Variable Cold-Induced Brown Adipose Tissue Response to Thyroid Hormone Status.

BACKGROUND: In addition to its role in adaptive thermogenesis, brown adipose tissue (BAT) may protect from weight gain, insulin resistance/diabetes, and metabolic syndrome. Prior studies have shown contradictory results regarding the influence of thyroid hormone (TH) levels on BAT volume and activity. The aim of this pilot study was to gain further insights regarding the effect of TH treatment on BAT function in adult humans by evaluating the BAT mass and activity prospectively in six patients, first in the hypothyroid and then in the thyrotoxic phase. METHODS: The study subjects underwent 18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) scanning after cold exposure to measure BAT mass and activity while undergoing treatment for differentiated thyroid cancer, first while hypothyroid following TH withdrawal at the time of the radioactive iodine treatment and then three to six months after starting TH suppressive treatment when they were iatrogenically thyrotoxic. Thermogenic and metabolic parameters were measured in both phases. RESULTS: All study subjects had detectable BAT under cold stimulation in both the hypothyroid and thyrotoxic state. The majority but not all (4/6) subjects showed an increase in detectable BAT volume and activity under cold stimulation between the hypothyroid and thyrotoxic phase (total BAT volume: 72.0 ± 21.0 vs. 87.7 ± 16.5 mL, p = 0.25; total BAT activity 158.1 ± 72.8 vs. 189.0 ± 55.5 SUV*g/mL, p = 0.34). Importantly, circulating triiodothyronine was a stronger predictor of energy expenditure changes compared with cold-induced BAT activity. CONCLUSIONS: Iatrogenic hypothyroidism lasting two to four weeks does not prevent cold-induced BAT activation, while the use of TH to induce thyrotoxicosis does not consistently increase cold-induced BAT activity. It remains to be determined which physiological factors besides TH play a role in regulating BAT function.

Anatomical localization, gene expression profiling and functional characterization of adult human neck brown fat.

The imbalance between energy intake and expenditure is the underlying cause of the current obesity and diabetes pandemics. Central to these pathologies is the fat depot: white adipose tissue (WAT) stores excess calories, and brown adipose tissue (BAT) consumes fuel for thermogenesis using tissue-specific uncoupling protein 1 (UCP1). BAT was once thought to have a functional role in rodents and human infants only, but it has been recently shown that in response to mild cold exposure, adult human BAT consumes more glucose per gram than any other tissue. In addition to this nonshivering thermogenesis, human BAT may also combat weight gain by becoming more active in the setting of increased whole-body energy intake. This phenomenon of BAT-mediated diet-induced thermogenesis has been observed in rodents and suggests that activation of human BAT could be used as a safe treatment for obesity and metabolic dysregulation. In this study, we isolated anatomically defined neck fat from adult human volunteers and compared its gene expression, differentiation capacity and basal oxygen consumption to different mouse adipose depots. Although the properties of human neck fat vary substantially between individuals, some human samples share many similarities with classical, also called constitutive, rodent BAT.

Circulating resistin levels are not associated with fat redistribution, insulin resistance, or metabolic profile in patients with the highly active antiretroviral therapy-induced metabolic syndrome.

CONTEXT: The mechanisms underlying the development of the highly active antiretroviral therapy (HAART)-induced metabolic syndrome remain to be fully elucidated. OBJECTIVE: The objective of this study was to investigate whether the adipocyte-secreted hormone, resistin, is associated with anthropometric and metabolic abnormalities of the HAART-induced metabolic syndrome. DESIGN, SETTING, AND PATIENTS: We conducted a cross-sectional study of 227 HIV-positive patients (37 women and 190 men) recruited from the infectious diseases clinics. On the basis of history, physical examination, dual-energy x-ray absorptiometry, and single-slice computed tomography, patients were classified into four groups: non-fat redistribution (n = 85), fat accumulation (n = 42), fat wasting (n = 35), and mixed fat redistribution (n = 56). MAIN OUTCOME MEASURES: The main outcome measures were serum resistin levels and anthropometric and metabolic variables. RESULTS: Mean serum resistin levels were not significantly different among subjects with fat accumulation, fat wasting, or mixed fat redistribution or between these groups and the non-fat redistribution group. We found a weak, but significant, positive correlation between resistin and percent total body fat (r = 0.20; P < 0.01), total extremity fat (r = 0.18; P < 0.01), and abdominal sc fat (r = 0.19; P < 0.01), but not abdominal visceral fat (r = -0.10; P = 0.16) or waist to hip ratio (r = -0.05; P = 0.43). When adjustments were made for gender (women, 3.92 +/- 2.71 ng/ml; men, 2.96 +/- 2.61 ng/ml; P = 0.05), correlations between resistin and the above parameters were no longer significant. Importantly, resistin levels were not correlated with fasting glucose, insulin, homeostasis model assessment of insulin resistance index, triglycerides, or cholesterol levels in the whole group. CONCLUSIONS: Resistin is related to gender, but is unlikely to play a major role in the insulin resistance and metabolic abnormalities of the HAART-induced metabolic syndrome.

