AJP - Endo Fuel your research with LabChart
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Am J Physiol Endocrinol Metab 292: E687-E692, 2007. First published October 24, 2006; doi:10.1152/ajpendo.00219.2006 Free Article
0193-1849/07 $8.00
This Article
Free upon publication Free Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
292/3/E687    most recent
00219.2006v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (3)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Sutinen, J.
Right arrow Articles by Yki-Järvinen, H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Sutinen, J.
Right arrow Articles by Yki-Järvinen, H.

Increased resting energy expenditure, fat oxidation, and food intake in patients with highly active antiretroviral therapy-associated lipodystrophy

Jussi Sutinen1,2 and Hannele Yki-Järvinen1

Department of Medicine, Divisions of 1Diabetes and 2Infectious Diseases, Helsinki University Central Hospital, Helsinki, Finland

Submitted 8 May 2006 ; accepted in final form 18 October 2006


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Highly active antiretroviral therapy (HAART) is associated with metabolic adverse events such as lipodystrophy in human immunodeficiency virus (HIV)-infected patients. The objective of the present study was to evaluate the effects of HAART-associated lipodystrophy on resting energy expenditure and caloric intake. In this cross-sectional study we compared resting energy expenditure (REE) and energy intake in 30 HAART-treated patients with lipodystrophy (HAART+LD+) with 13 HAART-treated patients without lipodystrophy (HAART+LD–). REE was measured using indirect calorimetry, and energy intake was recorded as a 3-day diary of food intake. REE (5,180 ± 160 vs. 4,260 ± 150 J/min, P < 0.01) and also REE expressed per fat-free mass (86 ± 1 vs. 78 ± 2 J·kg fat-free mass–1·min–1, P < 0.01) were significantly higher in the HAART+LD+ than the HAART+LD– group. Rate of lipid oxidation was significantly higher in the HAART+LD+ than the HAART+LD– group. Total energy and fat intakes were significantly increased in the HAART+LD+ compared with the HAART+LD– group. These results imply that HAART-associated lipodystrophy is associated with increased REE and lipid oxidation and with increased caloric and fat intake.

calorimetry; respiratory quotient; lipoatrophy; buffalo hump

HIGHLY ACTIVE ANTIRETROVIRAL THERAPY (HAART) has improved the prognosis of human immunodeficiency virus (HIV)-infected patients (25). HAART is, however, associated with metabolic complications, including lipodystrophy, insulin resistance, and dyslipidemia (19). As a result of widespread use of HAART, HAART-associated lipodystrophy (HAL) has become by far the most prevalent form of human lipodystrophies (16).

HAL is characterized by loss of subcutaneous fat (lipoatrophy) and a relative increase in central fat (19). Lipoatrophy has been suggested to be the dominant morphological change of HAL (56). The pathophysiology of this syndrome appears to be multifactorial, including HAART-induced inhibition of adipocyte differentiation, inflammatory changes, and mitochondrial dysfunction in adipose tissue (18). HAL also could affect energy metabolism, albeit this aspect of HAL has been sparsely studied.

When the effects of HAL on resting energy expenditure (REE) are studied, the confounding effects of HIV infection or HAART per se on REE must be taken into account. According to a very recent meta-analysis, REE expressed per fat-free mass (FFM) is significantly higher in HIV-positive subjects than in healthy controls (6). Among HIV-infected subjects, the prevalence of lipodystrophy was not associated with an increase in REE/FFM. However, in these studies lipodystrophic patients did not have significantly less subcutaneous fat compared with HAART-treated nonlipodystrophic patients (1, 6, 21, 31, 32, 43). Thus whether patients with significantly reduced amounts of subcutaneous fat have an increase in REE/FFM is still unknown. Furthermore, food intake has not been quantified in any study involving lipoatrophic patients. The aim of the current study was to evaluate the effects of HAL on both REE and energy intake by comparing two previously characterized groups of HIV-infected, HAART-treated patients with and without significant loss of subcutaneous fat.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Subjects and Study Design

This is a cross-sectional study on energy metabolism in two groups of HIV-infected, HAART-treated patients, one group with (HAART+LD+) and the other group without lipodystrophy (HAART+LD–). As previously described, the patients were recruited from the outpatient clinic of the Helsinki University Central Hospital (29, 51–54, 61). All participants had to have been treated with combination antiretroviral therapy for at least 18 mo before enrollment and did not have any signs or symptoms of current opportunistic infections. Indirect calorimetry was performed and blood samples were drawn after an overnight fast.

HAART+LD+ patients had self-reported symptoms of loss of subcutaneous fat with or without increased abdominal girth, breast size, or development of a buffalo hump. HAART+LD– patients had received antiretroviral therapy without developing symptoms of lipodystrophy. Both the presence and absence of lipodystrophy was confirmed by a single investigator before enrollment.

The purpose, nature, and potential risks of the study were explained to the patients before their written, informed consent was obtained. The protocol was approved by the ethics committee of the Helsinki University Central Hospital.

Methods

Indirect calorimetry. Respiratory gas exchange and REE were recorded for 40 min by indirect calorimetry using the Deltatrac metabolic monitor (Datex, Helsinki, Finland). Substrate oxidation rates and rates of energy expenditure were calculated from the gas exchange data as previously described (15, 60).

