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Division of Biological Sciences and Department of Nutrition (Q.T., G.T., G.S.H.), and Department of Immunology and Infectious Diseases (J.-L.S., P.J.K.), Harvard School of Public Health, Boston, Massachusetts 02115; and Combined Program in Pediatric Gastroenterology and Nutrition (C.M.H., S.K.G.), Program in Nutritional Metabolism (C.M.H., S.K.G.), and Division of Infectious Disease (E.S.R.), Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114
Address all correspondence and requests for reprints to: Dr. Gökhan S. Hotamisligil, Division of Biological Sciences and Department of Nutrition, Harvard School of Public Health, 665 Huntington Avenue, Boston, Massachusetts 02115. E-mail: ghotamis{at}hsph.harvard.edu; or Dr. Steven K. Grinspoon, Director, Program in Nutritional Metabolism, Massachusetts General Hospital, Harvard Medical School, LON207, Fruit Street, Boston, Massachusetts 02114. E-mail: sgrinspoon{at}partners.org.
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Abstract |
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Introduction |
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Several molecules, such as TNF
, leptin, resistin, and adiponectin, are secreted by adipose tissue and exert significant metabolic effects on other tissues (16). These so-called adipokines might link the changes in adipose distribution and the metabolic abnormalities in patients with HIV infection. For example, TNF is an important mediator of insulin resistance (17). Increased soluble TNF receptor levels have also been shown in association with sc fat loss and insulin resistance in HIV-infected patients (18). Leptin, which signals a complex network of metabolic responses both centrally and peripherally, is also strongly related to the accumulation of adipose tissue. Whether a specific alteration in leptin production is associated with HIV lipodystrophy is unclear (19, 20, 21, 22). Recently, another adipose-born peptide has been identified as a systemic regulator of glucose and lipid metabolism. Adiponectin, also called ACRP30 (23), AdipoQ (24), apm1 (25), or GBP28 (26), is a 30-kDa protein secreted by differentiated adipocytes. Adiponectin can directly influence muscle and liver to stimulate fatty acid oxidation and insulin sensitivity, respectively (27, 28, 29, 30). Adiponectin expression is suppressed in patients with obesity (24, 31), type 2 diabetes (32, 33, 34), and cardiovascular disease (35, 36). Furthermore, genetic variations at the adiponectin locus are linked to obesity, insulin resistance, and dyslipidemia (37, 38, 39).
In this study, we investigated whether alterations in adiponectin might be related to metabolic abnormalities seen in HIV-infected patients. Our data demonstrate that there is no significant change of adiponectin levels during the acute phase of HIV infection. In contrast, adiponectin concentrations are significantly decreased among HIV-infected patients with lipodystrophy and severe fat redistribution, compared with age- and body mass index (BMI)-matched HIV-infected patients without significant fat redistribution and compared with healthy control subjects.
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Subjects and Methods |
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Studies in acutely infected patients. Adiponectin levels, CD4, and viral load were measured from plasma obtained from 10 patients during the acute phase of HIV infection (2–6 wk after infection), and then again, 6–8 months later, after the subsequent introduction of antiretroviral therapy.
Studies in chronically infected patients
Adiponectin levels were measured in 61 patients (21 HIV-infected men with evidence of fat redistribution; 20 HIV-infected men without evidence of significant fat redistribution; and 20 HIV-negative, healthy, age- and BMI-matched male control subjects) who had previously undergone hormonal and body composition assessment between October 1999 and June 2000 (40). HIV status was confirmed by both ELISA and Western blot analysis in all subjects. Lipodystrophic subjects were characterized based on a waist to hip ratio more than 0.95 and a history of significant change in fat distribution in the trunk, extremities, neck, or face. The presence of changes in fat distribution was confirmed by physical examination and scored, by a single investigator, as severe (
1.5, on a scale of 0–2) in one or more areas. Nonlipodystrophic subjects were characterized based on a waist to hip ratio less than 0.95 and did not demonstrate significant fat redistribution in any area, on physical examination. The non-HIV-infected control subjects were in good health, with a waist to hip ratio less than 0.95. Subjects receiving testosterone, GH, anabolic hormones, glucocorticoid, antidiabetic agents, or megestrol acetate were excluded. Subjects with known diabetes mellitus, hemoglobin level less than 9.0 g/dl [90.0 g/liter], and age more than 60 and less than 18 yr were also excluded. All HIV-infected subjects were on a stable antiretroviral regimen for more than 6 wk.