Improvement in highly active antiretroviral therapy-induced metabolic syndrome by treatment with pioglitazone but not with fenofibrate: a 2 x 2 factorial, randomized, double-blinded, placebo-controlled trial.

We designed a 2 x 2 factorial, randomized, double-blinded, placebo-controlled trial to evaluate the effects of treatment with pioglitazone and/or fenofibrate in patients with highly active antiretroviral therapy (HAART)-induced metabolic syndrome. We found that the administration of pioglitazone, but not fenofibrate, improved insulin resistance, blood pressure, and lipid profile over a 12-month period.

Circulating melanin-concentrating hormone, agouti-related protein, and alpha-melanocyte-stimulating hormone levels in relation to body composition: alterations in response to food deprivation and recombinant human leptin administration.

We evaluated whether circulating levels of melanin-concentrating hormone (MCH), agouti-related protein (AGRP), and alpha-MSH could serve as useful markers of energy homeostasis in humans. We first assessed correlations of serum MCH, AGRP, and alpha-MSH with anthropometric, dietary, and hormonal variables in a cross-sectional study of 108 healthy humans. We then performed interventional studies to evaluate the effects of fasting and/or leptin administration. In eight healthy, normal weight men, we measured serum MCH, AGRP, and alpha-MSH levels at baseline, after 2 d of fasting alone (a low leptin state), and after 2 d of fasting with replacement dose recombinant methionyl human leptin (r-metHuLeptin) administration to normalize circulating leptin levels. In a separate group of five lean and five obese men, we measured MCH levels in response to increasing circulating leptin levels to the pharmacological range by administration of one r-metHuLeptin dose in the fed state. In the cross-sectional study, serum MCH levels were independently and positively associated with body mass index and fat mass and were higher in women than in men. Furthermore, in our interventional studies, fasting for 2 d significantly decreased leptin levels and increased serum MCH levels. Administration of replacement dose r-metHuLeptin during fasting prevented the fasting-induced increase in MCH levels, but administration of a pharmacological r-metHuLeptin dose in the fed state did not further alter MCH levels. Serum AGRP levels tended to change in directions similar to MCH, but this change was less pronounced and needs to be investigated in larger studies. In contrast, serum alpha-MSH levels did not correlate with body composition parameters, were not associated with caloric or macronutrient intake, and were not significantly affected by fasting or r-metHuLeptin administration. These findings suggest that serum MCH and possibly AGRP levels could serve as useful peripheral markers of changes in energy homeostasis and thus merit additional investigation.

Serum adiponectin concentrations in relation to maternal and perinatal characteristics in newborns.