Food intake and physical activity. The participants kept a 3-day diary of food and fluid intake on 2 days of normal working and 1 day off from work. The patients were instructed not to change their regular diet on the days of data recording. The quality of food intake recording was confirmed, and data analysis was performed by an experienced dietician who was unaware of the absence or presence of lipodystrophy of the participants. Food diaries were analyzed using NUTRICA software (version 3.0; Research Centre of the Social Insurance Institution, Helsinki, Finland). Patients were asked about their physical activity during a structured interview. Physical activity was classified as light, such as walking, or strenuous, defined as any activity making patients to be out of breath or to sweat.

Body composition. Total body fat mass and lean body mass were determined using BIA (BioElectrical Impedance Analyzer System model BIA-101A; RJL Systems, Detroit, MI). The volumes of intra-abdominal and subcutaneous fat were measured using magnetic resonance imaging. A total of 16 T1-weighed transaxial scans extending from 8 cm above to 8 cm below the fourth and fifth lumbar interspace were analyzed (field of view, 375 x 500 mm2; slice thickness, 10 mm; breath-hold repetition time, 138.9 ms; echo time, 4.1 ms). Intra-abdominal and subcutaneous fat volumes were quantified using image analysis software (Alice 3.0; Parexel, Waltham, MA). In our hands, the reproducibility of intra-abdominal and subcutaneous fat measurements performed on two separate occasions was 5 and 3% (coefficient of variation) (50). Subscapular skin fold thickness (mean of triplicate measurements) was performed using Harpender calipers (John Bull British Indicators, West Sussex, UK).

Laboratory analyses. Serum free insulin concentrations were determined with radioimmunoassay (Phadeseph Insulin RIA; Pharmacia & Upjohn Diagnostics, Uppsala, Sweden) after precipitation with polyethylene glycol (13). Plasma glucose concentrations were measured using a hexokinase method. Serum total and HDL cholesterol and triglyceride concentrations were measured using respective enzymatic kits from Roche Diagnostics with an autoanalyzer (Roche Diagnostics Hitachi 917; Hitachi, Tokyo, Japan). Serum free fatty acid (FFA) concentrations were measured using fluorometric assay (38). Serum leptin concentrations were quantified by radioimmunoassay with a commercial kit (Human Leptin RIA kit; Linco Research, St. Charles, MO). Serum concentrations of tumor necrosis factor (TNF)-{alpha} and IL-6 were measured using commercial enzyme-linked immunoassays (Quantikine; R&D Systems, Minneapolis, MN). The HIV viral load was measured using the HIV-1 Monitor Test (Roche Diagnostics, Branchburg, NJ) with a detection limit of 50 copies/ml.

Statistical Analysis

The unpaired t-test was used to compare differences between the groups. Logarithmic transformation was performed on skewed data. Correlations were calculated using Spearman's rank correlation coefficient. Categorical variables were compared using Fisher's exact test. All data are given as means ± SE. All calculations were performed using the Systat statistical package (version 10.0; Systat, Evanston, IL) or GraphPad Prism (version 3.0; GraphPad, San Diego, CA). A P value <0.05 was considered statistically significant.


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
HIV-Related Characteristics

The mean time since the diagnosis of HIV was 8.2 ± 0.6 vs. 8.6 ± 1.3 yr (not significant, NS) in the HAART+LD+ compared with the HAART+LD– group. None of the patients had symptoms or signs of an acute opportunistic infection at the time of the study, but eight patients (27%) in the HAART+LD+ and one patient (8%) in the HAART+LD– group (NS) had a history of a previous AIDS-defining illness. The groups were comparable regarding the viral load (1.87 ± 0.15 vs. 1.65 ± 0.25 log10 copies/ml, HAART+LD+ vs. HAART+LD–, NS), CD4 count (572 ± 54 vs. 516 ± 70 x 106/l, respectively, NS), and the duration of combination antiretroviral therapy (4.2 ± 0.2 vs. 3.8 ± 0.4 yr, respectively, NS). All participants in both groups were receiving nucleoside reverse transcriptase inhibitors as part of the combination therapy. Of the thymidine analogs, zidovudine was used by 7 patients (23%) in the HAART+LD+ group and 10 patients (77%) in the HAART+LD– group (P < 0.01), whereas stavudine was used by 21 (70%) and 3 patients (23%), respectively (P < 0.01). Thirty-three percent of the patients in the HAART+LD+ group and 38% of those in the HAART+LD– group (NS) used nonnucleoside reverse transcriptase inhibitors, and 73 and 69%, respectively (NS), used protease inhibitors.

Body Composition and Biochemical Characteristics

As previously described (29, 51–54, 61), the age, body mass index, and total body fat mass values were comparable between the HAART+LD+ and the HAART+LD– groups. The HAART+LD+ group had, however, significantly less subcutaneous fat (1,100 ± 200 vs. 1,800 ± 300 cm3, P < 0.05) and more intra-abdominal fat (1,900 ± 200 vs. 900 ± 300 cm3, P < 0.01) than the HAART+LD– group (Table 1). The HAART+LD+ group also had higher fasting serum insulin and triglyceride concentrations and lower HDL cholesterol concentrations than the HAART+LD– group. Serum FFA concentrations were slightly but not significantly increased in the HAART+LD+ group compared with the HAART+LD– group. Serum leptin concentration was not significantly different between the two groups. Serum TNF-{alpha} (1.6 ± 0.1 vs. 1.5 ± 0.2 pg/ml, HAART+LD+ vs. HAART+LD–, NS) and IL-6 (2.2 ± 0.3 vs. 1.9 ± 0.6 pg/ml, respectively, NS) concentrations were not significantly different between the groups.


