The long-term effect of intentional weight loss on changes in bone mineral density in persons with type 2 diabetes: results from the Look AHEAD randomized trial.

Intentional weight loss has been shown to increase bone loss short term but the long-term effects are not known. Data from the Look AHEAD clinical trial shows that a long term intentional weight loss intervention was associated with greater bone loss at the hip in men. PURPOSE: Intentional weight loss has been shown to increase bone loss short term and increase frailty fracture risk, but the long-term effects on bone mineral density (BMD) are not known. METHODS: Data from a subgroup from the Look AHEAD (LA) multicenter, randomized clinical trial was used to evaluate whether a long term intentional weight loss intervention would increase bone loss. In a preplanned substudy, BMD was assessed at 5 of the 16 LA clinical centers using dual-energy X-ray absorptiometry at baseline, year 8, and the observational visit 12.6-16.3 years after randomization (year 12-16). RESULTS: At year 8, bone density loss (%) was greater in the Intensive Lifestyle Intervention (ILI) group compared with the control group (DSE) for the femoral neck (p = 0.0122) but this finding was not observed at the year 12-16 visit. In analyses stratified by gender, bone density loss (%) was greater at the total hip for men in the ILI group than the DSE group at both the year 8 and year 12-16 visits (year 8 p = 0.0263 and year 12-16 p = 0.0062). This finding was not observed among women. CONCLUSION: Long term intentional weight loss was associated with greater bone loss at the hip in men. These results taken with the previously published Look AHEAD data from the entire clinical trial showing increased frailty fracture risk with weight loss in the ILI group suggest that when intentional weight loss is planned, consideration of bone density preservation and fracture prevention strategies is warranted. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT00017953. June 21, 2001.

Comparison of high-resolution peripheral quantitative computerized tomography with dual-energy X-ray absorptiometry for measuring bone mineral density.

BACKGROUND/OBJECTIVES: The objective of this study was to compare the measurement of areal bone mineral density (aBMD) by dual-energy X-ray absorptiometry (DXA) with the measurement of volumetric bone mineral density (vBMD) by high-resolution peripheral computerized tomography (HR-pQCT) in subjects with a wide range of body mass indices (BMI). SUBJECTS/METHODS: We scanned the arms and legs of 49 premenopausal women, aged 21-45 years, with BMI from 18.5 to 46.5, by HR-pQCT and found that there was a nonsignificant change in vBMD associated with increased BMI, whereas aBMD (DXA) was associated with a positive significant increase. HR-pQCT scans a slice at the extremity of the tibia and radius, whereas DXA scans the entire leg and arm. RESULTS: The correlation coefficients (r) of BMD (DXA) of the legs with BMI were 0.552, P<0.001, with %fat it was 0.378, P<0.01 and with W it was 0.633, P<0.001. The r of BMD (DXA) of the arms with BMI was 0.804, P<0.001, with %fat it was 0.599, P<0.001 and with W it was 0.831, P<0.001, whereas the r of the average bone density (D100) of legs and arms measured by HR-pQCT with BMI, W and %fat were not significant. CONCLUSIONS: Although HR-pQCT and DXA scan different parts of the bone, the high r of BMD with BMI and low r of bone density measured by HR-pQCT with BMI suggest that BMD measured by DXA is artifactually increased in the presence of obesity.

Body composition during fetal development and infancy through the age of 5 years.

Fetal body composition is an important determinant of body composition at birth, and it is likely to be an important determinant at later stages in life. The purpose of this work is to provide a comprehensive overview by presenting data from previously published studies that report on body composition during fetal development in newborns and the infant/child through 5 years of age. Understanding the changes in body composition that occur both in utero and during infancy and childhood, and how they may be related, may help inform evidence-based practice during pregnancy and childhood. We describe body composition measurement techniques from the in utero period to 5 years of age, and identify gaps in knowledge to direct future research efforts. Available literature on chemical and cadaver analyses of fetal studies during gestation is presented to show the timing and accretion rates of adipose and lean tissues. Quantitative and qualitative aspects of fetal lean and fat mass accretion could be especially useful in the clinical setting for diagnostic purposes. The practicality of different pediatric body composition measurement methods in the clinical setting is discussed by presenting the assumptions and limitations associated with each method that may assist the clinician in characterizing the health and nutritional status of the fetus, infant and child. It is our hope that this review will help guide future research efforts directed at increasing the understanding of how body composition in early development may be associated with chronic diseases in later life.