OBJECTIVE: To assess serum adiponectin levels of neonates in relation to ponderal index and birth length with and without adjustment for potential confounding factors including maternal factors and perinatal characteristics. DESIGN: A cross-sectional study. METHODS: Three hundred and three newborns (Caucasian, singleton, full term, with a birth weight of > or =2500 g, and apparently healthy) were included in the study. Blood samples were collected from the newborns no later than the fifth day of life for measurements of adiponectin and major IGF system components (IGF-I, IGF-II, IGF binding protein-3 (IGFBP-3)). The data were analyzed using simple and multiple regression analyses. RESULTS: Adiponectin is substantially higher in neonates than in adults, with no evidence of the gender dimorphism observed among adults. We found an inverse association between neonatal adiponectin levels and newborn ponderal index and a positive association with newborn length by univariate analysis. We also found a statistically significant inverse association of adiponectin with jaundice/bilirubin, and a marginally significant positive association of this hormone with IGFBP-3 but no significant association with any maternal factors. In multivariate analysis, the inverse association between serum adiponectin and ponderal index does not remain significant after adjustment for potential confounding factors. In contrast, neonatal adiponectin levels correlate inversely significantly and independently with liver maturity and IGF-II and tend to remain positively associated with IGFBP-3 and increased birth length. CONCLUSIONS: An inverse association of adiponectin with ponderal index by univariate analysis is not independent from confounding factors. In contrast, the positive association between serum adiponectin and birth length may reflect either a direct effect of adiponectin or an adiponectin-mediated increase in the sensitivity of tissues to insulin and components of the IGF system, and needs to be explored further.

Serum adiponectin levels are inversely associated with overall and central fat distribution but are not directly regulated by acute fasting or leptin administration in humans: cross-sectional and interventional studies.

Adiponectin is an adipocyte-secreted protein that circulates in high concentrations in the serum and acts to increase insulin sensitivity. Previous studies have shown that serum adiponectin is inversely associated with fat mass and insulin resistance in humans and that acute fasting decreases adipose tissue adiponectin mRNA expression in rodents. Whether acute energy deprivation, body fat distribution, or serum hormone levels are associated with circulating adiponectin in humans remains largely unknown. To identify predictors of serum adiponectin levels, we evaluated the association of adiponectin with several anthropometric, metabolic, and hormonal variables in a cross-sectional study of 121 women without a known history of diabetes. We also performed interventional studies to assess whether fasting for 48 h and/or leptin administration regulates serum adiponectin in healthy men and women. Our cross-sectional study shows that, in addition to overall obesity, central fat distribution is an independent negative predictor of serum adiponectin and suggests that adiponectin may represent a link between central obesity and insulin resistance. In addition, estradiol is negatively and independently associated with adiponectin, whereas there is no association between serum adiponectin and leptin, cortisol, or free testosterone levels. Our interventional studies demonstrate that neither fasting for 48 h, resulting in a low leptin state, nor leptin administration at physiological or pharmacological doses alters serum adiponectin levels. Further studies are needed to fully elucidate the physiology of adiponectin in humans and its role in the pathogenesis of insulin-resistant states.

Exercise and vitamin E intake are independently associated with metabolic abnormalities in human immunodeficiency virus-positive subjects: a cross-sectional study.

We investigated the relationship among habitual exercise, diet, and the presence of metabolic abnormalities (body fat redistribution, dyslipidemia, and insulin resistance) in a cross-sectional study of 120 human immunodeficiency virus (HIV)-infected subjects with use of bivariate and multivariate regression-analysis models. Total and aerobic exercise were significantly and negatively associated with fasting plasma triglyceride levels in the entire sample and in the fat redistribution group. Inverse associations between total or aerobic exercise and insulin resistance were suggestive but did not achieve statistical significance. Diastolic blood pressure was significantly and inversely associated with supplemental or total but not habitual dietary intake of vitamin E. In conclusion, exercise and vitamin E intake were independently and negatively associated with several phenotypic manifestations of HIV-associated metabolic syndrome, whereas other macro- or micronutrients did not have comparable significance.

Diurnal and ultradian dynamics of serum adiponectin in healthy men: comparison with leptin, circulating soluble leptin receptor, and cortisol patterns.

Adiponectin is an abundant serum adipokine secreted exclusively from differentiated adipocytes, which plays an important role in regulating insulin sensitivity. The dynamics of circulating adiponectin concentrations have yet to be systematically investigated. We sought to determine whether serum adiponectin levels exhibit diurnal or ultradian rhythms in healthy normal-weight men and to compare the 24-h profile of adiponectin fluctuations with those of leptin, leptin-binding protein (sOB-R), and cortisol. We collected blood samples at 15-min intervals over 24 h from six subjects receiving an isocaloric diet, and we measured adiponectin, leptin, sOB-R, and cortisol levels. Fourier and cross-correlation analyses were performed on these time series to study diurnal variations, and the Cluster7 program was used for pulsatility analysis. Circulating adiponectin and sOB-R levels exhibited ultradian pulsatility as well as a diurnal variation with a significant decline at night, reaching a nadir in the early morning. The 24-h variations of serum adiponectin and sOB-R were nearly identical and followed those of cortisol after a few hours, but were out-of-phase with leptin diurnal rhythms. These data suggest that adiponectin and sOB-R levels might be influenced by common regulatory factors and challenge the notion that cortisol may have a direct inhibitory effect on adiponectin in humans.