View this table:
[in this window]
[in a new window]

  		Table 1. Body composition and metabolic characteristics of patients with and without HAART-associated lipodystophy

 
Energy Metabolism

REE (kJ/min) was 21%, REE adjusted for body weight was 13%, and REE adjusted for FFM was 11% greater in the HAART+LD+ than the HAART+LD– group (Table 2). The increase in energy expenditure also remained significant if women were excluded from the analysis (data not shown). REE (kJ/day) correlated closely with FFM in both groups (r = 0.89, P < 0.0001 in the HAART+LD+ group and r =0.83, P = 0.005 in the HAART+LD– group) (Fig. 1). The respiratory quotient (RQ) was significantly lower in the HAART+LD+ than the HAART+LD– group. The rate of lipid oxidation was significantly increased in the HAART+LD+ compared with the HAART+LD– group.


View this table:
[in this window]
[in a new window]

  		Table 2. Resting metabolic rate and substrate use in patients with and without HAART-associated lipodystrophy

 

Figure 1
View larger version (8K):
[in this window]
[in a new window]

  		Fig. 1. Relationship between fat-free mass (FFM) and daily resting energy expenditure (REE) in patients with highly active antiretroviral therapy (HAART)-associated lipodystrophy (bullet, r = 0.89, P < 0.0001) and HAART-treated patients without lipodystrophy ({circ}, r =0.83, P = 0.005).

 
Within the HAART+LD+ group, serum FFA concentration was significantly correlated with the rate of lipid oxidation (r = 0.40, P < 0.05) (Fig. 2). Neither serum FFA concentrations nor lipid oxidation rates correlated with dietary fat intake among the lipodystrophic patients. Serum C-reactive protein, IL-6, or TNF-{alpha} concentrations did not correlate with REE expressed per kilogram of body weight or FFM.


Figure 2
View larger version (7K):
[in this window]
[in a new window]

  		Fig. 2. Relationship between serum free fatty acid (FFA) concentration and lipid oxidation rate in patients with HAART-associated lipodystrophy (r = 0.40, P < 0.05).

 
Food Intake and Physical Activity

Total caloric intake was significantly higher in the HAART+LD+ group compared with the HAART+LD– group (Table 3). Both fat intake in grams and the proportion of fat of total energy intake were significantly increased in the HAART+LD+ compared with the HAART+LD– group. All significant differences in dietary intake between the groups shown in Table 3 remained unchanged even if women were excluded from the analysis, with the exception of total energy intake, which did not remain statistically significant (9,730 ± 380 vs. 8,300 ± 810 kJ/day, HAART+LD+ vs. HAART+LD–, P = 0.09). Serum leptin concentrations did not correlate with daily energy intake. Light (6.9 ± 0.8 vs. 5.7 ± 2.3 h/wk, HAART+LD+ vs. HAART+LD–, NS) and strenuous physical activity (2.4 ± 0.7 vs. 2.7 ± 0.8 h/wk, respectively, NS) was comparable between the groups.


View this table:
[in this window]
[in a new window]

  		Table 3. Dietary intake in patients with HAART+LD+ and HAART+LD–

 

   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In the present study, REE was significantly higher in HIV-infected, HAART-treated patients with lipodystrophy than in HIV-infected, HAART-treated patients without lipodystrophy. The higher dietary energy intake in the HAART+LD+ group is consistent with the higher energy expenditure. Patients with HAL also had higher lipid oxidation rates in both relative and absolute terms than patients without lipodystrophy.

Since HIV-infection itself has been associated with higher REE (20, 24, 35) and HAART with a decrease in REE (42), we compared two groups of HIV-infected, HAART-treated patients, one group with and the other without lipodystrophy. This comparison makes it possible to differentiate between effects of lipodystrophy from those of HIV infection and HAART per se. However, although all patients in the current study were using HAART, their antiretroviral combinations were not identical. Therefore, the possibility cannot be fully excluded that the differences in patients' antiretroviral regimens may have contributed to the differences in energy metabolism between the groups also by a direct drug-induced effect, which was not mediated by lipodystrophy. The use of different control groups, such as HIV-negative subjects or HIV-positive but untreated patients, may explain some of the discrepancies in the literature, such as a decreased REE in patients with HAL compared with HIV-infected but untreated patients (58). In this comparison, the observed difference may not exclusively reflect a decrease in REE in HAL but also an increase in REE in the control group due to untreated HIV infection (6, 24).

A few previous studies have examined effects of HAL on REE. However, none of the previous studies has compared significantly lipoatrophic HAL patients with nonlipodystrophic HAART-treated patients, which may explain some of the differences in results. Our findings are in keeping with those by Kosmiski et al. (31), who found a higher REE expressed per FFM in protease inhibitor (PI)-treated patients with lipodystrophy compared with that in PI- and non-PI-treated nonlipodystrophic patients (31). These data contrast the results of three studies which found no difference in REE between lipodystrophic and weight-stable, nonlipodystrophic HIV-infected patients (1, 7, 43). In another study by Kosmiski et al. (32), total energy expenditure (TEE) consisting of REE, postprandial thermogenesis, and physical activity was higher in patients with HAL compared with HAART-treated patients without HAL and HIV-negative subjects. The increase in TEE could be attributed to an increase in REE (32).

