Marie S. Thearle

Lower Energy Expenditure Predicts Long-Term Increases in Weight and Fat Mass

CONTEXT The relevance of the contribution of energy expenditure (EE) and substrate oxidation to weight change has not been fully confirmed. OBJECTIVE The objective of the study was to determine whether metabolic parameters measured in a whole room indirect calorimeter are predictive of long-term body weight change. SETTING The study was conducted at a clinical research unit in Phoenix, Arizona, from 1985 to 2005. PARTICIPANTS A total of 612 healthy subjects (384 males and 228 females; aged 29.5 ± 8.1 years; body mass index 33.0 ± 8.7 kg/m(2); percent body fat 30.9 ± 9.6%), including 422 Native Americans and 190 whites. Follow-up data were available for 292 Native Americans with a median follow-up time of 6.7 years (interquartile range 3.9-10.5). MAIN OUTCOME MEASURES Twenty-four-hour EE, sleeping metabolic rate, daily (fed) and sleeping (fasting) respiratory quotient, and carbohydrate and fat oxidation rates were measured during a 24-hour respiratory chamber. Body composition was assessed by underwater weighing or dual-energy x-ray absorptiometry. RESULTS After accounting for demographic and body composition measures, the remaining variance of 24-hour EE was inversely related to the rate of weight change (ρ = -0.158, P = .007) and fat mass change (ρ = -0.179, P = .012), such that 100 kcal below the expected 24-hour EE corresponded to 0.2 kg/y weight gain, of which 0.1 kg/y was fat mass. Deviations from the predicted values of the sleeping metabolic rate (ρ = -0.121, P = .039) and fed respiratory quotient (ρ = 0.119, P = .042) were also associated with future weight change, whereas the fat oxidation rate was inversely associated with weight change in men (ρ = -0.174, P = .024) but not in women (ρ = 0.018, P = .853). CONCLUSIONS Measures of energy expenditure and substrate oxidation are predictors of long-term weight change, indicating a small but significant role for reduced metabolic rate in weight gain.

Higher Daily Energy Expenditure and Respiratory Quotient, Rather Than Fat-Free Mass, Independently Determine Greater ad Libitum Overeating

CONTEXT Body fat-free mass (FFM), energy expenditure (EE), and respiratory quotient (RQ) are known predictors of daily food intake. Because FFM largely determines EE, it is unclear whether body composition per se or the underlying metabolism drives dietary intake. OBJECTIVE The objective of the study was to test whether 24-hour measures of EE and RQ and their components influence ad libitum food intake independently of FFM. DESIGN AND PARTICIPANTS One hundred seven healthy individuals (62 males/45 females, 84 Native Americans/23 whites; age 33 ± 8 y; body mass index 33 ± 8 kg/m(2); body fat 31% ± 8%) had 24-hour measures of EE in a whole-room indirect calorimeter during energy balance, followed by 3 days of ad libitum food intake using computerized vending machine systems. Body composition was estimated by dual-energy x-ray absorptiometry. MAIN OUTCOME MEASURES FFM, 24-hour EE, RQ, spontaneous physical activity, sleeping EE (sleeping metabolic rate), awake and fed thermogenesis, and ad libitum food intake (INTAKE) were measured. RESULTS Higher 24-hour RQ (P < .001, partial R(2) = 16%) and EE (P = .01, partial R(2) = 7%), but not FFM (P = .65), were independent predictors of INTAKE. Mediation analysis demonstrated that 24-hour EE is responsible for 80% of the FFM effect on INTAKE (44.5 ± 16.9 kcal ingested per kilogram of FFM, P= .01), whereas the unique effect due to solely FFM was negligible (10.6 ± 23.2, P = .65). Spontaneous physical activity (r = 0.33, P = .001), but not sleeping metabolic rate (P = .71), positively predicted INTAKE, whereas higher awake and fed thermogenesis determined greater INTAKE only in subjects with a body mass index of 29 kg/m(2) or less (r = 0.44, P = .01). CONCLUSIONS EE and RQ, rather than FFM, independently determine INTAKE, suggesting that competitive energy-sensing mechanisms driven by the preferential macronutrient oxidation and total energy demands may regulate food intake.

