Changes in weight and lean body mass during highly active antiretroviral therapy.
(1/2014)
BACKGROUND: Few studies have prospectively evaluated the impact of highly active antiretroviral therapy (HAART) on body weight and lean body mass (LBM) or explored the impact of baseline immunologic or virological changes on these parameters. METHODS: Adult AIDS Clinical Trials Group (ACTG) protocol 892 was a prospective, 48-week, multisite observational study of body composition conducted during 1997-2000 among 224 antiretroviral-naive and antiretroviral-experienced subjects coenrolled into various adult ACTG antiretroviral studies. Assessments included human immunodeficiency virus type 1 (HIV-1) RNA load (by polymerase chain reaction); T lymphocyte subset analysis; Karnofsky score; height (baseline only); weight, LBM, and fat (by bioelectrical impedance analysis); and functional performance (by questionnaire). RESULTS: Overall, only modest median increases in body weight (1.9 kg) and LBM (0.6 kg) occurred after 16 weeks of therapy. Significantly greater median increases in body weight (2.1 vs. 0.5 kg; P=.045) occurred in subjects who achieved virological suppression (HIV-1 RNA load, <500 copies/mL) at week 16 than in subjects who did not. Subjects who were antiretroviral naive at baseline gained more weight (median increase in body weight, 2.6 vs. 0.0 kg; P<.001) and LBM (1.0 vs. 0.1 kg; P=.002) after 16 weeks of treatment than did subjects who were antiretroviral experienced. Subjects with lower baseline CD4 cell counts (<200 cells/mm3) and subjects with higher baseline HIV-1 RNA loads (> or =100,000 copies/mL) were more likely to show increases in LBM of >1.5 kg (P=.013 and P=.005, respectively). CONCLUSIONS: HAART had modestly favorable effects on body composition, particularly in patients with greater pretreatment immunocompromise and virological compromise. The difference between antiretroviral-naive and antiretroviral-experienced subjects with regard to the ability to achieve increased body weight and LBM requires more study. (+info)
Elevated soluble ICAM-1 levels induce immune deficiency and increase adiposity in mice.
(2/2014)
Elevated soluble intercellular adhesion molecule-1 (sICAM-1) levels have been found in many pathological conditions, including obesity. To determine the effects of elevated sICAM-1 on immune responses and metabolism, we generated a transgenic mouse model overexpressing the extracellular domain of mouse ICAM-1 in the liver. The mice, showing 10-fold higher sICAM-1 levels than wild-type mice, presented elevated neutrophil count. Despite this, after intraperitoneal injection of thioglycollate, neutrophil recruitment into the peritoneal cavity was reduced, and the delayed macrophage recruitment was also affected in the transgenic mice compared with wild-type mice. Inhibition of contact hypersensitivity response in the sICAM-1 transgenic mice was comparable to ICAM-1-deficient mice and characterized by significantly less ear swelling and inflammatory cell infiltration than in wild-type mice. sICAM-1transgenic mice were more susceptible to weight gain on a Western-type diet than wild-type mice, and older animals showed excessive fat accumulation, again reminiscent of ICAM-1-deficient mice. Together, these data indicate that sICAM-1 interferes with ICAM-1-mediated cell-cell interactions, which could produce immune-suppressant effects and alteration of metabolism in persons with high levels of this soluble adhesion receptor. (+info)
Rise in insulin resistance is associated with escalated telomere attrition.
(3/2014)
BACKGROUND: Insulin resistance predisposes to cardiovascular disease and shortens human lifespan. We therefore tested the hypothesis that a rise in insulin resistance in concert with gain in body mass is associated with accelerated white blood cell telomere attrition. METHODS AND RESULTS: We measured white blood cell telomere dynamics and age-related changes in insulin resistance and body mass index in young adults of the Bogalusa Heart Study. Over 10.1 to 12.8 years, the relative changes in telomere length were correlated with the homeostasis model assessment of insulin resistance (r=-0.531, P<0.001) and changes in the body mass index (r=-0.423, P<0.001). CONCLUSIONS: These findings provide the first tangible nexus of telomere biology with insulin resistance and adiposity in humans. (+info)
Genetic modifiers interact with Cpe(fat) to affect body weight, adiposity, and hyperglycemia.