Thyroid hormones and catecholamines increase REE (12, 17, 48). These hormones were not measured in the current study, but the patients had no signs or symptoms suggestive of excess production of either hormone, i.e., the patients were clinically euthyroid, and blood pressures and heart rates were comparable between the groups (Table 1). The available data do not suggest that hyperthyroidism would be a contributor to higher REE in HAL. In a cohort of 350 HIV-infected subjects, hypo- rather than hyperthyroidism was the most common form of thyroid dysfunction, and HAL was not associated with thyroid function abnormalities (8). In a study comparing patients with HAL to HAART-treated patients without lipodystrophy, thyroid hormone concentrations were normal and similar in both groups (43). However, the same study reported increased 24-h urinary catecholamine concentrations, which correlated with total resting metabolic rate in patients with HAL (43). A limitation of this study is that REE was not expressed per FFM. Another study has found increased plasma norepinephrine but not epinephrine concentrations in HAART-treated lipodystrophic patients compared with untreated HIV-infected patients (58). However, the same study reported a decrease in REE adjusted for lean body mass in patients with HAL independent of increased plasma norepinephrine concentration (58). The latter finding argues against a role for catecholamines in the etiology of increased REE in patients with HAL.

Increased circulating concentrations of proinflammatory cytokines TNF-{alpha} and IL-6 have been associated with hypermetabolism in AIDS patients with acute opportunistic infections (55). In the present study, serum IL-6 or TNF-{alpha} concentrations did not differ between the HAART+LD+ and HAART+LD– groups, and their concentrations did not correlate with REE. However, systemic concentrations of inflammatory cytokines may not reflect their action in target tissues. It therefore remains possible that increased local inflammation, as has been demonstrated in lipoatrophic adipose tissue (5, 26, 29, 34), may contribute to increased energy expenditure.

In vitro, nucleoside analog reverse transcriptase inhibitors are known to inhibit mitochondrial DNA polymerase {gamma} (28), and this has been suggested to be the underlying mechanisms for HAL (9). Mitochondrial DNA is reduced in lipoatrophic adipose tissue in patients with HAL (47, 59) and also in individual human adipocytes (40), which appears to impair mitochondrial function (22). It was recently shown that during standardized exercise, mitochondrial dysfunction indeed characterizes patients with HAL (10). In the latter study, a rapid increase in lactic acid concentration, an impairment in the activities of respiratory chain enzymes, and mitochondrial histoenzymatic abnormalities were observed during exercise in skeletal muscle in patients with HAL (10). Hypothetically, therefore, reduced efficacy of the respiratory chain to produce ATP may contribute to increased oxygen consumption in patients with HAL.

Another hypothetical mitochondrion-related cause for increased energy demand in HAL is an increase in the number of heat-producing brown fat cells. Uncoupling protein 1 (UCP-1) is exclusively expressed in brown adipocytes and is required for heat production. In rodents, interscapular and perirenal fat depots contain mainly brown adipocytes (23). In healthy adult humans, there are no specific brown fat depots, but occasional brown adipocytes can be detected within normal white adipose tissue (23). Interestingly, development of buffalo hump (19) and, more recently, increased perirenal fat mass (3) have been described as part of HAL syndrome. Increased UCP-1 gene expression has been demonstrated in HAL-associated buffalo humps compared with UCP-1 expression in subcutaneous adipose tissue from control subjects (44). In the current study, patients with HAL had significantly thicker subscapular skin folds than the HAART+LD– group. Therefore, an increased number of heat-producing brown adipocytes could contribute to the higher REE observed in patients with HAL. On the other hand, it can be hypothesized that patients with significant lipoatrophy loose more heat through radiation due to the lack of an insulating subcutaneous fat layer apart from the shoulder area.

Another possibility that could contribute to the higher REE in patients with HAL is futile triglyceride/fatty acid cycling. Rates of lipolysis have been found to be elevated in patients with HAL compared with HIV-negative subjects (46). The increased rate of lipolysis was associated with higher plasma concentrations of glycerol, palmitate, and total FFA (46). An increased shuttling of fatty acids together with breakdown and reassembly of triglycerides consumes considerable amounts of energy. It has been estimated that as much as one-half of the prolonged increase in O2 consumption after physical exercise may be consumed for triglyceride/fatty acid cycling in healthy adults (4).

In addition to higher REE, we also found a significantly reduced RQ in the patients with HAL, implying higher oxidation of lipids relative to that of carbohydrates. Lipid oxidation was also higher in absolute terms in the HAART+LD+ group. This finding is consistent with the data of Sekhar et al. (46), who reported increased whole body fatty acid oxidation in patients with HAL compared with healthy controls. On the other hand, Kosmiski et al. (31) did not observe a difference in RQ when comparing patients with HAL to those without HAL.

The cause for the increased lipid oxidation in the HAART+LD+ group cannot be determined in this cross-sectional study. High FFA concentrations may promote lipid oxidation via mass action. In the current study, the HAART+LD+ group tended to have higher FFA concentrations than the HAART+LD– group, but the difference did not reach statistical significance. Several other studies have reported significantly increased FFA concentrations in patients with HAL (37, 46, 57). The significant positive correlation between fasting serum FFA concentration and lipid oxidation rate among patients with HAL is in keeping with this possibility (Fig. 2). In the current study, both absolute and relative dietary fat intake was increased in the HAART+LD+ group, which could contribute to the increased lipid oxidation rate (45, 49).