Informed consent
Written informed consent was obtained from all subjects before testing in accordance with the Committee on the Use of Humans as Experimental Subjects of the Massachusetts Institute of Technology and the Subcommittee on Human Studies at the Massachusetts General Hospital.
Biochemical measurements
Fasting serum insulin, cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides, and adiponectin were determined in all subjects, at 0800 h, after a 12-h overnight fast, as previously reported (40). Subjects were instructed to take their usual medications on the morning of testing. Subjects underwent a standard 75-g oral glucose tolerance test at 0800 h, after a 12-h overnight fast, with insulin and glucose levels drawn at baseline and at 30, 60, 90, and 120 min. HgbA1c, CD4, and viral load were also determined. Insulin level was measured by RIA (Diagnostics Products, Los Angeles, CA), with an intra-assay coefficient of variation of 4.7–7.7%. CD4 cell counts, viral burden, HgbAIc, cholesterol, LDL, HDL, and triglyceride levels were determined using previously published methods (41).
Adiponectin measurements
The serum adiponectin was measured using an RIA kit (Linco Research, Inc., St. Charles, MO). Briefly, 50 µl of 1:250 diluted serum samples were used, and all other reagents were used at 50% the amount, as indicated by the manufacturer. The RIA results were also validated by quantitative immunoblot analyses. For this, 5 µl of 1:200 diluted serum samples were resolved with 10% SDS-PAGE and transferred to membranes. Adiponectin levels were detected by a rabbit antihuman adiponectin antibody (gift from Dr. Philipp E. Sherer, Albert Einstein College of Medicine, Bronx, NY) and 125I-labeled antirabbit IgG secondary antibody (NEN Life Science Products, Boston, MA) and quantitated by a phosphoimager (Bio-Rad Laboratories, Inc., Hercules, CA).
Nutritional assessment and body composition analysis
Weight was determined after an overnight fast. Fat and fat-free mass were determined by dual-energy x-ray absorptiometry (DEXA) using a Hologic-4000 densitometer (Hologic, Inc., Waltham, MA). Whole-body and regional fat measurements (trunk and extremity) were determined as previously described (42). The technique has a precision error of 3% for fat and 1.5% for fat-free mass. Cross-sectional abdominal computed tomography (CT) scanning was performed to assess the distribution of sc and visceral abdominal fat, as previously described (43). Visceral adipose tissue (VAT) area and sc adipose tissue (SAT) fat area and the ratio of VAT:TAT (total abdominal cross-section area) and VAT:SAT were determined and compared between groups.
Statistical analysis
Adiponectin levels were compared, over time, in patients with acute HIV infection, by paired t test. Comparison of adiponectin levels was made between the patient groups with chronic HIV infection, by t test. Univariate regression analyses were performed to evaluate relationships between adiponectin and other clinical variables among all HIV-infected patients. Trunk fat, extremity fat, and protease inhibitor and nucleoside reverse transcriptase inhibitor use were assessed in a multivariate regression model for adiponectin. Similarly, age, BMI, and adiponectin were assessed in a multivariate regression model for insulin area under the curve (AUC). Other variables were not tested in the models. Statistical analyses were made using JMP Statistical Database Software (SAS Institute, Inc., Cary, NC). Statistical significance was defined as P < 0.05.