(4/2014)
Obesity and Type II diabetes are complex diseases in the human population. The existence of a large number of contributing loci and gene-gene as well as gene-environment interactions make it difficult to identify the disease genes underlying these complex traits. In mouse models of obesity and Type II diabetes such as the murine fat mutation, genetic crosses can be used to dissect the genetic complexity influencing the observed phenotypes. The underlying defect in the fat mutant is a Ser202Pro change in carboxypeptidase E (CPE), an enzyme responsible for the final proteolytic processing step of prohormone intermediates. On the HRS/J (HRS) inbred strain background, mice homozygous for the fat mutation exhibit early onset hyperinsulinemia followed by postpubertal moderate obesity without hyperglycemia. In contrast, on the C57BLKS/J (BKS) genetic background, fat/fat mice become severely obese, hyperinsulinemic, and hyperglycemic. Therefore, in the Cpe(fat) genetic model, the fat mutation is necessary but not sufficient for the development of obesity, Type II diabetes, and related metabolic disorders. To dissect the susceptibility loci responsible for modifying obesity- and diabetes-associated traits, we characterized, both genetically and phenotypically, fat/fat male progeny from a large intercross between BKS. HRS-fat/fat and HRS-+/+ mice. Four major loci were mapped, including a locus for body weight (body weight 1) on chromosome 14; a locus for hyperglycemia (fat-induced diabetes 1) on chromosome 19; a locus for hyperglycemia, hyperinsulinemia, and hypercholesterolemia (fat-induced diabetes 2) on chromosome 5; and a locus for adiposity and body weight (fat-induced adiposity 1) on chromosome 11. The identification of these interacting genetic determinants for obesity and Type II diabetes may allow better definition of the obesity/diabetes-related hormone signaling pathways and ultimately may provide new insights into the pathogenesis of these complex diseases. (+info)
Body mass index in relation to ovarian cancer survival.
(5/2014)
Evidence for an association between indicators of adiposity and survival after ovarian cancer has been inconsistent. A prospective cohort study was conducted in China to examine the relationship between ovarian cancer survival and body mass index (BMI). From the 214 patients recruited in 1999 to 2000 with histopathologically confirmed invasive epithelial ovarian cancer, 207 patients or their close relatives (96.7% of cases) were traced and followed to 2003. Deaths were recorded and Cox proportional hazards regression was used to obtain hazard ratios (HR) and 95% confidence intervals (95% CI) from multivariate models. Reduced survival was observed among patients with BMI > or = 25 kg/m(2) at 5 years before diagnosis (P = 0.001). There were 98 (59.8%) of 164 patients with BMI <25 kg/m(2) survived to the time of interview compared with only 15 women (34.9%) among the 43 patients whose BMI was > or =25 kg/m(2). The HRs significantly increased with higher BMI at 5 years before diagnosis but not at diagnosis nor at age 21 years. The adjusted HR was 2.33 (95% CI, 1.12-4.87) for BMI of > or =25 versus <20 kg/m(2), with a significant dose-response relationship. The HR was 3.31 (95% CI, 1.26-8.73) among patients who had been overweight or obese at age 21 years, but a linear dose-response was not found. We conclude that premorbid BMI may have independent prognostic significance in ovarian cancer. (+info)
Recombinant leptin promotes atherosclerosis and thrombosis in apolipoprotein E-deficient mice.