The HAART+LD+ group had significantly higher dietary energy intake than the HAART+LD– group. This is an expected finding in the view of the higher energy expenditure but stable body weight. Leptin is a known regulator of satiety and food intake in mice, but its role as a satiety factor in humans is controversial (2, 27). In the current study, serum leptin concentrations were somewhat decreased in the HAART+LD+ group compared with the HAART+LD– group, although the difference was not statistically significant. In non-HIV-lipodystrophic patients with severe hypoleptinemia, leptin treatment has decreased energy intake and REE (36, 41). However, the role of leptin in HAL is not clear: HAL has been associated with decreased (14), unchanged (11, 39), and even increased (30) leptin concentrations. Therefore, it seems unlikely that slightly decreased leptin concentration in the HAART+LD+ group would drive the observed hyperphagia in the current study. Increased ghrelin concentrations in patients with non-HIV lipodystrophy have been suggested to contribute to increased energy intake (36). This is, again, an unlikely explanation for the higher food intake in the current study, since ghrelin concentrations have been decreased and not increased in patients with HAL (33). One simple possibility for the increased food and fat intake in patients with HAL is patients' conscious or unconscious attempt to compensate for the fat atrophy.

In conclusion, REE was significantly higher in HIV-infected patients with HAART-associated lipodystrophy compared with HIV-infected HAART-treated patients who had not developed lipodystrophy, implying that lipodystrophy per se is associated with increased energy expenditure. Lipid oxidation is favored over carbohydrate oxidation in these patients. Both increased REE and lipid oxidation are linked with increased food and fat intake in patients with HAL.


   ACKNOWLEDGMENTS
 
We gratefully acknowledge Katja Tuominen for excellent technical assistance. We are grateful for being able to perform part of the laboratory analyses at the Minerva Medical Research Institute, Helsinki, Finland.


