Exogenous Ketone Esters as a Potential Therapeutic for Treatment of Sarcopenic Obesity.

Identifying effective treatment(s) for sarcopenia and sarcopenic obesity are of paramount importance as the global population advances in age and obesity continues to be a worldwide concern. Evidence has shown that a ketogenic diet can be beneficial for preservation of muscle quality and function in older adults, but long-term adherence is low due in part to the high-fat (> 80%), very low carbohydrate (< 5%) composition of the diet. When provided in adequate amounts, exogenous ketone esters can increase circulating ketones to concentrations that exceed those observed during prolonged fasting or starvation without significant alterations in the diet. Ketone esters first emerged in the mid-1990s and their use in pre-clinical and clinical research has escalated within the past 10-15 years. We present findings from a narrative review of the existing literature for a proposed hypothesis on the effects of exogenous ketones as a therapeutic for preservation of skeletal muscle and function within the context of sarcopenic obesity and future directions for exploration. Much of the reviewed literature herein examines the mechanisms of the ketone diester (R, S-1,3-butanediol diacetoacetate) on skeletal muscle mass, muscle protein synthesis, and epigenetic regulation in murine models. Additional studies are needed to further examine the key regulatory factors producing these effects in skeletal muscle, examine convergent and divergent effects among different ketone ester formulations, and establish optimal frequency and dosing regimens to translate these findings into humans.

Breaking down silos: the multifaceted nature of obesity and the future of weight management.

The continued global increase in the prevalence of obesity prompted a meeting at the Royal Society of London investigating causal mechanisms of the disease, 'Causes of obesity: theories, conjectures, and evidence' in October 2022. Evidence presented indicates areas of obesity science where there have been advancements, including an increased understanding of biological and physiological processes of weight gain and maintenance, yet it is clear there is still debate on the relative contribution of plausible causes of the modern obesity epidemic. Consensus was reached that obesity is not a reflection of diminished willpower, but rather the confluence of multiple, complex factors. As such, addressing obesity requires multifactorial prevention and treatment strategies. The accumulated evidence suggests that a continued focus primarily on individual-level contributors will be suboptimal in promoting weight management at the population level. Here, we consider individual biological and physiological processes within the broader context of sociodemographic and sociocultural exposures as well as environmental changes to optimize research priorities and public health efforts. This requires a consideration of a systems-level approach that efficiently addresses both systemic and group-specific environmental determinants, including psychosocial factors, that often serve as a barrier to otherwise efficacious prevention and treatment options. This article is part of a discussion meeting issue 'Causes of obesity: theories, conjectures and evidence (Part I)'.

Effects of an exogenous ketone ester using multi-omics in skeletal muscle of aging C57BL/6J male mice.

Exogenous ketone ester supplementation provides a means to increase circulating ketone concentrations without the dietary challenges imposed by ketogenic diets. Our group has shown that oral R,S-1,3, butanediol diacetoacetate (BD-AcAc2) consumption results in body weight loss or maintenance with moderate increases in circulating ketones. We have previously shown a diet consisting of 25% BD-AcAc2 can maintain lean body mass (LBM) and induce fat mass (FM) loss in young, healthy male mice, but the underlying mechanisms are still unknown. Therefore, the purpose of this study was to determine if a diet consisting of 25% BD-AcAc2 (ketone ester, KE) would alter body composition, transcriptional regulation, the proteome, and the lipidome of skeletal muscle in aged mice. We hypothesized that the KE group would remain weight stable with improvements in body composition compared to controls, resulting in a healthy aging phenotype. Male C57BL/6J mice (n = 16) were purchased from Jackson Laboratories at 72 weeks of age. After 1 week of acclimation, mice were weighed and randomly assigned to one of two groups (n = 8 per group): control (CON) or KE. A significant group by time interaction was observed for body weight (P < 0.001), with KE fed mice weighing significantly less than CON. FM increased over time in the control group but was unchanged in the KE group. Furthermore, LBM was not different between CON and KE mice despite KE mice weighing less than CON mice. Transcriptional analysis of skeletal muscle identified 6 genes that were significantly higher and 21 genes that were significantly lower in the KE group compared to CON. Lipidomic analysis of skeletal muscle identified no differences between groups for any lipid species, except for fatty acyl chains in triacylglycerol which was 46% lower in the KE group. Proteomics analysis identified 44 proteins that were different between groups, of which 11 were lower and 33 were higher in the KE group compared to CON. In conclusion, 72-week-old male mice consuming the exogenous KE, BD-AcAc2, had lower age-related gains in body weight and FM compared to CON mice. Furthermore, transcriptional and proteomics data suggest a signature in skeletal muscle of KE-treated mice consistent with markers of improved skeletal muscle regeneration, improved electron transport chain utilization, and increased insulin sensitivity.