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Results |
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To determine whether the change of adiponectin levels occurs during early or late phases of HIV infection, we measured plasma adiponectin levels of patients in the acute phase of HIV infection and again after 6–8 months. There was no significant difference in plasma adiponectin levels (5.8 ± 0.4 vs. 5.9 ± 0.7 µg/ml, P = 0.96, Table 1
) between the samples obtained at the time of high viral load (2–6 wk after infection) vs. samples obtained from the same subjects6–8 months after the initial diagnosis and treatment with HAART, at which time the viral count was very low (85 ± 35 copies/ml). Weight increased from 77.9 ± 3.3 to 81.6 ± 3.7kg (P = 0.04), but the change in weight did not correlate with the change in adiponectin (P = 0.31).
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Age and BMI were similar among the three patient groups (Table 2). CD4 cell count and viral load were not significantly different between the HIV-infected groups. Duration of HIV and total months on HAART were greater in the patients with evidence of fat redistribution, compared with those without clinically significant fat redistribution. Furthermore, the percentage of patients using a protease inhibitor (90 vs. 45%, P < 0.01) and nucleoside reverse transcriptase inhibitor (100 vs. 60%, P < 0.01) was different between the groups. Whole-body lean and fat mass determined by DEXA were not significantly different between the groups. Regional trunk fat determined by DEXA was increased and extremity fat decreased in the lipodystrophy group, compared with the other subject groups. In contrast, no significant differences in either truncal or extremity fat were observed between the HIV-positive patients without fat redistribution and control subjects. Visceral abdominal fat and the ratio of visceral abdominal to sc abdominal fat were significantly increased in the subjects with fat redistribution, compared with the other subject groups.
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). Among all the HIV-infected patients, adiponectin concentrations correlated positively with percentage body fat by DEXA and extremity to total fat ratio by DEXA and inversely with trunk to total fat ratio by DEXA, the trunk to extremity fat ratio by DEXA, and the visceral to total abdominal cross-sectional area (VAT:TAT) ratio (Table 3). Adiponectin was also inversely correlated with insulin AUC and triglycerides and positively with HDL but not with blood glucose or glucose AUC. Furthermore, adiponectin was inversely correlated with total months on HAART and months on a protease inhibitor (PI) (correlation coefficient = -0.40, P = 0.01). Adiponectin concentrations were lower in patients on a PI (13.9 ± 1.7 vs. 18.7 ± 3.3, P = 0.08), and this result approached, but did not reach, statistical significance. Adiponectin concentrations were significantly reduced among subjects receiving a nonnucleoside reverse transcriptase inhibitor (NRTI) (13.8 ± 1.5 vs. 22.0 ± 4.6, P = 0.04), although this may reflect the fact that this class of drug may be associated with significant changes in body composition. In multivariate regression modeling, adiponectin concentrations were a significant correlate of insulin AUC, controlling for age and BMI, overall R2 = 0.46 (Table 4). Trunk and extremity fat were independent correlates of adiponectin in multivariate modeling, controlling for PI and NRTI use (R2 = 0.29, Table 4).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Although patients were characterized, in part, based on an absolute waist to hip criterion, it is recognized that changes in body composition form a continuum in HIV disease; and therefore, all HIV-infected patients were considered as a group, for the univariate and multivariate regression modeling, to determine the relationship between adiponectin and metabolic variables. Of note, adiponectin also correlated significantly with insulin response to standard glucose challenge, controlling for age and BMI among the HIV-infected patients. The reduction of adiponectin was also associated with elevated triglycerides and decreased HDL levels. Taken together, our data suggest that abnormal regulation of adiponectin may occur in association with fat redistribution and may contribute to abnormal insulin response to glucose tolerance testing and dyslipidemia in this unique population of patients.
We did not detect a significant difference in adiponectin levels between HIV-infected patients without clinical or anthropometric evidence of fat redistribution and normal controls. Furthermore, adiponectin levels did not change significantly during the early phases of HIV infection. Acutely infected patients gained weight with the introduction of antiretroviral therapy, and viral load decreased significantly in response to antiretroviral therapy, but adiponectin levels did not change significantly, and there was no correlation between the change in adiponectin levels and the change in weight. Body composition and insulin sensitivity data were not available from this group of patients. In general, adiponectin levels were somewhat lower among patients in the early phases of HIV disease, in comparison with chronically infected HIV patients or healthy control subjects, and further studies will be necessary to determine the potential mechanisms for these differences.
