Soren Snitker

Effects of novel capsinoid treatment on fatness and energy metabolism in humans: possible pharmacogenetic implications

BACKGROUND Capsinoids from the Capsicum genus of plants are nonpungent capsaicin-related substances with effects on metabolism and body weight in animals. OBJECTIVES Our objectives were to explore the safety and efficacy of capsinoids taken orally (6 mg/d) for weight loss, fat loss, and change in metabolism and to examine whether candidate genes are predictors of capsinoid response. DESIGN This was a 12-wk, placebo-controlled, double-blind, randomized study. Eligibility criteria included a body mass index (BMI; in kg/m(2)) of 25-35. Body weight was measured, and dual-energy X-ray absorptiometry, indirect calorimetry (men only), and genotyping were conducted. RESULTS Forty women and 40 men with a mean (+/- SD) age of 42 +/- 8 y and BMI of 30.4 +/- 2.4 were randomly assigned to a capsinoid or placebo group. Capsinoids were well tolerated. Mean (+/- SD) weight change was 0.9 +/- 3.1 and 0.5 +/- 2.4 kg in the capsinoid and placebo groups, respectively (P = 0.86). There was no significant group difference in total change in adiposity, but abdominal adiposity decreased more (P = 0.049) in the capsinoid group (-1.11 +/- 1.83%) than in the placebo group (-0.18 +/- 1.94%), and this change correlated with the change in body weight (r = 0.46, P < 0.0001). Changes in resting energy expenditure did not differ significantly between groups, but fat oxidation was higher at the end of the study in the capsinoid group (least-squares mean difference: 21.0 mg/min; P = 0.06). Of 13 genetic variants tested, TRPV1 Val585Ile and UCP2 -866 G/A correlated significantly with change in abdominal adiposity. CONCLUSIONS Treatment with 6 mg/d capsinoids orally appeared to be safe and was associated with abdominal fat loss. Capsinoid ingestion was associated with an increase in fat oxidation that was nearly significant. We identified 2 common genetic variants that may be predictors of therapeutic response.

Ethnic Differences in Insulinemia and Sympathetic Tone as Links Between Obesity and Blood Pressure

Hyperinsulinemia and increased sympathetic nervous system (SNS) activity are thought to be pathophysiological links between obesity and hypertension. In the present study, we examined the relation among heart rate (HR), blood pressure (BP), and percent body fat (hydrodensitometry or DEXA), fasting plasma insulin concentration, and muscle sympathetic nerve activity (MSNA, microneurography) in male, normotensive whites (n=42) and Pima Indians (n=77). Pima Indians have a high prevalence of obesity and hyperinsulinemia but a relatively low prevalence of hypertension. Compared with whites, Pima Indian men had a higher percent body fat (28% versus 21%) and higher fasting insulin concentrations (210 versus 132 pmol/L) but lower MSNA (27 versus 33 bursts/min) (all P <0.001). In both ethnic groups, HR and BP were positively related to percent body fat and MSNA, and both were significant independent determinants of HR and BP in multiple regression analyses. However, MSNA was positively related to percent body fat and the fasting insulin concentration in whites (r =0.60 and r =0.47, both P <0.01) but not in Pima Indians (r =0.15 and r =0.03, NS) (P <0.01 for ethnic differences in the slope of the regression lines). These results confirm the physiological importance of the SNS in normal BP regulation but indicate that the roles of hyperinsulinemia and increased SNS activity as mediators for the relation between obesity and hypertension can differ between different ethnic groups. The lack of an increase in SNS activity with increasing adiposity and insulinemia in Pima Indians may contribute to the low prevalence of hypertension in this population.

Thermic effect of food in humans: methods and results from use of a respiratory chamber.

During the past two decades, many investigators have measured the thermic effect of food (TEF) in humans and have speculated on its role in the development of obesity. In this study we compared different ways of computing TEF from daily energy expenditure measurements in a respiratory chamber, evaluated the determinants of TEF, and more importantly assessed for the first time the relation between TEF and change in body weight. In 471 subjects, TEF was 1697 +/- 857 kJ/d (mean +/- SD), ie, 18 +/- 9% of energy intake. In 114 subjects studied more than once, intraindividual TEF variability was very high (CV = 48%). TEF correlated positively with the level of spontaneous physical activity (SPA) and negatively with fasting plasma glucose and insulin concentrations. TEF correlated inversely with age (males only) and body weight, percent body fat, and waist-to-hip ratio (females only). The level of SPA and fasting plasma glucose concentration were the only significant determinants of TEF, explaining 15% of its variance. In 137 subjects in whom body weight was measured > or = 6 mo after TEF measurement (mean follow-up duration of 2.9 +/- 1.7 y), a low TEF was not predictive of body weight gain. We conclude that, despite the low reproducibility of TEF from use of a respiratory chamber, data in a large number of subjects suggest that TEF is increased by higher SPAs and that insulin resistance is associated with a low TEF. More important, longitudinal data indicate that the variability in TEF is not associated with changes in body weight.