Human immunodeficiency virus type 1-related lipoatrophy and lipohypertrophy are associated with serum concentrations of leptin.

The relationship between the adipocyte-derived hormone leptin, insulin resistance, and fat redistribution in patients with human immunodeficiency virus (HIV) infection has not been established. We classified a cohort of HIV type 1 (HIV-1)-infected patients with >or=6 months of antiretroviral exposure as having no lipodystrophy (51 patients [43% of the cohort]), lipoatrophy (23 patients [19% of the cohort]), mixed lipodystrophy (29 patients [24% of the cohort]), or lipohypertrophy (17 patients [14% of the cohort]), on the basis of physical examination, anthropometric measurements, and the findings of dual-emission x-ray absorptiometry and computed tomography. Measurements of insulin resistance were higher for patients with each category of lipodystrophy, compared with those observed for patients with no lipodystrophy (P<.001). Mean leptin levels (+/- standard deviation) were lowest in patients with lipoatrophy (1.76+/-1.20 ng/mL), highest in patients with lipohypertrophy (9.10+/-6.86 ng/mL), and significantly different from those in patients without lipodystrophy (3.14+/-2.30 ng/mL; both P<.01). In this cohort of antiretroviral-experienced HIV-infected patients, a low serum level of leptin was independently associated with insulin resistance in patients with lipoatrophy, after controlling for total and regional body fat.

Hypoadiponectinemia is associated with insulin resistance, hypertriglyceridemia, and fat redistribution in human immunodeficiency virus-infected patients treated with highly active antiretroviral therapy.

A lipodystrophic syndrome and metabolic abnormalities have been observed in HIV-infected patients treated with highly active antiretroviral therapy (HAART). A murine model of lipodystrophy is associated with decreased levels of adiponectin, an adipocyte-secreted protein, the administration of which improves the metabolic syndrome in these mice. To investigate the association of adiponectin with metabolic changes in human lipodystrophy, we conducted a cross-sectional study of 112 HIV-infected patients treated with HAART. Mean adiponectin levels were higher in patients with no fat redistribution (FR) vs. FR (4.8 +/- 5.0 vs. 2.2 +/- 2.7 microg/ml, P < 0.01), but no significant differences in adiponectin levels were observed between FR subgroups. The difference in adiponectin levels between subjects with and without FR remained significant after adjusting for age, gender, leptin, HIV medication use, and CD4 count using logistic regression (odds ratio, 0.54, P = 0.008). Adiponectin was significantly correlated with triglycerides (r = -0.40), abdominal visceral fat (r = -0.35), extremity fat (r = 0.37), insulin resistance (HOMA-IR) (r = -0.28), nucleoside reverse transcriptase inhibitor (NRTI) use (r = -0.32), and high-density lipoprotein (HDL) (r = 0.41) using bivariate analysis (all P < 0.01). The association with HDL weakened but remained significant on multivariate analysis (standard beta = 0.29, P = 0.01). However, the association of adiponectin with HOMA-IR became nonsignificant after adjusting for NRTI use (standard beta = -0.15, P = 0.12), suggesting that changes in adiponectin levels may underlie the effect of NRTI use on insulin resistance. The associations of adiponectin with triglycerides and HOMA-IR were also slightly weakened after adjusting for visceral and extremity fat, indicating that adiponectin may, in part, mediate the effect of FR on triglycerides and insulin resistance. This study indicates that adiponectin is inversely correlated with abdominal visceral fat mass, serum triglycerides, and insulin resistance and is directly correlated with HDL and extremity fat in a sample of HIV-infected patients treated with HAART. The results also indicate that NRTI use may worsen insulin resistance by decreasing adiponectin levels. Thus, adiponectin replacement may be a potential treatment option to ameliorate the metabolic changes observed in this patient population.