Impaired metabolic flexibility to fasting is associated with increased ad libitum energy intake in healthy adults.

OBJECTIVE: We investigated how changes in 24-h respiratory exchange ratio (RER) and substrate oxidation during fasting versus an energy balance condition influence subsequent ad libitum food intake. METHODS: Forty-four healthy, weight-stable volunteers (30 male and 14 female; mean [SD], age 39.3 [11.0] years; BMI 31.7 [8.3] kg/m2) underwent 24-h energy expenditure measurements in a respiratory chamber during energy balance (50% carbohydrate, 30% fat, and 20% protein) and 24-h fasting. Immediately after each chamber stay, participants were allowed 24-h ad libitum food intake from computerized vending machines. RESULTS: Twenty-four-hour RER decreased by 9.4% (95% CI: -10.4% to -8.5%; p < 0.0001) during fasting compared to energy balance, reflecting a decrease in carbohydrate oxidation (mean [SD], -2.6 [0.8] MJ/day; p < 0.0001) and an increase in lipid oxidation (2.3 [0.9] MJ/day; p < 0.0001). Changes in 24-h RER and carbohydrate oxidation in response to fasting were correlated with the subsequent energy intake such that smaller decreases in fasting 24-h RER and carbohydrate oxidation, but not lipid oxidation, were associated with greater energy intake after fasting (r = 0.31, p = 0.04; r = 0.40, p = 0.007; and r = -0.27, p = 0.07, respectively). CONCLUSIONS: Impaired metabolic flexibility to fasting, reflected by an inability to transition away from carbohydrate oxidation, is linked with increased energy intake.

Dietary Adherence Is Associated with Perceived Stress, Anhedonia, and Food Insecurity Independent of Adiposity.

We examined whether perceived stress, anhedonia, and food insecurity were associated with dietary adherence during a 6-week intervention. Sixty participants (23 m; 53 ± 14 y) completed psychosocial measures and were provided with full meals. Individuals with obesity were randomized to a weight-maintaining energy needs (WMENs) (n = 18; BMI 33 ± 4) or a 35% calorie-reduced diet (n = 19; BMI 38 ± 9); normal-weight individuals (n = 23; BMI 23 ± 2) were assigned to a WMENs diet. Adherence scores were determined via weekly assessments and daily ecological momentary assessments (EMAs) of real-time behavior in a natural environment. Perceived stress and anhedonia were associated with % body fat (all r-values > 0.25, all p-values < 0.05), but food insecurity and adherence were not. Higher perceived stress (r = -0.31, p = 0.02), anhedonia (r = -0.34, p = 0.01), and food insecurity (r = -0.27, p = 0.04) were associated with lower adherence scores, even after adjusting for age, sex, and % body fat. In all adjusted models, % body fat was not associated with adherence. Higher measures of stress, anhedonia, and food insecurity predicted lower adherence independently of body fat, indicating that psychosocial factors are important targets for successful adherence to dietary interventions, regardless of body size.

Insulin resistance before type 2 diabetes onset is associated with increased risk of albuminuria after diabetes onset: A prospective cohort study.

AIM: Reduced renal insulin signalling is implicated in the pathogenesis of albuminuria. We sought to investigate whether insulin action and secretion, measured before diabetes onset, are associated with the development of albuminuria after diabetes onset. MATERIALS AND METHODS: Baseline body composition, insulin sensitivity by hyperinsulinaemic-euglycaemic clamp at submaximal and maximal insulin stimulation (240 and 2400 pmol/m2/min; M-low and M-high), and insulin secretion by intravenous glucose tolerance test [acute insulin response (AIR)] were measured in 170 Southwestern Indigenous American adults who subsequently developed diabetes. After diabetes onset and during the median follow-up of 13.6 years, 81 participants (48%) developed albuminuria (urine albumin-to-creatinine ratio ≥30 mg/g). Separate associations of M-low, M-high and AIR (per 1-SD change) with the risk of albuminuria were assessed by Cox regression models adjusted for age, sex and body fat (%). RESULTS: Participants who developed albuminuria were of similar age (26.4 ± 5.4 vs. 27.5 ± 6.1 years), sex (46% vs. 48% male), body fat (36.4 ± 7.5 vs. 35.7 ± 7.9%) and AIR [2.3 ± 0.3 vs. 2.3 ± 0.3, pmol/L (log)] as those who did not develop albuminuria but had lower insulin sensitivity [M-low: 0.33 ± 0.08 vs. 0.36 ± 0.12, p = .03; M-high: 0.87 ± 0.11 vs. 0.91 ± 0.12, p = .02; mg/kg-metabolic body size/min (log)]. In separate adjusted models, lower M-low and M-high were both associated with an increased risk for albuminuria [hazard ratio (HR) 1.51, 95% confidence interval (CI) 1.14, 2.00, p = .004; HR 1.31, 95% CI 1.06, 1.63, p = .01), whereas AIR was not (HR 1.15, 95% CI 0.87, 1.56, p = .3). CONCLUSIONS: Lower insulin sensitivity is associated with the development of albuminuria, suggesting a role for insulin signalling in the pathogenesis of proteinuria.

Adipocyte size, adipose tissue calories, and circulating adipokines, before and after diet-induced weight loss in humans.