Common variants in genes encoding adiponectin (ADIPOQ) and its receptors (ADIPOR1/2), adiponectin concentrations, and diabetes incidence in the Diabetes Prevention Program.

AIMS: Baseline adiponectin concentrations predict incident Type 2 diabetes mellitus in the Diabetes Prevention Program. We tested the hypothesis that common variants in the genes encoding adiponectin (ADIPOQ) and its receptors (ADIPOR1, ADIPOR2) would associate with circulating adiponectin concentrations and/or with diabetes incidence in the Diabetes Prevention Program population. METHODS: Seventy-seven tagging single-nucleotide polymorphisms (SNPs) in ADIPOQ (24), ADIPOR1 (22) and ADIPOR2 (31) were genotyped. Associations of SNPs with baseline adiponectin concentrations were evaluated using linear modelling. Associations of SNPs with diabetes incidence were evaluated using Cox proportional hazards modelling. RESULTS: Thirteen of 24 ADIPOQ SNPs were significantly associated with baseline adiponectin concentrations. Multivariable analysis including these 13 SNPs revealed strong independent contributions of rs17366568, rs1648707, rs17373414 and rs1403696 with adiponectin concentrations. However, no ADIPOQ SNPs were directly associated with diabetes incidence. Two ADIPOR1 SNPs (rs1342387 and rs12733285) were associated with ∼18% increased diabetes incidence for carriers of the minor allele without differences across treatment groups, and without any relationship with adiponectin concentrations. CONCLUSIONS: ADIPOQ SNPs are significantly associated with adiponectin concentrations in the Diabetes Prevention Program cohort. This observation extends prior observations from unselected populations of European descent into a broader multi-ethnic population, and confirms the relevance of these variants in an obese/dysglycaemic population. Despite the robust relationship between adiponectin concentrations and diabetes risk in this cohort, variants in ADIPOQ that relate to adiponectin concentrations do not relate to diabetes risk in this population. ADIPOR1 variants exerted significant effects on diabetes risk distinct from any effect of adiponectin concentrations.

Elderly Mexicans have less muscle and greater total and truncal fat compared to African-Americans and Caucasians with the same BMI.

BACKGROUND: How body composition, specifically skeletal muscle mass, compares in Mexican elderly to other ethnic groups has not previously been reported. We tested the hypothesis that older adults from Northwest Mexico (Mex) would have similar total appendicular skeletal muscle (TASM) compared with New York dwelling Caucasians (Cauc) and African-Americans (AA). METHODS: Two hundred and eighty nine Mex (135 males and 154 females), 166 AA (36 males and 130 females) and 229 Cauc (64 males and 165 females), aged 60-98 years were assessed. Total and regional fat and lean tissues were measured by whole-body dual energy X-ray absorptiometry where TASM is the sum of arm and leg bone-free and fat-free lean tissue. Differences in TASM were tested by ANCOVA, with age, height, and body mass index (BMI) as covariates. RESULTS: TASM adjusted for ethnicity, age, height and BMI, were 22.6 +/- 0.2 kg and 17.8 +/- 0.1 kg for males and females, respectively (p < 0.001). Among males with similar age, height, and BMI, Mex had less TASM compared with AA and Cauc (p < 0.001). Total body fat and truncal fat were higher (p < 0.001) and FFM lower (p < 0.001) in Mex compared to both AA and Cauc males after adjusting for age and BMI. Among females, Mex had higher total and truncal fat (p < 0.001) after adjusting for age and BMI, and significantly lower TASM (p < 0.001) after adjusting for age, height, and BMI compared to AA and Cauc females. CONCLUSIONS: Elderly Mex have a different body composition compared with AA and Cauc of a similar BMI and age. Mex have significantly less TASM with greater total and truncal fat. In the long-term, Mex elderly may be at greater risk for sarcopenic obesity compared to other ethnic groups.