Extent and Determinants of Thermogenic Responses to 24 Hours of Fasting, Energy Balance, and Five Different Overfeeding Diets in Humans

CONTEXT Individual variation in the ability to convert excess calories to heat and the effects of dietary macronutrient composition are unclear. OBJECTIVE Stability and determinants of the energy expenditure (EE) response to overconsumption were assessed. DESIGN, SETTING, AND PARTICIPANTS Twenty subjects (75% male) with normal glucose regulation were evaluated during 24 hours each of energy balance, fasting, and 5 different diets with 200% energy requirements in a clinical research unit. INTERVENTIONS Five 1-day overfeeding diets were given in random order: high carbohydrate (75%) and low protein (3%); high carbohydrate and normal protein (20%); high fat (46%) and low protein; high fat (60%) and normal protein; and balanced (50% carbohydrates, 20% protein). MAIN OUTCOME MEASURES The 24-hour EE, sleeping EE, and thermic effect of food (TEF) during each diet were measured with a metabolic chamber. Appetitive hormones were measured before and after the diets. RESULTS The EE response to overfeeding exhibited good intraindividual reproducibility. Similar increases above eucaloric feeding in 24-hour EE (mean 10.7 ± 5.7%, P < .001; range 2.9-18.8%) and sleeping EE (14.4 ± 11.3%, P < .001; range 1.0-45.1%) occurred when overfeeding diets containing 20% protein, despite differences in fat and carbohydrate content, but the EE response during overfeeding diets containing 3% protein was attenuated. The percent body fat negatively correlated with TEF during normal protein overfeeding (r = -0.53, P < .01). Fasting peptide YY negatively correlated with TEF (r = -0.56, P < .01) and the increase in sleeping EE (r = -0.54, P < .01) during overfeeding. CONCLUSIONS There is an intrinsic EE response to overfeeding that negatively associates with adiposity, although it represents a small percentage of consumed calories.

Lower “Awake and Fed Thermogenesis” Predicts Future Weight Gain in Subjects with Abdominal Adiposity

Awake and fed thermogenesis (AFT) is the energy expenditure (EE) of the nonactive fed condition above the minimum metabolic requirement during sleep and is composed of the thermic effect of food and the cost of being awake. AFT was estimated from whole-room 24-h EE measures in 509 healthy subjects (368 Native Americans and 141 whites) while subjects consumed a eucaloric diet. Follow-up data were available for 290 Native Americans (median follow-up time: 6.6 years). AFT accounted for ∼10% of 24-h EE and explained a significant portion of deviations from expected energy requirements. Energy intake was the major determinant of AFT. AFT, normalized as a percentage of intake, was inversely related to age and fasting glucose concentration and showed a nonlinear relationship with waist circumference and BMI. Spline analysis demonstrated that AFT becomes inversely related to BMI at an inflection point of 29 kg/m2. The residual variance of AFT, after accounting for covariates, predicted future weight change only in subjects with a BMI >29 kg/m2. AFT may influence daily energy balance, is reduced in obese individuals, and predicts future weight gain in these subjects. Once central adiposity develops, a blunting of AFT may occur that then contributes to further weight gain.

A Human Thrifty Phenotype Associated With Less Weight Loss During Caloric Restriction

Successful weight loss is variable for reasons not fully elucidated. Whether effective weight loss results from smaller reductions in energy expenditure during caloric restriction is not known. We analyzed whether obese individuals with a “thrifty” phenotype, that is, greater reductions in 24-h energy expenditure during fasting and smaller increases with overfeeding, lose less weight during caloric restriction than those with a “spendthrift” phenotype. During a weight-maintaining period, 24-h energy expenditure responses to fasting and 200% overfeeding were measured in a whole-room indirect calorimeter. Volunteers then underwent 6 weeks of 50% caloric restriction. We calculated the daily energy deficit (kilocalories per day) during caloric restriction, incorporating energy intake and waste, energy expenditure, and daily activity. We found that a smaller reduction in 24-h energy expenditure during fasting and a larger response to overfeeding predicted more weight loss over 6 weeks, even after accounting for age, sex, race, and baseline weight, as well as a greater rate of energy deficit accumulation. The success of dietary weight loss efforts is influenced by the energy expenditure response to caloric restriction. Greater decreases in energy expenditure during caloric restriction predict less weight loss, indicating the presence of thrifty and spendthrift phenotypes in obese humans.

