineRV, SinhaMK, HeimanMLet al.Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med, 1996; 334,5:292–295.
16.
ZhangY, ProencaR, MaffeiM, BaroneM, LeopoldL, FriedmanJM. Positional cloning of the mouse obese gene and its human homologue. Nature, 1994; 372,6505:425–432.
ReingoldJ, WankeC, KotlerDet al.Association of HIV infection and HIV/HCV coinfection with C-reactive protein levels: The fat redistribution and metabolic change in HIV infection (FRAM) study. J Acquir Immune Defic Syndr, 2008; 48,2:142–148.
19.
BogerMS, ShintaniA, RedhageLAet al.Highly sensitive C-reactive protein, body mass index, and serum lipids in HIV-infected persons receiving antiretroviral therapy: A longitudinal study. J Acquir Immune Defic Syndr, 2009; 52,4:480–487.
20.
PouKM, MassaroJM, HoffmannUet al.Visceral and subcutaneous adipose tissue volumes are cross-sectionally related to markers of inflammation and oxidative stress: The Framingham Heart Study. Circulation, 2007; 116,11:1234–1241.
21.
VisserM, BouterLM, McQuillanGM, WenerMH, HarrisTB. Elevated C-reactive protein levels in overweight and obese adults. JAMA, 1999; 282,22:2131–2135.
22.
CarrA, SamarasK, BurtonSet al.A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients receiving HIV protease inhibitors. AIDS, 1998; 12,7:F51–58.
23.
BrownTT, XuX, JohnMet al.Fat distribution and longitudinal anthropometric changes in HIV-infected men with and without clinical evidence of lipodystrophy and HIV-uninfected controls: A substudy of the Multicenter AIDS Cohort Study. AIDS Res Ther, 2009; 6:8.
24.
KotlerDP, RosenbaumK, WangJ, PiersonRN. Studies of body composition and fat distribution in HIV-infected and control subjects. J Acquir Immune Defic Syndr Hum Retrovirol, 1999; 20,3:228–237.
25.
MulliganK, AnastosK, JustmanJet al.Fat distribution in HIV-infected women in the United States: DEXA substudy in the Women's Interagency HIV Study. J Acquir Immune Defic Syndr, 2005; 38,1:18–22.
26.
BaronRM, KennyDA. The moderator-mediator variable distinction in social psychological research: Conceptual, strategic, and statistical considerations. J Pers Soc Psychol, 1986; 51,6:1173–1182.
27.
KleinbaumD, KupperL, MullerK. Applied Regression Analysis and Other Multivariate Methods, 2nd. PWS-Kent: Boston, 1998.
28.
HickeyMS, IsraelRG, GardinerSNet al.Gender differences in serum leptin levels in humans. Biochem Mol Med, 1996; 59,1:1–6.
29.
ParkKG, ParkKS, KimMJet al.Relationship between serum adiponectin and leptin concentrations and body fat distribution. Diabetes Res Clin Pract, 2004; 63,2:135–142.
30.
StaigerH, TschritterO, MachannJet al.Relationship of serum adiponectin and leptin concentrations with body fat distribution in humans. Obes Res, 2003; 11,3:368–372.
31.
WoloshinS, SchwartzLM. Distribution of C-reactive protein values in the United States. N Engl J Med, 2005; 352,15:1611–1613.
32.
KosmiskiL, KuritzkesD, HamiltonJet al.Fat distribution is altered in HIV-infected men without clinical evidence of the HIV lipodystrophy syndrome. HIV Med, 2003; 4,3:235–240.
33.
HotamisligilGS. Inflammation and metabolic disorders. Nature, 2006; 444,7121:860–867.
34.
ShamsuzzamanAS, WinnickiM, WolkRet al.Independent association between plasma leptin and C-reactive protein in healthy humans. Circulation, 2004; 109,18:2181–2185.
35.
Santos-AlvarezJ, GobernaR, Sanchez-MargaletV. Human leptin stimulates proliferation and activation of human circulating monocytes. Cell Immunol, 1999; 194,1:6–11.
36.
CancelloR, HenegarC, ViguerieNet al.Reduction of macrophage infiltration and chemoattractant gene expression changes in white adipose tissue of morbidly obese subjects after surgery-induced weight loss. Diabetes, 2005; 54,8:2277–2286.
37.
FRAM: Fat distribution in women with HIV infection. J Acquir Immune Defic Syndr, 2006; 42,5:562–571.
38.
BacchettiP, GripshoverB, GrunfeldCet al.Fat distribution in men with HIV infection. J Acquir Immune Defic Syndr, 2005; 40,2:121–131.
39.
GrunfeldC, SaagM, CofrancescoJJret al.Regional adipose tissue measured by MRI over 5 years in HIV-infected and control participants indicates persistence of HIV-associated lipoatrophy. AIDS, 2010; 24,11:1717–1726.
40.
MauryE, Ehala-AleksejevK, GuiotY, DetryR, VandenhooftA, BrichardSM. Adipokines oversecreted by omental adipose tissue in human obesity. Am J Physiol Endocrinol Metab, 2007; 293,3:E656–665.
41.
NdumeleCE, NasirK, ConceicaoRD, CarvalhoJA, BlumenthalRS, SantosRD. Hepatic steatosis, obesity, and the metabolic syndrome are independently and additively associated with increased systemic inflammation. Arterioscler Thromb Vasc Biol, 2011; 31,8:1927–1932.
42.
BrownTT, MehtaSH, SutcliffeCet al.Hepatic steatosis associated with increased central body fat by dual-energy X-ray absorptiometry and uncontrolled HIV in HIV/hepatitis C co-infected persons. AIDS, 2010; 24,6:811–817.