Robust improvements in fasting and prandial measures of beta-cell function with vildagliptin in drug-naïve patients: analysis of pooled vildagliptin monotherapy database.

AIM: To assess the effects of 24-week treatment with vildagliptin on measures of beta-cell function in a broad spectrum of drug-naïve patients with type 2 diabetes (T2DM). METHODS: Data from all double-blind, multicentre, randomized, placebo- or active-controlled trials conducted in drug-naïve patients with T2DM were pooled from all patients receiving monotherapy with vildagliptin (100 mg daily: 50 mg twice daily or 100 mg once daily, n = 1855) or placebo (n = 347). Fasting measures of beta-cell function [homeostasis model assessment of beta-cell function (HOMA-B) and proinsulin : insulin ratio] were assessed in the overall pooled monotherapy population. Standard meal tests were performed at baseline and week 24 in a subset of patients, and effects of vildagliptin (100 mg daily, n = 227) on dynamic (meal test-derived) measures of beta-cell function [insulin secretion rate relative to glucose (ISR/G) and insulinogenic indices] were assessed relative to baseline and vs. placebo (n = 29). RESULTS: In the overall population, vildagliptin significantly increased HOMA-B both relative to baseline [adjusted mean change (AMDelta) = 10.3 +/- 1.5] and vs. placebo (between-treatment difference in AMDelta = 11.5 +/- 4.5, p = 0.01) and significantly decreased the proinsulin : insulin ratio relative to baseline (AMDelta = -0.05 +/- 0.01) and vs. placebo (between-treatment difference in AMDelta = -0.09 +/- 0.02, p < 0.001). Relative to baseline, vildagliptin monotherapy significantly increased all meal test-derived parameters, and ISR/G (between-treatment difference in AMDelta = 9.8 +/- 2.8 pmol/min/m(2)/mM, p < 0.001) and the insulinogenic index(0-peak glucose) (between-treatment difference in AMDelta = 0.24 +/- 0.05 pmol/mmol, p = 0.045) were significantly increased vs. placebo. CONCLUSIONS: Vildagliptin monotherapy consistently produced robust improvements in both fasting and meal test-derived measures of beta-cell function across a broad spectrum of drug-naïve patients with T2DM. All Phase III trials described (NCT 00099905, NCT 00099866, NCT 00099918, NCT 00101673, NCT 00101803 and NCT 00120536) are registered with ClinicalTrials.gov.

Body composition analysis: Cellular level modeling of body component ratios.

During the past two decades, a major outgrowth of efforts by our research group at St. Luke's-Roosevelt Hospital is the development of body composition models that include cellular level models, models based on body component ratios, total body potassium models, multi-component models, and resting energy expenditure-body composition models. This review summarizes these models with emphasis on component ratios that we believe are fundamental to understanding human body composition during growth and development and in response to disease and treatments. In-vivo measurements reveal that in healthy adults some component ratios show minimal variability and are relatively 'stable', for example total body water/fat-free mass and fat-free mass density. These ratios can be effectively applied for developing body composition methods. In contrast, other ratios, such as total body potassium/fat-free mass, are highly variable in vivo and therefore are less useful for developing body composition models. In order to understand the mechanisms governing the variability of these component ratios, we have developed eight cellular level ratio models and from them we derived simplified models that share as a major determining factor the ratio of extracellular to intracellular water ratio (E/I). The E/I value varies widely among adults. Model analysis reveals that the magnitude and variability of each body component ratio can be predicted by correlating the cellular level model with the E/I value. Our approach thus provides new insights into and improved understanding of body composition ratios in adults.

Critical assessment of the current guidelines for the management and treatment of morbidly obese patients.