Genetic risk score prediction of leg fat and insulin sensitivity differs by race/ethnicity in early pubertal children.

BACKGROUND: In the United States, the underlying reasons for racial/ethnic disparities in type 2 diabetes risk remain unclear. However, differences in genetic risk for insulin resistance and peripheral adipose tissue distribution may be contributing factors. OBJECTIVE: To investigate racial/ethnic differences in associations of genetic risk for insulin resistance with leg fat and insulin sensitivity in a cohort of American children. METHODS: Participants were healthy European-American (n = 83), African-American (n = 79) and Hispanic-American (n = 74) children aged 7-12 years. Genetic risk scores were derived from published variants associated with insulin resistance phenotypes in European adults. Body composition was assessed using dual-energy X-ray absorptiometry. Insulin sensitivity was determined from the frequently sampled intravenous glucose tolerance test and minimal modelling. Statistical models were adjusted for age, sex, pubertal stage and body composition. RESULTS: In the combined cohort, risk score was inversely associated with insulin sensitivity (p = 0.033) but not leg fat (p = 0.170). Within Hispanic Americans, risk score was inversely associated with insulin sensitivity (p = 0.027) and leg fat (p = 0.005), while associations were non-significant in European and African Americans (p > 0.200). CONCLUSIONS: The higher type 2 diabetes risk observed among Hispanic Americans may have a genetic basis related to an inability to store lipid in peripheral adipose tissue.

Changes in Ghrelin and Glucagon following a Low Glycemic Load Diet in Women with PCOS.

CONTEXT: Altered satiety hormones in women with polycystic ovarian syndrome (PCOS) may contribute to obesity. Diets with a low glycemic load (GL) may influence appetite-regulating hormones including glucagon and ghrelin. OBJECTIVE: To test the hypothesis that following a 4-week, eucaloric low vs high GL diet habituation, a low vs high GL meal will increase glucagon and decrease ghrelin to reflect greater satiety and improve self-reported fullness. METHODS: Secondary analysis of a randomized crossover trial. PARTICIPANTS: Thirty women diagnosed with PCOS. INTERVENTION: Participants were provided low (41:19:40% energy from carbohydrate:protein:fat) and high (55:18:27) GL diets for 8 weeks each. At each diet midpoint, a solid meal test was administered to examine postprandial ghrelin, glucagon, glucose, insulin, and self-reported appetite scores. RESULTS: After 4 weeks, fasting glucagon was greater with the low vs high GL diet (P = .035), and higher fasting glucagon was associated with lesser feelings of hunger (P = .009). Significant diet effects indicate 4-hour glucagon was higher (P < .001) and ghrelin was lower (P = .009) after the low vs high GL meal. A trending time × diet interaction (P = .077) indicates feelings of fullness were greater in the early postprandial phase after the high GL meal, but no differences were observed the late postprandial phase. CONCLUSION: These findings suggest after low GL diet habituation, a low GL meal reduces ghrelin and increases glucagon in women with PCOS. Further research is needed to determine the influence of diet composition on ad libitum intake in women with PCOS.

A dietary ketone ester mitigates histological outcomes of NAFLD and markers of fibrosis in high-fat diet fed mice.