(6/2014)
OBJECTIVE: The direct role of leptin in vascular disease remains controversial. The objective of this study was to examine the effects of leptin treatment on atherosclerosis and thrombosis in atherosclerotic-prone mice. METHODS AND RESULTS: Sixteen-week-old, male apolipoprotein E-deficient mice were treated with injections of recombinant leptin (125 microg per day IP; n=10) or vehicle (n=10) for 4 weeks. Leptin treatment resulted in reduced epididymal fat (352+/-30.7 versus 621+/-61.5 mg; P=0.005) and fasting insulin (0.57+/-0.25 versus 1.7+/-0.22 ng/mL; P=0.014). Despite these metabolic benefits, leptin treatment resulted in an increase in atherosclerosis (8.0+/-0.95% versus 5.4+/-0.59% lesion surface coverage; P<0.05). Leptin treatment also resulted in a shortened time to occlusive thrombosis after vascular injury (21+/-2.1 versus 34.6+/-5.4 minutes; P=0.045). CONCLUSIONS: These studies indicate that exogenous leptin promotes atherosclerosis and thrombosis and support the concept that elevations of leptin may increase the risk for cardiovascular disease. (+info)
Cathepsin S, a novel biomarker of adiposity: relevance to atherogenesis.
(7/2014)
The molecular mechanisms by which obesity increases the risk of cardiovascular diseases are poorly understood. The purpose of this study was to identify candidate biomarkers overexpressed in adipose tissue of obese subjects that could link expanded fat mass to atherosclerosis. We compared gene expression profile in subcutaneous adipose tissue (scWAT) of 28 obese and 11 lean subjects using microarray technology. This analysis identified 240 genes significantly overexpressed in scWAT of obese subjects. The genes were then ranked according to the correlation between gene expression and body mass index (BMI). In this list, the elastolytic cysteine protease cathepsin S was among the highly correlated genes. RT-PCR and Western blotting confirmed the increase in cathepsin S mRNA (P=0.006) and protein (P<0.05) in obese scWAT. The circulating concentrations of cathepsin S were also significantly higher in obese than in nonobese subjects (P<0.0001). Both cathepsin S mRNA in scWAT and circulating levels were positively correlated with BMI, body fat, and plasma triglyceride levels. In addition, we show that the proinflammatory factors, lipopolysaccharide, interleukin-1beta, and tumor necrosis factor-alpha increase cathepsin S secretion in human scWAT explants. This study identifies cathepsin S as a novel marker of adiposity. Since this enzyme has been implicated in the development of atherosclerotic lesions, we propose that cathepsin S represents a molecular link between obesity and atherosclerosis. (+info)
Body fatness during childhood and adolescence and incidence of breast cancer in premenopausal women: a prospective cohort study.
(8/2014)
INTRODUCTION: Body mass index (BMI) during adulthood is inversely related to the incidence of premenopausal breast cancer, but the role of body fatness earlier in life is less clear. We examined prospectively the relation between body fatness during childhood and adolescence and the incidence of breast cancer in premenopausal women. METHODS: Participants were 109,267 premenopausal women in the Nurses' Health Study II who recalled their body fatness at ages 5, 10 and 20 years using a validated 9-level figure drawing. Over 12 years of follow up, 1318 incident cases of breast cancer were identified. Cox proportional hazards regression was used to compute relative risks (RRs) and 95% confidence intervals (CIs) for body fatness at each age and for average childhood (ages 5-10 years) and adolescent (ages 10-20 years) fatness. RESULTS: Body fatness at each age was inversely associated with premenopausal breast cancer incidence; the multivariate RRs were 0.48 (95% CI 0.35-0.55) and 0.57 (95% CI 0.39-0.83) for the most overweight compared with the most lean in childhood and adolescence, respectively (P for trend < 0.0001). The association for childhood body fatness was only slightly attenuated after adjustment for later BMI, with a multivariate RR of 0.52 (95% CI 0.38-0.71) for the most overweight compared with the most lean (P for trend = 0.001). Adjustment for menstrual cycle characteristics had little impact on the association. CONCLUSION: Greater body fatness during childhood and adolescence is associated with reduced incidence of premenopausal breast cancer, independent of adult BMI and menstrual cycle characteristics. (+info)