An interdisciplinary panel of specialists met in Mallorca in the first European Symposium on Morbid Obesity entitled; "Morbid Obesity, an Interdisciplinary Approach". During the two and half days of the meeting, the participants discussed several aspects related to pathogenesis, evaluation, and treatment of morbid obesity. The expert panel included basic research scientists, dietitians and nutritionists, exercise physiologists, endocrinologists, psychiatrists, cardiologists, pneumonologists, anesthesiologists, and bariatric surgeons with expertise in the different weight loss surgeries. The symposium was sponsored by the Balearic Islands Health Department; however, this statement is an independent report of the panel and is not a policy statement of any of the sponsors or endorsers of the Symposium. The prevalence of morbid obesity, the most severe state of the disease, has become epidemic. The current recommendations for the therapy of the morbidly obese comes as a result of a National Institutes of Health (NIH) Consensus Conference held in 1991 and subsequently reviewed in 2004 by the American Society for Bariatric Surgery. This document reviews the work-up evaluation of the morbidly obese patient, the current status of the indications for bariatric surgery and which type of procedure should be recommended; it also brings up for discussion some important real-life clinical practice issues, which should be taken into consideration when evaluating and treating morbidly obese patients. Finally, it also goes through current scientific evidence supporting the potential effectiveness of medical therapy as treatment of patients with morbid obesity.

Adiponectin levels during low- and high-fat eucaloric diets in lean and obese women.

OBJECTIVE: Adiponectin influences insulin sensitivity (S(I)) and fat oxidation. Little is known about changes in adiponectin with changes in the fat content of eucaloric diets. We hypothesized that dietary fat content may influence adiponectin according to an individual's SI. RESEARCH METHODS AND PROCEDURES: We measured changes in adiponectin, insulin, glucose, and leptin in response to high-fat (HF) and low-fat (LF) eucaloric diets in lean (n = 10) and obese (n = 11) subjects. Obese subjects were further subdivided in relation to a priori SI. RESULTS: We found significantly higher insulin, glucose, and leptin and lower adiponectin in obese vs. lean subjects during both HF and LF. The mean group values of these measurements, including adiponectin (lean, HF 21.9 +/- 9.8; LF, 20.8 +/- 6.6; obese, HF 10.0 +/- 3.3; LF, 9.5 +/- 2.3 ng/mL; mean +/- SD), did not significantly change between HF and LF diets. However, within the obese group, the insulin-sensitive subjects had significantly higher adiponectin during HF than did the insulin-resistant subjects. Additionally, the change in adiponectin from LF to HF diet correlated positively with the obese subjects' baseline SI. DISCUSSION: Although in lean and obese women, group mean values for adiponectin did not change significantly with a change in fat content of a eucaloric diet, a priori measured SI in obese subjects predicted an increase in adiponectin during the HF diet; this may be a mechanism that preserves SI in an already obese group.

Effects of liraglutide (NN2211), a long-acting GLP-1 analogue, on glycaemic control and bodyweight in subjects with Type 2 diabetes.

AIMS: Liraglutide (NN2211) is a long-acting GLP-1 analogue, with a pharmacokinetic profile suitable for once-daily administration. This multicentre, double-blind, parallel-group, double-dummy study explored the dose-response relationship of liraglutide effects on bodyweight and glycaemic control in subjects with Type 2 diabetes. METHODS: Subjects (BMI 27-42 kg/m(2)) with Type 2 diabetes who were previously treated with an OAD (oral anti-diabetic drug) monotherapy (69% with metformin), and had HbA(1c) < or = 10% were enrolled. After a 4-week metformin run-in period, 210 subjects (27-73 years, 60% female) were randomised to receive liraglutide (0.045-0.75 mg) once daily or continued on metformin 1000 mg b.d. for 12 weeks. RESULTS: Mean baseline values for the six treatment groups ranged from 6.8 to 7.5% for HbA(1c), and 8.06-9.44 mmol/l (145-170 mg/dl) for fasting plasma glucose. After 12-week treatment, a weight change of -0.05 to -1.9% was observed for the six treatment groups. Mean HbA(1c) changes from baseline for 0.045, 0.225, 0.45, 0.6, 0.75 mg liraglutide and metformin were +1.28%, +0.86%, +0.22%, +0.16%, +0.30% and +0.09%, respectively. No significant differences in HbA(1c) were observed between liraglutide and metformin groups at the three highest liraglutide dose levels (0.45, 0.6 and 0.75 mg). The lowest two liraglutide doses (0.045 mg and 0.225 mg) were not sufficient to maintain the fasting plasma glucose values achieved by metformin. No major hypoglycaemic episodes were reported. Episodes of nausea and/or vomiting were reported by 11 patients (6.3%) receiving liraglutide and three (8.8%) receiving metformin. CONCLUSIONS: Once-daily liraglutide improved glycaemic control and weight, in a comparable degree to metformin. Liraglutide appeared to be safe and generally well tolerated. Higher doses of liraglutide merit study in future clinical trials.