Nutritional ketosis as a therapeutic tool has been extended to the treatment of metabolic diseases, including obesity, type 2 diabetes, and nonalcoholic fatty liver disease (NAFLD). The purpose of this study was to determine whether dietary administration of the ketone ester (KE) R,S-1,3-butanediol diacetoacetate (BD-AcAc2) attenuates markers of hepatic stellate cell (HSC) activation and hepatic fibrosis in the context of high-fat diet (HFD)-induced obesity. Six-week-old male C57BL/6J mice were placed on a 10-wk ad libitum HFD (45% fat, 32% carbohydrates, 23% proteins). Mice were then randomized to one of three groups (n = 10 per group) for an additional 12 wk: 1) control (CON), continuous HFD; 2) pair-fed (PF) to KE, and 3) KE (HFD + 30% energy from BD-AcAc2, KE). KE feeding significantly reduced histological steatosis, inflammation, and total NAFLD activity score versus CON, beyond improvements observed for calorie restriction alone (PF). Dietary KE supplementation also reduced the protein content and gene expression of profibrotic markers (α-SMA, COL1A1, PDGF-ß, MMP9) versus CON (P < 0.05), beyond reductions observed for PF versus CON. Furthermore, KE feeding increased hepatic markers of anti-inflammatory M2 macrophages (CD163) and also reduced proinflammatory markers [tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and cellular communication network factor 1 (CCN1)] versus CON and PF (P ≤ 0.05), in the absence of changes in markers of total hepatic macrophage content (F4/80 and CD68; P > 0.05). These data highlight that the dietary ketone ester BD-AcAc2 ameliorates histological NAFLD and inflammation and reduces profibrotic and proinflammatory markers. Future studies to further explore potential mechanisms are warranted.NEW & NOTEWORTHY To our knowledge, this is the first study focusing on hepatic outcomes in response to dietary ketone ester feeding in male mice with HFD-induced NAFLD. Novel findings include that dietary ketone ester feeding ameliorates NAFLD outcomes via reductions in histological steatosis and inflammation. These improvements were beyond those observed for caloric restriction alone. Furthermore, dietary ketone ester feeding was associated with greater reductions in markers of hepatic fibrogenesis and inflammation compared with control and calorie-restricted mice.

Exogenous Dietary Ketone Ester Decreases Body Weight and Adiposity in Mice Housed at Thermoneutrality.

OBJECTIVE: The aim of this study was to examine the effects of a ketone ester (KE)-supplemented diet on energy expenditure (EE) and adiposity in mice housed at 23 °C versus thermoneutrality (30 °C), in which sympathetic nervous system activity is diminished. METHODS: Thirty-two 10-week-old male C57BL/6J mice were assigned to 1 of 4 groups (n = 8 per group): 30% KE diet + 23 °C (KE23), control (CON) diet + 23 °C (CON23), 30% KE diet + 30 °C (KE30), or CON diet + 30 °C (CON30). CON mice were pair-fed to the average intake of mice consuming the KE diet (ad libitum) for 8 weeks. Body composition and components of energy balance were measured at completion of the study. RESULTS: CON23 (mean ± SD, 26.0 ± 1.6 g) and CON30 (29.7 ± 1.4 g) mice weighed more than KE groups (P < 0.03 for both) and were also different from each other (CON23 vs. CON30, P < 0.01). However, KE23 (23.4 ± 2.7 g) and KE30 (23.1 ± 1.9 g) mice were not different in body weight. As expected, food intake at 30 °C (2.0 ± 0.3 g/d) was lower than at 23 °C (2.6 ± 0.3 g/d, P < 0.01). Diet did not influence resting and total EE, but mice housed at 30 °C had lower EE compared with mice at 23 °C (P < 0.01). CONCLUSIONS: Dietary KEs attenuate body weight gain at standard (23 °C) and thermoneutral (30 °C) housing temperatures, and this effect is not mediated by increased EE under these conditions.

Impact of ketosis on appetite regulation-a review.

To reduce the health burden of obesity, it is important to identify safe and practical treatments that are effective for weight loss while concurrently preventing weight regain. Diet-induced weight loss is usually followed by a concomitant increase in ghrelin secretion and feelings of hunger, which may compromise weight loss goals and increase the risk of weight regain. The aim of this review is to describe the status of knowledge regarding the impact of ketosis, induced by diet or exogenous ketones (ketone esters), on appetite and the potential mechanisms involved. Ketogenic diets (KDs) have been shown to prevent an increase in ghrelin secretion, otherwise seen with weight loss, as well as to reduce hunger and/or prevent hunger. However, the exact threshold of ketosis needed to induce appetite suppression, as well as the exact mechanisms that mediate such an effect, has yet to be elucidated. Use of exogenous ketones may provide an alternative to KDs, which have poor long-term adherence due to their restrictive nature. Ketone esters have been shown to have concentration-dependent effects on food intake and body weight in rodent models, with effects becoming apparent when 30% of total dietary energy comes from ketone esters (threshold effect). In humans, acute consumption of a ketone ester drink reduced feelings of hunger and increased satiety compared to a dextrose drink. With the emerging widespread acceptance of KDs and exogenous ketones in mainstream media and the diet culture, it is important to fully understand their role on appetite control and weight management and the potential mechanisms mediating this role.