   FOOTNOTES
 

Address for reprint requests and other correspondence: J. Sutinen, Dept. of Medicine, Helsinki Univ. Central Hospital, PO Box 348, FIN-00029 HUS, Helsinki, Finland (e-mail: jussi.sutinen{at}hus.fi)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Andersen O, Haugaard SB, Andersen UB, Friis-Moller N, Storgaard H, Volund A, Nielsen JO, Iversen J, Madsbad S. Lipodystrophy in human immunodeficiency virus patients impairs insulin action and induces defects in beta-cell function. Metabolism 52: 1343–1353, 2003.[CrossRef][ISI][Medline]
  2. Andersson LB. Genes and obesity. Ann Med 28: 5–7, 1996.[ISI][Medline]
  3. Asensi V, Martin-Roces E, Carton JA, Collazos J, Maradona JA, Alonso A, Medina M, Aburto JM, Martinez E, Rojo C, Bustillo E, Fernandez C, Arribas JM. Perirenal fat diameter measured by echography could be an early predictor of lipodystrophy in HIV type 1-infected patients receiving highly active antiretroviral therapy. Clin Infect Dis 39: 240–247, 2004.[CrossRef][ISI][Medline]
  4. Bahr R, Hansson P, Sejersted OM. Triglyceride/fatty acid cycling is increased after exercise. Metabolism 39: 993–999, 1990.[CrossRef][ISI][Medline]
  5. Bastard JP, Caron M, Vidal H, Jan V, Auclair M, Vigouroux C, Luboinski J, Laville M, Maachi M, Girard PM, Rozenbaum W, Levan P, Capeau J. Association between altered expression of adipogenic factor SREBP1 in lipoatrophic adipose tissue from HIV-1-infected patients and abnormal adipocyte differentiation and insulin resistance. Lancet 359: 1026–1031, 2002.[CrossRef][ISI][Medline]
  6. Batterham MJ. Investigating heterogeneity in studies of resting energy expenditure in persons with HIV/AIDS: a meta-analysis. Am J Clin Nutr 81: 702–713, 2005.[Abstract/Free Full Text]
  7. Batterham MJ, Garsia R, Greenop PA. Dietary intake, serum lipids, insulin resistance and body composition in the era of highly active antiretroviral therapy "Diet FRS Study". AIDS 14: 1839–1843, 2000.[CrossRef][ISI][Medline]
  8. Beltran S, Lescure FX, Desailloud R, Douadi Y, Smail A, El Esper I, Arlot S, Schmit JL. Increased prevalence of hypothyroidism among human immunodeficiency virus-infected patients: a need for screening. Clin Infect Dis 37: 579–583, 2003.[CrossRef][ISI][Medline]
  9. Brinkman K, Smeitink JA, Romijn JA, Reiss P. Mitochondrial toxicity induced by nucleoside-analogue reverse-transcriptase inhibitors is a key factor in the pathogenesis of antiretroviral-therapy-related lipodystrophy. Lancet 354: 1112–1115, 1999.[CrossRef][ISI][Medline]
  10. Chapplain JM, Beillot J, Begue JM, Souala F, Bouvier C, Arvieux C, Tattevin P, Dupont M, Chapon F, Duvauferrier R, Hespel JP, Rochcongar P, Michelet C. Mitochondrial abnormalities in HIV-infected lipoatrophic patients treated with antiretroviral agents. J Acquir Immune Defic Syndr 37: 1477–1488, 2004.[CrossRef][ISI][Medline]
  11. Christeff N, Melchior JC, de Truchis P, Perronne C, Nunez EA, Gougeon ML. Lipodystrophy defined by a clinical score in HIV-infected men on highly active antiretroviral therapy: correlation between dyslipidaemia and steroid hormone alterations. AIDS 13: 2251–2260, 1999.[CrossRef][ISI][Medline]
  12. Danforth E Jr, Burger A. The role of thyroid hormones in the control of energy expenditure. Clin Endocrinol Metab 13: 581–595, 1984.[ISI][Medline]
  13. Desbuquois B, Aurbach GD. Use of polyethylene glycol to separate free and antibody-bound peptide hormones in radioimmunoassay. J Clin Endocrinol Metab 33: 732–738, 1971.[ISI][Medline]
  14. Estrada V, Serrano-Rios M, Larrad MT, Villar NG, Lopez AG, Tellez MJ, Fernandez C. Leptin and adipose tissue maldistribution in HIV-infected male patients with predominant fat loss treated with antiretroviral therapy. J Acquir Immune Defic Syndr 29: 32–40, 2002.[ISI][Medline]
  15. Ferrannini E. The theoretical bases of indirect calorimetry: a review. Metabolism 37: 287–301, 1988.[CrossRef][ISI][Medline]
  16. Garg A. Acquired and inherited lipodystrophies. N Engl J Med 350: 1220–1234, 2004.[Free Full Text]
  17. Gelfand RA, Hutchinson-Williams KA, Bonde AA, Castellino P, Sherwin RS. Catabolic effects of thyroid hormone excess: the contribution of adrenergic activity to hypermetabolism and protein breakdown. Metabolism 36: 562–569, 1987.[CrossRef][ISI][Medline]
  18. Gougeon ML, Penicaud L, Fromenty B, Leclercq P, Viard JP, Capeau J. Adipocytes targets and actors in the pathogenesis of HIV-associated lipodystrophy and metabolic alterations. Antivir Ther 9: 161–177, 2004.[ISI][Medline]
  19. Grinspoon S, Carr A. Cardiovascular risk and body-fat abnormalities in HIV-infected adults. N Engl J Med 352: 48–62, 2005.[Free Full Text]
  20. Grunfeld C, Pang M, Shimizu L, Shigenaga JK, Jensen P, Feingold KR. Resting energy expenditure, caloric intake, and short-term weight change in human immunodeficiency virus infection and the acquired immunodeficiency syndrome. Am J Clin Nutr 55: 455–460, 1992.[Abstract/Free Full Text]
  21. Hadigan C, Borgonha S, Rabe J, Young V, Grinspoon S. Increased rates of lipolysis among human immunodeficiency virus-infected men receiving highly active antiretroviral therapy. Metabolism 51: 1143–1147, 2002.[CrossRef][ISI][Medline]
  22. Hammond E, Nolan D, James I, Metcalf C, Mallal S. Reduction of mitochondrial DNA content and respiratory chain activity occurs in adipocytes within 6–12 months of commencing nucleoside reverse transcriptase inhibitor therapy. AIDS 18: 815–817, 2004.[CrossRef][ISI][Medline]
  23. Himms-Hagen J. Does brown adipose tissue (BAT) have a role in the physiology or treatment of human obesity? Rev Endocr Metab Disord 2: 395–401, 2001.[CrossRef][Medline]