Intralipid/heparin infusion suppresses serum leptin in humans.

BACKGROUND/AIM: Our previous studies showed that administration of dexamethasone plus food increased serum leptin levels 100% more than dexamethasone alone. We hypothesized that this increase in leptin from the meal could result directly from the provision of fuel metabolites rather than from the meal-induced rise in insulin. In the current study, we tested the effect of an i.v. lipid fuel source (Intralipid 20%/heparin) that would incur only a modest increase in insulin. This study was undertaken because the role of lipid in the regulation of human leptin levels has been controversial, with differing effects reported: stimulatory, inhibitory, or no effect at all. METHODS: In order to evaluate how lipids affect serum leptin in humans, we administered the following to seven lean, healthy, fasting subjects: (i) Intralipid 20% at 0.83 ml/kg.h plus heparin (800 IE/h) infused i.v. for 7 h (LIPID), (ii) LIPID with one initial pulse of insulin (0.09 U/kg) given s.c. (LIPID+INS), (iii) LIPID with dexamethasone (2 mg i.v. push) given at the start of the infusion (LIPID+DEX), and (iv) LIPID with insulin plus dexamethasone (LIPID+INS+DEX). Control trials in another 14 subjects matched hormonal conditions but lacked the LIPID infusion. Blood levels were collected over 8 h for determination of free fatty acids (FFA), glucose, insulin, and leptin under each experimental condition. RESULTS: Over the 420 min of LIPID infusion, FFA levels rose four-fold from 0.28+/-0.05 mmol/l to 0.99+/-0.05 mmol/l. Serum leptin levels were suppressed by 10-20% in the LIPID condition as compared with control (no LIPID) between 90 min (P=0.008) and 360 min (P=0.045). LIPID+DEX did not increase leptin. A pulse of insulin (INS) increased serum insulin levels to 49.9+/-6.1 U/ml at 90 min and increased serum leptin by 21.3+/-6.6% at 480 min (P=0.054). LIPID decreased leptin in the face of this insulin-induced increase (LIPID+INS), between 360 min (P=0.017) and 420 min (P=0.003), with a 23% suppressive effect at 420 min. LIPID+DEX elevated leptin levels by 112.5+/-35.8% at 480 min (P=0.037), however, the Intralipid/heparin infusion did not blunt the rise of leptin under these conditions. CONCLUSIONS: These data showed that Intralipid/heparin: (i) are not sufficient to trigger the effect of dexamethasone on leptin, (ii) have an acute inhibitory effect on both fasting and insulin-stimulated leptin levels, and (iii) that this inhibitory effect cannot reverse the strong stimulatory effect of dexamethasone and insulin on serum leptin.

Sexual dimorphism in the energy content of weight change.