The Impact of a Large Bolus Dose of l-leucine and l-isoleucine on Enteroendocrine and Pancreatic Hormones, and Glycemia in Healthy, Inactive Adults.

BACKGROUND: The ingestion of whey protein and amino acids with carbohydrate (CHO) enhances the release of glucagon-like peptide-1 (GLP-1) and glucose-dependent-insulinotropic peptide (GIP) that promote insulin secretion. It is unknown if L-isoleucine (Ile) and L-leucine (Leu) have this same effect. The purpose of this study was to examine how Ile and Leu influence both GLP-1 and GIP, subsequent pancreatic hormones, and glycemia in healthy, inactive adults. METHODS: Twelve adults (6F/6M; age 27.4 ± 2 years; BMI 26.3 ± 2 kg/m2; lean body mass 53.2 ± 5 kg; body fat 34.1 ± 3%) completed four conditions in a randomized, cross-over fashion. Treatments standardized (0.3 g/kg·LBM-1) (1) Leu, (2) Ile, (3) Equal (1:1 g) of Leu + Ile, and (4) placebo (Pla, 3.5 g inert stevia) ingested 30 min prior to an oral glucose tolerance test (OGTT). Samples of plasma glucose, insulin, glucagon, GIPTotal, and GLP-1Active were assessed. RESULTS: A treatment (p = 0.01) effect comparing Ile vs. Leu (p = 0.02) in GIPTotal. Area under the curve showed an increase in GIPTotal from Ile compared to Leu and Pla (p = 0.03). No effect was found on GLP-1. The ingestion of Ile prior to CHO augmented GIP concentration greater than Leu or Pla. No correlation was found between GIP, insulin, and glucose between conditions. CONCLUSIONS: Ile impacts GIP concentration, which did not relate to either insulin or glucose concentrations. Neither Ile, nor Leu seem to have an effect on hyperglycemia ingested prior to a CHO drink.

Consecutive days of exercise decrease insulin response more than a single exercise session in healthy, inactive men.

PURPOSE: It is reported that a single bout of exercise can lower insulin responses 12-24 h post-exercise; however, the insulin responses to alternate or consecutive bouts of exercise is unknown. Thus, the purpose of this study was to examine the effect of exercise pattern on post-exercise insulin and glucose responses following a glucose challenge. METHODS: Ten male participants (n = 10, mean ± SD, Age 29.5 ± 7.7 years; BMI 25.7 ± 3.0 kg/m2) completed three exercise trials of walking for 60 min at ~ 70% of VO2max. The trials consisted of: three consecutive exercise days (3CON), three alternate exercise days (3ALT), a single bout of exercise (SB), and a no exercise control (R). Twelve to fourteen hours after the last bout of exercise or R, participants completed a 75 g oral glucose tolerance test (OGTT) and blood was collected at 30 min intervals for the measurement of glucose, insulin, and C-peptide. RESULT: Calculated incremental area under the curve (iAUC) for glucose and C-peptide was not different between the four trials. Insulin iAUC decreased 34.9% for 3CON compared to R (p < 0.01). CONCLUSION: Three consecutive days of walking at ~ 70% VO2max improved insulin response following an OGTT compared to no exercise. It is possible, that for healthy males, the effect of a single bout of exercise or exercise bouts separated by more than 24 h may not be enough stimulus to lower insulin responses to a glucose challenge.

Concentration-Dependent Effects of a Dietary Ketone Ester on Components of Energy Balance in Mice.