  24. Hommes MJ, Romijn JA, Endert E, Sauerwein HP. Resting energy expenditure and substrate oxidation in human immunodeficiency virus (HIV)-infected asymptomatic men: HIV affects host metabolism in the early asymptomatic stage. Am J Clin Nutr 54: 311–315, 1991.[Abstract/Free Full Text]
  25. Jaggy C, von Overbeck J, Ledergerber B, Schwarz C, Egger M, Rickenbach M, Furrer HJ, Telenti A, Battegay M, Flepp M, Vernazza P, Bernasconi E, Hirschel B. Mortality in the Swiss HIV Cohort Study (SHCS) and the Swiss general population. Lancet 362: 877–878, 2003.[CrossRef][ISI][Medline]
  26. Jan V, Cervera P, Maachi M, Baudrimont M, Kim M, Vidal H, Girard PM, Levan P, Rozenbaum W, Lombes A, Capeau J, Bastard JP. Altered fat differentiation and adipocytokine expression are inter-related and linked to morphological changes and insulin resistance in HIV-1-infected lipodystrophic patients. Antivir Ther 9: 555–564, 2004.[ISI][Medline]
  27. Jequier E. Leptin signaling, adiposity, and energy balance. Ann NY Acad Sci 967: 379–388, 2002.[Abstract/Free Full Text]
  28. Kakuda TN. Pharmacology of nucleoside and nucleotide reverse transcriptase inhibitor-induced mitochondrial toxicity. Clin Ther 22: 685–708, 2000.[CrossRef][ISI][Medline]
  29. Kannisto K, Sutinen J, Korsheninnikova E, Fisher RM, Ehrenborg E, Gertow K, Virkamäki A, Nyman T, Vidal H, Hamsten A, Yki-Järvinen H. Expression of adipogenic transcription factors, peroxisome proliferator-activated receptor {gamma} co-activator 1, IL-6 and CD45 in subcutaneous adipose tissue in lipodystrophy associated with highly active antiretroviral therapy. AIDS 17: 1753–1762, 2003.[CrossRef][ISI][Medline]
  30. Kosmiski L, Kuritzkes D, Lichtenstein K, Eckel R. Adipocyte-derived hormone levels in HIV lipodystrophy. Antivir Ther 8: 9–15, 2003.[ISI][Medline]
  31. Kosmiski LA, Kuritzkes DR, Lichtenstein KA, Glueck DH, Gourley PJ, Stamm ER, Scherzinger AL, Eckel RH. Fat distribution and metabolic changes are strongly correlated and energy expenditure is increased in the HIV lipodystrophy syndrome. AIDS 15: 1993–2000, 2001.[CrossRef][ISI][Medline]
  32. Kosmiski LA, Kuritzkes DR, Sharp TA, Hamilton JT, Lichtenstein KA, Mosca CL, Grunwald GK, Eckel RH, Hill JO. Total energy expenditure and carbohydrate oxidation are increased in the human immunodeficiency virus lipodystrophy syndrome. Metabolism 52: 620–625, 2003.[CrossRef][ISI][Medline]
  33. Koutkia P, Meininger G, Canavan B, Breu J, Grinspoon S. Metabolic regulation of growth hormone by free fatty acids, somatostatin, and ghrelin in HIV-lipodystrophy. Am J Physiol Endocrinol Metab 286: E296–E303, 2004.[Abstract/Free Full Text]
  34. Lihn AS, Richelsen B, Pedersen SB, Haugaard SB, Rathje GS, Madsbad S, Andersen O. Increased expression of TNF-{alpha}, IL-6, and IL-8 in HIV-associated lipodystrophy. Implications for the reduced expression and plasma levels of adiponectin. Am J Physiol Endocrinol Metab 285: E1072–E1080, 2003.[Abstract/Free Full Text]
  35. Macallan DC, Noble C, Baldwin C, Jebb SA, Prentice AM, Coward WA, Sawyer MB, McManus TJ, Griffin GE. Energy expenditure and wasting in human immunodeficiency virus infection. N Engl J Med 333: 83–88, 1995.[Abstract/Free Full Text]
  36. McDuffie JR, Riggs PA, Calis KA, Freedman RJ, Oral EA, DePaoli AM, Yanovski JA. Effects of exogenous leptin on satiety and satiation in patients with lipodystrophy and leptin insufficiency. J Clin Endocrinol Metab 89: 4258–4263, 2004.[Abstract/Free Full Text]
  37. Meininger G, Hadigan C, Laposata M, Brown J, Rabe J, Louca J, Aliabadi N, Grinspoon S. Elevated concentrations of free fatty acids are associated with increased insulin response to standard glucose challenge in human immunodeficiency virus-infected subjects with fat redistribution. Metabolism 51: 260–266, 2002.[CrossRef][ISI][Medline]
  38. Miles J, Classcock R, Aikens J, Gerich J, Haymond N. A microfluorometric method for the determination of free fatty acids in plasma. J Lipid Res 24: 96–99, 1983.[Abstract]
  39. Mynarcik DC, Combs T, McNurlan MA, Scherer PE, Komaroff E, Gelato MC. Adiponectin and leptin levels in HIV-infected subjects with insulin resistance and body fat redistribution. J Acquir Immune Defic Syndr 31: 514–520, 2002.[ISI][Medline]
  40. Nolan D, Hammond E, James I, McKinnon E, Mallal S. Contribution of nucleoside-analogue reverse transcriptase inhibitor therapy to lipoatrophy from the population to the cellular level. Antivir Ther 8: 617–626, 2003.[Medline]
  41. Oral EA, Simha V, Ruiz E, Andewelt A, Premkumar A, Snell P, Wagner AJ, DePaoli AM, Reitman ML, Taylor SI, Gorden P, Garg A. Leptin-replacement therapy for lipodystrophy. N Engl J Med 346: 570–578, 2002.[Abstract/Free Full Text]
  42. Pernerstorfer-Schoen H, Schindler K, Parschalk B, Schindl A, Thoeny-Lampert S, Wunderer K, Elmadfa I, Tschachler E, Jilma B. Beneficial effects of protease inhibitors on body composition and energy expenditure: a comparison between HIV-infected and AIDS patients. AIDS 13: 2389–2396, 1999.[CrossRef][ISI][Medline]
  43. Renard E, Fabre J, Paris F, Reynes J, Bringer J. Syndrome of body fat redistribution in HIV-1-infected patients: relationships to cortisol and catecholamines. Clin Endocrinol (Oxf) 51: 223–230, 1999.[CrossRef][Medline]
  44. Rodriguez de la Concepcion ML, Domingo JC, Domingo P, Giralt M, Villarroya F. Uncoupling protein 1 gene expression implicates brown adipocytes in highly active antiretroviral therapy-associated lipomatosis. AIDS 18: 959–960, 2004.[CrossRef][ISI][Medline]
  45. Schrauwen P, van Marken Lichtenbelt WD, Saris WH, Westerterp KR. Changes in fat oxidation in response to a high-fat diet. Am J Clin Nutr 66: 276–282, 1997.[Abstract/Free Full Text]