BACKGROUND: The energy content of weight change is assumed to be sex- and age-neutral at 3,500 kcal/pound or 32.2 MJ/kg. OBJECTIVES: As sexual dimorphism in body composition generally exists in mammals, the primary hypothesis advanced and tested was that the energy content of weight change differs between men and women. DESIGN: The energy content of 129 adult men and 287 women was measured by neutron activation analysis. Cross-sectional energy content prediction models were developed and then evaluated in two longitudinal samples: one that used the same methods in 26 obese women losing weight; and the other a compilation of 18 previously reported weight change-body composition studies. RESULTS: Multiple regression modeling identified weight, sex, age and height as total energy content predictor variables with significant sex x weight (P<0.001) and age x weight (P<0.001) interactions; total model r(2) and s.e.e. were 0.89 and 107.3 MJ, respectively. The model's predictive value was supported in both longitudinal evaluation samples. Model calculations using characteristics of representative adults gaining or losing weight suggested that the energy content of weight change in women (approximately 30.1-32.2 MJ/kg) is near to the classical value of 32.2 MJ/kg and that in men the value is substantially lower, approximately 21.8-23.8 MJ/kg. The predicted energy content of weight change increases by about 10% in older (age approximately 70 y) vs younger (approximately 35 y) men and women. CONCLUSIONS: Sexual dimorphism and age-dependency appears to exist in the estimated energy content of weight change and these observations have important clinical and research implications.

A pulse of insulin and dexamethasone stimulates serum leptin in fasting human subjects.

OBJECTIVES: We have previously shown that dexamethasone increases serum leptin in fed but not in fasted human subjects. We hypothesized that insulin and/or glucose mediated the effect of food intake. The primary aim of this study was to determine whether the administration of a pulse of insulin with dexamethasone was sufficient to increase serum leptin in vivo in fasted human subjects. Whether the presence of transient hyperglycemia and the dose of insulin were important was tested as a secondary aim. METHODS: Twenty-nine normal subjects were studied. In experiment 1 (meal-like), a pulse of insulin (0.03 U/kg s.c.) and of dexamethasone (2 mg i.v.) was given, and the blood glucose transiently elevated to 50 mg/dl above baseline for the first 2 h. In experiments 2 and 3 (dose-response), the effect of two doses of insulin (0.03 U/kg in experiment 2 and 0.06 U/kg in experiment 3) was tested in combination with dexamethasone, this time without transient hyperglycemia. Nine subjects were studied under fasting conditions, with or without dexamethasone, as a control experiment. RESULTS: A meal-like transient hyperinsulinemia and hyperglycemia, with a pulse of dexamethasone, increased serum leptin levels from baseline by 54+/-21% at 9 h (P=0.038). In the absence of transient hyperglycemia, leptin increased significantly after doses of both insulin and dexamethasone. The effect of insulin was dose-dependent, with a larger increment of serum leptin at 9 h after the highest dose of insulin (75.2+/-15.7% vs 21.3+/-8.5%, P=0.013). Fasting, with or without dexamethasone, resulted in a significant 20% decrease in leptin from morning basal levels. Conversely, the administration of a pulse of insulin and glucose, in the absence of dexamethasone, prevented the drop in serum leptin observed during fasting, regardless of the insulin dose or the serum glucose elevation. CONCLUSIONS: With the permissive effect of dexamethasone, a single pulse of insulin triggered a rise in serum leptin in humans, even in the absence of transient hyperglycemia. A single pulse of insulin with glucose can prevent the drop in serum leptin normally observed during fasting.

Sleeping metabolic rate in relation to body mass index and body composition.

OBJECTIVES: To determine whether patterns of sleeping metabolic rate (SMR) are altered in obesity. Specifically to determine the relationship between changes in SMR and body weight, body mass index (BMI, kg/m(2)), and fat-free mass (FFM); and to compare resting metabolic rate (RMR) with SMR during different periods of sleep. SUBJECTS: Eighteen healthy, pre-menopausal, obese (BMI >30, n=9) and non-obese (BMI <30, n=9), female subjects (six Caucasians and 12 African-Americans), with an average age of 36 y (range 22-45). MEASUREMENTS: Total energy expenditure (TEE or 24 h EE), metabolic rate (MR), SMR (minimum, average and maximum) and resting metabolic rate (RMR) or resting energy expenditure (REE) measured by human respiratory chamber, and external mechanical work measured by a force platform within the respiratory chamber. Physical activity index (PAL) was derived as TEE/REE. Body composition was determined by dual-energy X-ray absorptiometry (DXA). RESULTS: SMR decreased continuously during sleep and reached its lowest point just before the subject was awakened in the morning by the research staff. Although averages for RMR and SMR were similar, RMR was lower than SMR at the beginning of the sleeping period and higher than SMR in the morning hours. The rate of decrease in SMR was faster with increasing body weight (-0.829, P<0.0001), BMI (correlation factor -0.896, P<0.0001) and FFM (-0.798, P=0.001). The relationship between the slope of SMR decrease and BMI (y=-5 x 10(-6)x(2)+0.0002x-0.0028) is highly significant, with a P-value of <0.0001 and r(2) value of 0.9622. CONCLUSIONS: The rate of decline in metabolic rate during sleep is directly related to body weight, BMI and FFM. Average SMR tends to be lower than RMR in obese subjects and higher than RMR in non-obese subjects.