Childhood Predictors of Adult Acute Insulin Response and Insulin Action

OBJECTIVE Because declines in acute insulin response (AIR) and insulin action (M) predict development of type 2 diabetes, we sought to determine childhood factors that predict insulin action and AIR using longitudinal data from young Pima Indian adults with normal glucose regulation. RESEARCH DESIGN AND METHODS Predictors of adult M, measured by the euglycemic-hyperinsulinemic clamp, and AIR, measured after a 25-g glucose bolus, were assessed in 76 individuals from a set of childhood data (BMI, systolic blood pressure [sBP] and diastolic blood pressure, cholesterol, fasting and 2-h insulin, and glucose levels during an oral glucose tolerance test). RESULTS After adjustment for sex, adult percent body fat, adult and childhood age, childhood BMI, and sBP were negative and independent predictors of adult M. A 5 kg/m2 increase in childhood BMI was associated with a 7.4% decrease in adult insulin action (95% CI −12.7 to −1.8%, P = 0.01) and a 10-mmHg increase in childhood sBP with a 5.0% decrease in adult M (95% CI −8.4 to −1.4%, P = 0.007). After a similar adjustment with M as an additional covariate, childhood 2-h insulin was a positive predictor of adult AIR such that a 25% increase predicted a 7.3% increase in adult AIR (95% CI 1.5–13.5%, P = 0.014). CONCLUSIONS Childhood insulin response during an oral glucose challenge predicts adult AIR, indicating that β-cell capacity may be set early in life. Childhood measures related to adiposity predict adult insulin action, which may reflect common underlying mechanisms that may be amenable to modification through programs targeting prevention or treatment of childhood obesity.

Impaired glucose regulation is associated with poorer performance on the Stroop Task

BACKGROUND Type 2 diabetes is a risk factor for development of cognitive dysfunction. Impairments in glucose regulation have been associated with poorer performance on tests of executive function and information processing speed. METHODS We administered the Stroop Color Word Task, where higher interference scores are indicative of decreased selective attention, to 98 non-diabetic volunteers (64 m; %fat=37 ± 12; age=36 ± 9 yrs, race=41 NA/30 C/13 H/14 AA) on our inpatient unit. After 3d on a weight maintaining diet, % body fat was measured by DXA and a 75 g oral glucose tolerance test (OGTT) was administered. Impaired glucose regulation (IGR) was defined as: fasting plasma glucose ≥ 100 and ≤ 125 mg/dL and/or 2h plasma glucose between ≥ 140 and ≤ 199 mg/dL (IGR; n=48; NGR; n=50). Total and incremental area under the curve (AUC) for insulin and glucose were calculated. RESULTS Stroop interference scores were not significantly associated with any measure of adiposity or insulin concentrations. Individuals with IGR had significantly higher interference scores than those with normal glucose regulation (NGR; p=0.003). Higher interference scores were significantly correlated with fasting plasma glucose concentrations (r=0.26, p=0.007) and total glucose AUC (r=0.30, p=0.02) and only trending so for iAUC and 2h plasma glucose (r=0.18, p=0.08; r=0.17, p=0.09 respectively). In separate multivariate linear models, fasting plasma glucose (p=0.002) and total glucose AUC (p=0.0005) remained significant predictors of Stroop interference scores, even after adjustment for age, sex, race, education and %fat. CONCLUSIONS Individuals with IGR had decreased performance on a test of selective attention. Fasting plasma glucose was more strongly associated with lower performance scores than 2h plasma glucose. Our results indicate that even mild hyperglycemia in the non-diabetic range is associated with attentional processing difficulties in a sample of younger adults. Whether these impairments precede or are induced by impaired glucose regulation is not clear.

Energy expenditure responses to fasting and overfeeding identify phenotypes associated with weight change

Because it is unknown whether 24-h energy expenditure (EE) responses to dietary extremes will identify phenotypes associated with weight regulation, the aim of this study was to determine whether such responses to fasting or overfeeding are associated with future weight change. The 24-h EE during energy balance, fasting, and four different overfeeding diets with 200% energy requirements was measured in a metabolic chamber in 37 subjects with normal glucose regulation while they resided on our clinical research unit. Diets were given for 24 h each and included the following: 1) low protein (3%), 2) standard (50% carbohydrate, 20% protein), 3) high fat (60%), and 4) high carbohydrate (75%). Participants returned for follow-up 6 months after the initial measures. The decrease in 24-h EE during fasting and the increase with overfeeding were correlated. A larger reduction in EE during fasting, a smaller EE response to low-protein overfeeding, and a larger response to high-carbohydrate overfeeding all correlated with weight gain. The association of the fasting EE response with weight change was not independent from that of low protein in a multivariate model. We identified the following two independent propensities associated with weight gain: a predilection for conserving energy during caloric and protein deprivation and a profligate response to large amounts of carbohydrates.