Among patients with chronic HIV infection, circulating adiponectin levels were reduced in association with changes in body composition. In contrast, adiponectin levels were similar among chronically HIV-infected patients without changes in body composition and age and among BMI-matched control subjects. Taken together, these data suggest that HIV infection per se might not affect systematic adiponectin levels, but rather that adiponectin might be affected indirectly by body composition changes associated with HIV disease. Furthermore, medication use differed between the groups, and this difference may have contributed to differences in adiponectin directly, or through changes in fat redistribution. At the current time, it is not clear whether the reduction of adiponectin proceeds the development of lipodystrophy or is actually a consequence of maldistribution of adipose tissue. However, the latter scenario seems more likely, because there are no significant body weight or body composition changes in adiponectin-deficient animals (46, 47, 48).
Current studies suggest that adiponectin may play an important role in metabolic control. Though human studies are limited, there is ample data, from experimental systems, supporting a role for adiponectin in systemic metabolic control. Administration of purified adiponectin to obese mice can improve glucose metabolism and decrease blood glucose levels (27, 28, 29). This effect is primarily mediated by the inhibition of hepatic glucose production (30). In a mouse model of total lipodystrophy, which is associated with insulin resistance, serum adiponectin levels are also reduced, and replacement by recombinant protein corrects abnormal glucose homeostasis (28). Recently, definitive evidence has been produced in several mice models with null mutations in the adiponectin gene (46, 47). In humans, obesity (31), type 2 diabetes (32, 33, 34), and cardiovascular disease (35, 36) are associated with reduced adiponectin levels. Reduced adiponectin concentrations were also recently demonstrated in association with high triglyceride and low HDL levels in nondiabetic women with dyslipidemia (49). Finally, in humans, adiponectin gene polymorphisms are linked to adiponectin levels and metabolic syndrome, including obesity, insulin resistance, and dyslipidemia (37, 38, 39). Taken together, these data suggest that maintenance of stable systemic adiponectin levels might also be critical to glucose and lipid homeostasis.
Our study does not definitively address the role played by adiponectin to mediate the metabolic abnormalities associated with HIV lipodystrophy, and we did not make direct measures of insulin resistance but, instead, used insulin and glucose responses to OGTT as surrogate markers of insulin resistance. Nonetheless, these data are the first to suggest that adiponectin might be differentially regulated in HIV disease, based on strong (but opposing) correlations between adiponectin, truncal, and extremity fat. Additional studies of HIV-noninfected patients with increased waist to hip ratio and HIV-infected patients with increased visceral and sc fat will also be important to more definitively determine the relationship between body composition and adiponectin in HIV disease and normal physiology.
Our data suggest that abnormal regulation of adiponectin may contribute significantly to the abnormal insulin response to OGTT and dyslipidemia seen in this population. However, insulin resistance is a relatively early finding in patients receiving HAART, and may occur before or early in association with changes in body composition. Therefore, the relative contribution of adiponectin to the development of insulin resistance must be placed in the context of other factors that may equally contribute to insulin resistance in this population, and our data do not establish cause and effect. Nonetheless, this study also suggests an important potential therapeutic opportunity to target the metabolic abnormalities associated with this syndrome via replacement of adiponectin or with agents that stimulate its production, such as thiozolidinediones (28, 50). Further studies investigating the regulation of adiponectin and clinical consequences of reduced adiponectin in HIV-infected patients with fat redistribution are necessary.
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Acknowledgments |
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Footnotes |
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Abbreviations: AUC, Area under the curve; BMI, body mass index; CT, computed tomography; DEXA, dual-energy x-ray absorptiometry; HAART, highly active antiretroviral therapy; HDL, high-density lipoprotein; LDL, low-density lipoprotein; NRTI, nonnucleoside reverse transcriptase inhibitor; PI, protease inhibitor; SAT, sc adipose tissue; TAT, total abdominal cross-sectional area; VAT, visceral adipose tissue.
Received September 23, 2002.
Accepted December 26, 2002.
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