Magnitude and variation of ratio of total body potassium to fat-free mass: a cellular level modeling study.

Potassium is an essential element of living organisms that is found almost exclusively in the intracellular fluid compartment. The assumed constant ratio of total body potassium (TBK) to fat-free mass (FFM) is a cornerstone of the TBK method of estimating total body fat. Although the TBK-to-FFM (TBK/FFM) ratio has been assumed constant, a large range of individual and group values is recognized. The purpose of the present study was to undertake a comprehensive analysis of biological factors that cause variation in the TBK/FFM ratio. A theoretical TBK/FFM model was developed on the cellular body composition level. This physiological model includes six factors that combine to produce the observed TBK/FFM ratio. The ratio magnitude and range, as well as the differences in the TBK/FFM ratio between men and women and variation with growth, were examined with the proposed model. The ratio of extracellular water to intracellular water (E/I) is the major factor leading to between-individual variation in the TBK/FFM ratio. The present study provides a conceptual framework for examining the separate TBK/FFM determinants and suggests important limitations of the TBK/FFM method used in estimating total body fat in humans and other mammals.

High-fat diet feeding elevates skeletal muscle uncoupling protein 3 levels but not its activity in rats.

OBJECTIVE: The objective of this study is to test the impact of high-fat diet (HFD) feeding on skeletal muscle (SM) uncoupling protein 3 (UCP3) expression and its association with mitochondrial ion permeability and whole-body energy homeostasis. RESEARCH METHODS AND PROCEDURES: Sprague-Dawley rats were fed ad libitum either a HFD (60% of energy from fat, n = 6) or a low-fat diet (12% of energy from fat, n = 6) for 4 weeks. Twenty-four-hour energy expenditure was measured by indirect calorimetry in the last week of the dietary treatment. Blood samples were collected for plasma leptin and free fatty acid assays, and mitochondria were isolated from hindlimb SM for subsequent determinations of UCP3 levels and mitochondrial ion permeability. RESULTS: Plasma leptin levels were higher in rats fed the HFD despite the same body weight in two groups. The same dietary treatment also rendered a 2-fold increase in plasma free fatty acid and SM UCP3 protein levels (Western blot) compared with the group fed the low-fat diet. However, the elevated UCP3 protein levels did not correlate with mitochondrial swelling rates, a measure of mitochondrial chloride, and proton permeability, or with 24-hour energy expenditure. DISCUSSION: The high correlation between the levels of plasma free fatty acid levels and SM UCP3 suggests that circulating free fatty acid may play an important role in UCP3 expression during the HFD feeding. However, the dissociation between the UCP3 protein levels and 24-hour energy expenditure as well as mitochondrial ion permeability suggests that mitochondrial proton leak mediated by muscle UCP3 may not be a major contributor in energy balance in HFD feeding, and other regulatory mechanisms independent of gene regulation may be responsible for the control of UCP3-mediated uncoupling activity.

Impaired insulin action in subcutaneous adipocytes from women with visceral obesity.