Objectives: Exogenous ketones may provide therapeutic benefit in treatment of obesity. Administration of the ketone ester (KE) R,S-1,3-butanediol acetoacetate diester (BD-AcAc2) decreases body weight in mice, but effects on energy balance have not been extensively characterized. The purpose of this investigation was to explore concentration-dependent effects of BD-AcAc2 on energy intake and expenditure in mice. Methods: Forty-two male C57BL/6J mice were randomly assigned to one of seven isocaloric diets (n = 6 per group): (1) Control (CON, 0% KE by kcals); (2) KE5 (5% KE); (3) KE10 (10% KE); (4) KE15 (15% KE); (5) KE20 (20% KE); (6) KE25 (25% KE); and (7) KE30 (30% KE) for 3 weeks. Energy intake and body weight were measured daily. Fat mass (FM), lean body mass (LBM), and energy expenditure (EE) were measured at completion of the study. Differences among groups were compared to CON using ANOVA and ANCOVA. Results: Mean energy intake was similar between CON and each concentration of KE, except KE30 which was 12% lower than CON (P < 0.01). KE25 and KE30 had lower body weight and FM compared to CON, while only KE30 had lower LBM (P < 0.03). Adjusted resting and total EE were lower in KE30 compared to CON (P < 0.03), but similar for all other groups. Conclusions: A diet comprised of 30% energy from BD-AcAc2 results in lower energy intake, coincident with lower body weight and whole animal adiposity; while KE20 and KE25 have significantly lower body weight and adiposity effects independent of changes in energy intake or expenditure.

Dietary R, S-1,3-butanediol diacetoacetate reduces body weight and adiposity in obese mice fed a high-fat diet.

The dietary R-3-hydroxybutyrate- R-1,3-butanediol monoester increases resting energy expenditure (REE) and markers of brown and white adipose thermogenesis in lean mice. The purpose of this investigation was to determine whether the ketone ester, R, S-1,3-butanediol diacetoacetate (BD-AcAc2), increases energy expenditure and markers of adipose tissue thermogenesis in the context of high-fat diet (HFD)-induced obesity. Thirty-five-week-old male C57BL/6J mice were placed on an ad libitum HFD (45% kcal) for 10 wk. The mice were then randomized to 1 of 3 groups ( n = 10 per group) for an additional 12 wk: 1) control (Con), continuous HFD, 2) pair-fed (PF) to ketone ester (KE); and 3) KE: HFD+30% energy from BD-AcAc2. Mean energy intake throughout the study was ∼26% lower in the KE compared to the Con group (8.2 ± 0.5 vs. 11.2 ± 0.7 kcal/d; P < 0.05). Final body weight (26.8 ± 3.6 vs. 34.9 ± 4.8 g; P < 0.001) and fat mass (5.2 ± 1.2 vs. 11.3 ± 4.5 g; P < 0.001) of the KE group was significantly lower than PF, despite being matched for energy provisions. Differences in body weight and adiposity were accompanied by higher REE and total energy expenditure in the KE group compared to PF after adjustment for lean body mass and fat-mass ( P = 0.001 and 0.007, respectively). Coupled or uncoupled mitochondrial respiratory rates in skeletal muscle were not different among groups, but markers of mitochondrial uncoupling and thermogenesis (uncoupling protein-1, deiodinase-2, and peroxisome proliferator-activated receptor γ coactivator-1α) were higher in interscapular brown adipose tissue (BAT) of mice receiving the KE diet. The absence of mitochondrial uncoupling in skeletal muscle and increased markers of mitochondrial uncoupling in BAT suggest that BD-AcAc2 initiates a transcriptional signature consistent with BAT thermogenesis in the context of HFD-induced obesity.-Davis, R. A. H., Deemer, S. E., Bergeron, J. M., Little, J. T., Warren, J. L., Fisher, G., Smith, D. L., Jr., Fontaine, K. R., Dickinson, S. L., Allison, D. B., Plaisance, E. P. Dietary R, S-1,3-butanediol diacetoacetate reduces body weight and adiposity in obese mice fed a high-fat diet.

Pilot study: an acute bout of high intensity interval exercise increases 12.5 h GH secretion.

The purpose of this study was to test the hypothesis that high-intensity interval exercise (HIE) significantly increases growth hormone (GH) secretion to a greater extent than moderate-intensity continuous exercise (MOD) in young women. Five young, sedentary women (mean ± SD; age: 22.6±1.3 years; BMI: 27.4±3.1 kg/m2 ) were tested during the early follicular phase of their menstrual cycle on three occasions. For each visit, participants reported to the laboratory at 1700 h, exercised from 1730-1800 h, and remained in the laboratory until 0700 h the following morning. The exercise component consisted of either 30-min of moderate-intensity continuous cycling at 50% of measured peak power (MOD), four 30-s "all-out" sprints with 4.5 min of active recovery (HIE), or a time-matched sedentary control using a randomized, cross-over design. The overnight GH secretory profile of each trial was determined from 10-min sampling of venous blood from 1730-0600 h, using deconvolution analysis. Deconvolution GH parameters were log transformed prior to statistical analyses. Calculated GH AUC (0-120 min) was significantly greater in HIE than CON (P = 0.04), but HIE was not different from MOD. Total GH secretory rate (ng/mL/12.5 h) was significantly greater in the HIE than the CON (P = 0.05), but MOD was not different from CON or HIE. Nocturnal GH secretion (ng/mL/7.5 h) was not different between the three trials. For these women, in this pilot study, a single bout of HIE was sufficient to increase 12.5 h pulsatile GH secretion. It remains to be determined if regular HIE may contribute to increased daily GH secretion.