Hypothalamic-pituitary-adrenal axis and sympathetic nervous system activities in Pima Indians and Caucasians

It has been proposed that both hypercortisolism and low sympathetic nervous system (SNS) activity contribute to obesity. Because glucocorticoids inhibit SNS activity, we hypothesized that hypercortisolism and low SNS activity may be found in association in Pima Indians, a population with a high prevalence of obesity. We therefore measured indices of hypothalamic-pituitary-adrenal (HPA) axis and SNS activities in 39 nondiabetic men, 20 Pimas (age, 30+/-5 years; weight, 94+/-26 kg; 35%+/-8% body fat [mean +/- SD]) and 19 Caucasians (33+/-9 years, 91+/-23 kg, 28%+/-11% body fat). HPA axis activity was assessed by measurements of morning fasting plasma corticotropin (ACTH) and cortisol concentrations and 24-hour urinary free cortisol (UFC) excretion. SNS activity was assessed as muscle sympathetic nerve activity (MSNA) by microneurography and by measurement of catecholamines (fasting plasma concentration and 24-hour urinary excretion). Plasma ACTH and cortisol and UFC were similar in Pimas and Caucasians. MSNA was positively correlated with percent body fat (r = .49, P = .002) and was lower in Pimas compared with Caucasians after adjustment for percent body fat (24+/-9 v 31+/-10 bursts/min, P = .04). We conclude that Pima Indians, a population with a high prevalence of obesity, have lower SNS activity but normal HPA axis activity compared with Caucasians.

Decreased ratio of fat to carbohydrate oxidation with increasing age in Pima Indians.

BACKGROUND Some metabolic changes related to age may increase the prevalence of obesity. Previous studies have shown that a low relative metabolic rate and a low ratio of fat to carbohydrate utilization are predictors of body weight gain. However, a possible relationship between age and energy substrate utilization (respiratory quotient; RQ = VCO2/VO2) has not been reported. OBJECTIVE To determine whether RQ increases and therefore fat oxidation decreases with age in Pima Indian men, independent of body fat and energy balance. METHODS We analyzed longitudinal data collected in seven non-diabetic Pima Indian men (31 +/- 6 years, 167 +/- 8 cm, 111.0 +/- 23.7 kg and 41 +/- 9% fat at baseline) who had repeated measurements of 24-hour RQ 7 years apart. On both admissions, subjects were fed a weight maintenance diet (50% carbohydrate, 30% fat and 20% protein) for 3 days before spending 1 day within a respiratory chamber for measurements of 24-hour energy expenditure, basal metabolic rate, sleeping metabolic rate and 24-hour RQ. Paired t-test was used to determine differences between the first and last measurement of 24-hour RQ. Cross-sectional data in 131 Pima Indian men (28 +/- 9 years, 171 +/- 6 cm, 94.5 +/- 24.4 kg, and 32 +/- 9% fat) were also analyzed to determine the relationship between 24-hour RQ and age. Multiple regression analysis was used to adjust 24-hour RQ for differences in energy balance (intake/expenditure in %) and percent body fat and metabolic rate for differences in body size and composition. RESULTS Over a 7-year period, mean unadjusted and adjusted 24-hour RQ increased (p < 0.01). Cross-sectional data analysis showed that both the unadjusted (r = 0.19, p < 0.03) and adjusted (r = 0.19, p < 0.03) 24-hour RQ correlated with increasing age while adjusted BMR (r = -0.21, p < 0.02) correlated inversely with age. CONCLUSIONS Despite a higher body fat content, older individuals utilize less fat than their younger counterparts. Reduced fat utilization and decreased BMR with age may both contribute to increasing obesity in older individuals.

Whole body fat oxidation is related to in situ adipose tissue lipolytic response to isoproterenol in males

A high 24-h respiratory quotient (RQ), i.e., low fat oxidation, predicts weight gain. To determine whether impaired fat mobilization (lipolysis) may contribute to weight gain, we studied the relation between lipolytic response to nonselective β-adrenergic stimulation and RQ measured in a respiratory chamber in 21 males (11 Caucasians, 10 Pima Indians; age 32 ± 5 yr, weight 93 ± 24 kg, body fat 30 ± 8%; means ± SD) and 23 females (10 Caucasians, 13 Pima Indians; age 32 ± 9 yr, weight 95 ± 26 kg, body fat 44 ± 8%). Lipolytic response was assessed as the relative increase in dialysate glycerol concentration (% above baseline) when isoproterenol (1 μmol/l) was added to the perfusate of a microdialysis probe inserted in the abdominal subcutaneous adipose tissue. In males, but not in females, basal RQ measured during sleep from 0500 to 0630 and adjusted for waist circumference was negatively correlated to lipolytic response ( r = -0.66, P = 0.001). The results suggest that in males, impaired β-adrenergic-mediated lipolysis may contribute to low rates of fat oxidation, a condition known to predispose to weight gain.