Visceral obesity is associated with resistance to the antilipolytic effect of insulin in vivo. We investigated whether subcutaneous abdominal and gluteal adipocytes from viscerally obese women exhibit insulin resistance in vitro. Subjects were obese black and white premenopausal nondiabetic women matched for visceral adipose tissue (VAT), total adiposity, and age. Independently of race and adipocyte size, increased VAT was associated with decreased sensitivity to insulin's antilipolytic effect in subcutaneous abdominal and gluteal adipocytes. Absolute lipolytic rates at physiologically relevant concentrations of insulin or the adenosine receptor agonist N(6)-(phenylisopropyl)adenosine were higher in subjects with the highest vs. lowest VAT area. Independently of cell size, abdominal adipocytes were less sensitive to the antilipolytic effect of insulin than gluteal adipocytes, which may partly explain increased nonesterified fatty acid fluxes in upper vs. lower body obese women. Moreover, increased VAT was associated with decreased responsiveness, but not decreased sensitivity, to insulin's stimulatory effect on glucose transport in abdominal adipocytes. These data suggest that insulin resistance of subcutaneous abdominal and, to a lesser extent, gluteal adipocytes may contribute to increased systemic lipolysis in both black and white viscerally obese women.

PROP taster status and oral fatty acid perception.

Recent studies with rat taste cells treated with polyunsaturated fatty acids suggest that fatty acids may play a role in dietary fat perception. In humans, sensitivity to the textural properties of fat is associated with the genetic ability to taste the bitter compound 6-N-2-propylthiouracil (PROP). However, it has not been shown that PROP tasters are more sensitive in discriminating fatty acids in a high-fat food. Our study with human subjects was designed to test the hypothesis that the ability to orally detect food-grade conjugated linoleic acid added to high-fat vanilla ice cream is associated with the ability to taste PROP. Eighty percent of the PROP tasters in this study, but only 17% of the PROP nontasters correctly discriminated the sample containing the added free fatty acid in a difference test versus unadulterated high-fat vanilla ice cream (Fisher's Exact Test, P=.05). Because most fatty foods contain minute amounts of free fatty acids, further studies with humans examining the contribution of fatty acids to fat perception seem warranted.

Effect of one morning meal and a bolus of dexamethasone on 24-hour variation of serum leptin levels in humans.

OBJECTIVE: We have previously shown that morning administration of dexamethasone in combination with food induces a doubling of serum leptin levels starting at 7 hours after dexamethasone administration, with a maximum effect at 10 hours, the latest time point that we have studied. However, dexamethasone given in the absence of food had no effect on serum leptin at 10 hours. The present experiment was undertaken to determine the duration of the effect of dexamethasone on 24-hour serum leptin under fasted and fed conditions in humans. RESEARCH METHODS AND PROCEDURES: Six healthy non-obese male volunteers were studied under the following four conditions: 1) dexamethasone (2 mg intravenously, given at 0900 hours) with fasting; 2) dexamethasone with food (1,700 kcal, 55% carbohydrate, 15% protein, and 30% fat, given in one meal 2 hours after dexamethasone administration at 1100 hours); 3) saline with food (same meal); 4) saline with fasting. Serum leptin, glucose, insulin, and cortisol were monitored every 30 minutes for 24 hours. RESULTS: 1) Under the fasting condition, dexamethasone increased leptin nocturnal secretion between 2100 and 2400 hours. 2) A single meal (1,700 kcal) at 1100 hours increased nocturnal leptin secretion when compared with the fasting condition. The peak increase of leptin was 123% over baseline between 2100 and 2400 hours, 10 to 14 hours after the meal. 3) In the fed + dexamethasone condition, leptin levels increased from baseline starting 8 hours after dexamethasone injection, reached a maximum increase of 260% between 2100 and 2400 hours, then decreased thereafter, remaining elevated compared to baseline for 16 hours. There was a correlation between 24-hour leptin secretion and insulin secretion after a single morning meal. DISCUSSION: A single bolus of dexamethasone, given before a single large meal, produces a delayed (6-hour) but long-lasting increase in serum leptin (over 16 hours). Under fasted conditions, dexamethasone does not increase daytime leptin but does increase leptin during the night.