Increased 24-hour ad libitum food intake is associated with lower plasma irisin concentrations the following morning in adult humans.

BACKGROUND The relationship between food intake and irisin concentrations in humans is unclear. OBJECTIVES To determine whether the previous days intake impacts fasting plasma irisin concentrations, or whether fasting irisin concentrations associate with subsequent ad libitum food intake. METHODS Sixty-six nondiabetic adults (42 men) were admitted for a study of the determinants of energy intake. After 6 days of a weight maintaining diet, ad libitum energy intake over 3 days was assessed using a vending machine paradigm. Fasting plasma irisin concentrations were measured on the morning of the second day of the vending period. RESULTS There were no correlations between irisin and demographic or anthropometric parameters. On day 1, subjects consumed 144 ± 52% of weight maintaining energy needs. Every additional 500 kcal consumed on day 1 associated with a 3.4% lower irisin concentration the following morning (95% CI -6.2, -0.4%, p = 0.01; adjusted for age, sex and race). If energy intake was expressed as a percentage of weight maintaining energy needs, every 10% increase associated with a 1.9% lower irisin concentration (95% CI -3.7, -0.1%; adjusted p = 0.02). A 100 kcal increase in carbohydrate or fat consumption associated with a 1.3% (95% CI -2.5, -0.1%, p = 0.01) and a 0.6% (95% CI -1.1, -0.0%, p = 0.02) lower irisin concentration, respectively. There was no association between fasting irisin concentrations and subsequent energy intake on day 2 (r = 0.19, p = 0.1). CONCLUSIONS Higher ad libitum 24 h energy intake was associated with lower fasting irisin concentrations the following morning, but fasting irisin concentrations did not predict subsequent energy intake. The decrease in irisin concentrations with increased energy intake is consistent with the detrimental metabolic effects of overeating.

Fasting Hyperglycemia Predicts Lower Rates of Weight Gain by Increased Energy Expenditure and Fat Oxidation Rate

CONTEXT Increased adiposity and insulin resistance are associated with hyperglycemia and previous studies have reported that higher glucoses are associated with lower rates of weight gain. One possible mechanism is via increased energy expenditure (EE). OBJECTIVE To assess the relationships between changes in EE during spontaneous weight gain and concomitant changes in glucose levels. DESIGN AND PARTICIPANTS Body composition, metabolic, and glycemic data were available from nondiabetic Native Americans who underwent two measurements of 24-h EE during eucaloric feeding in a metabolic chamber (N = 144; time between measurements: 5.0 ± 3.3 years) or resting EE by ventilated hood system during the euglycemic-hyperinsulinemic clamp (N = 261; 4.5 ± 3.2 years). Long-term follow-up data (8.3 ± 4.3 years) for weight and body composition were available in 131 and 122 subjects, respectively. MAIN OUTCOME MEASURES Twenty four hour EE and respiratory quotient (RQ), resting (RMR), and sleeping (SMR) metabolic rates, glucose, and insulin levels, basal glucose output (BGO). RESULTS Weight gain-associated increase in fasting plasma glucose (FPG) levels was accompanied with decreased 24-h RQ (partial R = -0.24, P = .002) and increased 24-h EE, RMR, SMR, and fat oxidation after accounting for changes in body composition (partial R: 0.12 to 0.19, all P ≤ .05). Upon weight gain, BGO tended to increase (P = .07), while insulin infusion induced a decrease in EE (P = .04). Higher baseline FPG predicted lower rates of future weight gain (partial R = -0.18, P = .04). CONCLUSIONS Higher FPG after weight gain was associated with greater-than-expected increase in EE. The rise in BGO and the insulin-induced EE suppression at follow-up indicate that increased hepatic gluconeogenesis may be an important mediator of EE changes associated with weight gain.