  46. Sekhar RV, Jahoor F, White AC, Pownall HJ, Visnegarwala F, Rodriguez-Barradas MC, Sharma M, Reeds PJ, Balasubramanyam A. Metabolic basis of HIV-lipodystrophy syndrome. Am J Physiol Endocrinol Metab 283: E332–E337, 2002.[Abstract/Free Full Text]
  47. Shikuma CM, Hu N, Milne C, Yost F, Waslien C, Shimizu S, Shiramizu B. Mitochondrial DNA decrease in subcutaneous adipose tissue of HIV-infected individuals with peripheral lipoatrophy. AIDS 15: 1801–1809, 2001.[CrossRef][ISI][Medline]
  48. Sjostrom L, Schutz Y, Gudinchet F, Hegnell L, Pittet PG, Jequier E. Epinephrine sensitivity with respect to metabolic rate and other variables in women. Am J Physiol Endocrinol Metab 245: E431–E442, 1983.[Abstract/Free Full Text]
  49. Smith SR, de Jonge L, Zachwieja JJ, Roy H, Nguyen T, Rood JC, Windhauser MM, Bray GA. Fat and carbohydrate balances during adaptation to a high-fat. Am J Clin Nutr 71: 450–457, 2000.[Abstract/Free Full Text]
  50. Sutinen J, Häkkinen AM, Westerbacka J, Seppälä-Lindroos A, Vehkavaara S, Halavaara J, Järvinen A, Ristola M, Yki-Järvinen H. Increased fat accumulation in the liver in HIV-infected patients with antiretroviral therapy-associated lipodystrophy. AIDS 16: 2183–2193, 2002.[CrossRef][ISI][Medline]
  51. Sutinen J, Häkkinen AM, Westerbacka J, Seppälä-Lindroos A, Vehkavaara S, Halavaara J, Järvinen A, Ristola M, Yki-Järvinen H. Rosiglitazone in the treatment of HAART-associated lipodystrophy - a randomized double-blind placebo-controlled study. Antivir Ther 8: 199–207, 2003.[Medline]
  52. Sutinen J, Kannisto K, Korsheninnikova E, Fisher RM, Ehrenborg E, Nyman T, Virkamäki A, Funahashi T, Matsuzawa Y, Vidal H, Hamsten A, Yki-Järvinen H. Effects of rosiglitazone on gene expression in subcutaneous adipose tissue in highly active antiretroviral therapy-associated lipodystrophy. Am J Physiol Endocrinol Metab 286: E941–E949, 2004.[Abstract/Free Full Text]
  53. Sutinen J, Kannisto K, Korsheninnikova E, Nyman T, Ehrenborg E, Andrew R, Wake DJ, Hamsten A, Walker BR, Yki-Järvinen H. In the lipodystrophy associated with highly active antiretroviral therapy, pseudo-Cushing's syndrome is associated with increased regeneration of cortisol by 11beta-hydroxysteroid dehydrogenase type 1 in adipose tissue. Diabetologia 47: 1668–1671, 2004.[CrossRef][ISI][Medline]
  54. Sutinen J, Korsheninnikova E, Funahashi T, Matsuzawa Y, Nyman T, Yki-Järvinen H. Circulating concentration of adiponectin and its expression in subcutaneous adipose tissue in patients with highly active antiretroviral therapy-associated lipodystrophy. J Clin Endocrinol Metab 88: 1907–1910, 2003.[Abstract]
  55. Suttmann U, Holtmannspotter M, Ockenga J, Gallati H, Deicher H, Selberg O. Tumor necrosis factor, interleukin-6, and epinephrine are associated with hypermetabolism in AIDS patients with acute opportunistic infections. Ann Nutr Metab 44: 43–53, 2000.[CrossRef][ISI][Medline]
  56. Tien PC, Grunfeld C. What is HIV-associated lipodystrophy? Defining fat distribution changes in HIV infection. Curr Opin Infect Dis 17: 27–32, 2004.[CrossRef][ISI][Medline]
  57. Van der Valk M, Bisschop PH, Romijn JA, Ackermans MT, Lange JM, Endert E, Reiss P, Sauerwein HP. Lipodystrophy in HIV-1-positive patients is associated with insulin resistance in multiple metabolic pathways. AIDS 15: 2093–2100, 2001.[CrossRef][ISI][Medline]
  58. Van der Valk M, Reiss P, van Leth FC, Ackermans MT, Endert E, Romijn JA, Heijligenberg R, Sauerwein H. Highly active antiretroviral therapy-induced lipodystrophy has minor effects on human immunodeficiency virus-induced changes in lipolysis, but normalizes resting energy expenditure. J Clin Endocrinol Metab 87: 5066–5071, 2002.[Abstract/Free Full Text]
  59. Walker UA, Bickel M, Lutke Volksbeck SI, Ketelsen UP, Schofer H, Setzer B, Venhoff N, Rickerts V, Staszewski S. Evidence of nucleoside analogue reverse transcriptase inhibitor -associated genetic and structural defects of mitochondria in adipose tissue of HIV-infected patients. J Acquir Immune Defic Syndr 29: 117–121, 2002.[ISI][Medline]
  60. Yki-Järvinen H, Puhakainen I, Saloranta C, Groop L, Taskinen MR. Demonstration of a novel feedback mechanism between FFA oxidation from intracellular and intravascular sources. Am J Physiol Endocrinol Metab 260: E680–E689, 1991.[Abstract/Free Full Text]
  61. Yki-Järvinen H, Sutinen J, Silveira A, Korsheninnikova E, Fisher RM, Kannisto K, Ehrenborg E, Eriksson P, Hamsten A. Regulation of plasma PAI-1 concentrations in HAART-associated lipodystrophy during rosiglitazone therapy. Arterioscler Thromb Vasc Biol 23: 688–694, 2003.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 Am. J. Clin. Nutr.Home page
L. A Kosmiski, D. H Bessesen, S. A Stotz, J. R Koeppe, and T. J Horton
Short-term overfeeding increases resting energy expenditure in patients with HIV lipodystrophy
Am. J. Clinical Nutrition, October 1, 2007; 86(4): 1009 - 1015.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Endocrinol. Metab.Home page
J. Koska, E. Ortega, C. Bogardus, J. Krakoff, and J. C. Bunt
The effect of insulin on net lipid oxidation predicts worsening of insulin resistance and development of type 2 diabetes mellitus
Am J Physiol Endocrinol Metab, July 1, 2007; 293(1): E264 - E269.
[Abstract] [Full Text] [PDF]

This Article
Free upon publication Free Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
292/3/E687    most recent
00219.2006v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (3)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Sutinen, J.
Right arrow Articles by Yki-Järvinen, H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Sutinen, J.
Right arrow Articles by Yki-Järvinen, H.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online
Copyright © 2007 by the American Physiological Society.