Adiponectin is associated with risk of the metabolic syndrome and insulin resistance in women.

The purpose of this study was to examine insulin resistance, markers of the metabolic syndrome, cardiovascular disease (CVD) risk, and serum adiponectin concentrations in pre-menopausal Hispanic and non-Hispanic White (NHW) women. This cross-sectional study examined 119 pre-menopausal women (76 Hispanic, 45 NHW) for markers of the metabolic syndrome (ATP III criteria), level of insulin resistance (HOMA-IR), CVD risk factors, and serum total adiponectin concentrations. Relationships between variables were assessed using Student's t-tests, Pearson's and Spearman's Rho correlations, and stepwise multiple regression analysis. Hispanic women had significantly lower adiponectin concentrations than NHW women, even after controlling for body fat (%) (P < 0.01). Number of markers of the metabolic syndrome was inversely related to total adiponectin concentration for all women combined and for NHW women (P ≤ 0.04), but not for Hispanic women. Insulin resistance was inversely related to adiponectin for all women and for NHW women (P < 0.01), but not significantly associated in Hispanic women. Adiponectin concentration was not significantly associated with number of CVD risk factors for these women. While adiponectin was associated with markers of metabolic syndrome and insulin resistance for all women of this study and despite lower adiponectin concentrations for Hispanic women than NHW women, the role of adiponectin to these conditions among Hispanics remains unclear. There was no significant association between adiponectin and CVD risk for these women. Future research should focus on understanding mechanisms for up-regulating adiponectin secretion and if ethnicity affects adiponectin gene expression and secretion given the beneficial effects derived from elevated adiponectin levels.

Relationship between leptin, adiponectin, bone mineral density, and measures of adiposity among pre-menopausal Hispanic and Caucasian women.

OBJECTIVE: The purpose of this study was to examine the relationship between fasting serum leptin and adiponectin levels with bone mineral density (BMD) and body composition in pre-menopausal, middle-aged Hispanic and Caucasian women. OBJECTIVE: Participants' (68 Hispanic and 36 Caucasian) BMD and bone mineral content were measured by dual-energy X-ray absorptiometry, and body density was measured by hydrodensitometry. Serum leptin was determined by enzyme immunoassay and adiponectin by ELISA. RESULTS: Hispanic women had significantly higher leptin, BMD, and fat mass (FM), and lower adiponectin than Caucasian women. There was no significant correlation between leptin and BMD for Hispanic or Caucasian women; adiponectin was inversely correlated with BMD in Caucasian women only (p = 0.01). In both Hispanic and Caucasian women, lean body mass and adiponectin best explained the variance in BMD (r(2) = 0.25, p < 0.001). CONCLUSION: These data demonstrate no significant relationship between leptin and BMD of pre-menopausal, middle-aged Hispanic and Caucasian women, and a significant inverse relationship between adiponectin and BMD in Caucasian women. The role of adipocytokines in the regulation of BMD remains inconclusive and may vary across ethnic groups.

Relationship of leptin, resting metabolic rate, and body composition in premenopausal hispanic and non-Hispanic White women.

OBJECTIVE: The purpose was to evaluate the relationships between fasting serum leptin, resting metabolic rate (RMR), and body composition in premenopausal Hispanic and non-Hispanic White (White) women. METHODS: Participants were 67 Hispanic and 43 White women who arrived at the laboratory in a fasted state for measurement of RMR by indirect calorimetry, bone mineral content measured by dual-energy X-ray absorptiometry, and body density measured by hydrodensitometry. Serum leptin levels were determined by EIA. RESULTS: Multiple regression analysis revealed that body mass and lean body mass were the best predictors of RMR. Leptin was not a significant predictor of RMR. CONCLUSION: Further research needs to be done to examine the role of leptin on metabolism, especially in ethnic groups predisposed to development of obesity and related disorders.