OBJECTIVE: Adipose tissue (AT) contains a bimodal population of large and small adipocytes. Changes in fat cell size (FCS) distribution and AT caloric density (kcal/g) with weight loss are unclear. We aimed to evaluate changes in FCS and AT calories in weight loss and determine associations with anthropometrics. MATERIALS AND METHODS: Healthy adults (6 men/4 women; age 33 ± 11 years; BMI 35 ± 6 kg/m2) underwent DXA and subcutaneous abdominal/thigh fat biopsies, before and after 6 weeks of caloric restriction. AT calories (bomb calorimetry) and hormones (adiponectin, leptin, FGF21) were measured. RESULTS: Abdominal large cell diameter (LCD; Δ = -13.2 µm, p = 0.01) and nadir (Δ = -7.3 µm, p = 0.03) decreased. In repeated measures correlations (rrm), abdominal and thigh LCD and nadir were associated with fat mass (FM) loss (rrm = 0.68; rrm = 0.63; rrm = 0.66; rrm = 0.62, p's < 0.05, respectively) and waist circumference decrease (rrm = 0.70; rrm = 0.60, p's ≤ 0.05). Small cell percentage did not change and was not associated with FM changes. Abdominal AT calories were unchanged with weight loss. Change in leptin was associated with change in abdominal LCD (rrm = 0.77, p = 0.01). CONCLUSIONS: Caloric restriction reduces adipocyte LCD and nadir. These changes are associated with FM loss. Larger fat cells should be considered as phenotypic targets for weight loss. CLINICAL TRIALS REGISTRATION: clinicaltrials.gov identifier: NCT00687115, May 29, 2008.

Investigation of seasonality of human spontaneous physical activity and energy expenditure in respiratory chamber in Phoenix, Arizona.

OBJECTIVE: The existence of seasonal changes in energy metabolism is uncertain. We investigated the relationship between the seasons and spontaneous physical activity (SPA), energy expenditure (EE), and other components measured in a respiratory chamber. METHODS: Between 1985-2005, 671 healthy adults (aged 28.8 ± 7.1 years; 403 men) in Phoenix, Arizona had a 24-hour stay in the respiratory chamber equipped with radar sensors; SPA (expressed as a percentage over the time interval), the energy cost of SPA, EE, and respiratory exchange ratio (RER) were measured. RESULTS: In models adjusted for known covariates, SPA (%) was lower during summer (7.2 ± 2.9, p = 0.0002), spring (7.5 ± 2.9, p = 0.025), and fall (7.6 ± 3, p = 0.038) compared to winter (8.3 ± 3.5, reference). Conversely, energy cost of SPA (kcal/h/%) was higher during summer (2.18 ± 0.83, p = 0.0008), spring (2.186 ± 0.83, p = 0.017), and fall (2.146 ± 0.75, p = 0.038) compared to winter (2.006 ± 0.76). Protein (292 ± 117 kcal/day, ß = -21.2, p = 0.08) oxidation rates was lower in the summer compared to winter. Carbohydrate and lipid oxidation rates (kcal/day) did not differ across seasons. RER and 24-h EE did not differ by season. CONCLUSION: SPA, representing fidgeting-like behavior in the chamber, demonstrated a winter peak and summer nadir in humans living in a desert climate. These findings indicate that the physiological propensity for movement may be affected by seasonal factors. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT00340132, NCT00342732.

Diagnostic criteria and etiopathogenesis of type 2 diabetes and its complications: Lessons from the Pima Indians.

The Phoenix Epidemiology and Clinical Research Branch of the National Institute of Diabetes and Digestive and Kidney Diseases has conducted prospective studies of diabetes and its complications in the Pima Indians living in Arizona, USA for over 50 years. In this review we highlight areas in which these studies provided vital insights into the criteria used to diagnose type 2 diabetes, the pathophysiologic changes that accompany the development of type 2 diabetes, and the course and determinants of diabetes complications-focusing specifically on diabetic kidney disease. We include data from our longitudinal population-based study of diabetes and its complications, studies on the role of insulin resistance and insulin secretion in the pathophysiology of type 2 diabetes, and in-depth studies of diabetic kidney disease that include measures of glomerular function and research kidney biopsies. We also focus on the emerging health threat posed by youth-onset type 2 diabetes, which was first seen in the Pima Indians in the 1960s and is becoming an increasing issue worldwide.

Validation of Total Water Intake from the Automated Self-Administered 24-h Recall, 4-d Food Records, and a Food Frequency Questionnaire Using Doubly Labeled Water.

BACKGROUND: Although prior evidence indicates that water intake is important for health, the ability to accurately measure community-dwelling intake is limited. Only a few studies have evaluated self-reported water intake against an objective recovery biomarker. OBJECTIVES: The aim was to compare preformed water intakes (all sources including food) by multiple Automated Self-Administered 24-h recalls (ASA24s), food frequency questionnaires (FFQs), and 4-d food records (4DFRs) against a recovery biomarker, doubly labeled water (DLW), to assess measurement error. METHODS: Over 1 y, 1082 women and men (50%), aged 50 to 74 y, were asked to complete 6 ASA24s, 2 FFQs, 2 unweighted 4DFRs, and an administration of DLW (n = 686). Geometric means of water intake by self-report tools were compared with DLW. Attenuation factors and correlation coefficients between self-reported and the recovery biomarker (DLW) were estimated. RESULTS: Mean water intakes by DLW were 2777 mL/d (interquartile range, 2350 to 3331) in women and 3243 mL/d (interquartile range, 2720 to 3838) in men. Compared with DLW, water intake was underestimated by 18% to 31% on ASA24s and 43% to 44% on 4DFRs. Estimated geometric means from FFQs differed from DLW by -1% to +13%. For a single ASA24, FFQ, and 4DFR, attenuation factors were 0.28, 0.27, and 0.32 and correlation coefficients were 0.46, 0.48, and 0.49, respectively. Repeated use of 6 ASA24s, 2 FFQs, and 2 4DFRs improved attenuation factors to 0.43, 0.32, and 0.39 and correlation coefficients to 0.58, 0.53, and 0.54, respectively. CONCLUSIONS: FFQs may better estimate population means for usual water intake compared with ASA24 and 4DFR. Similar attenuation factors and correlation coefficients across all self-report tools indicate that researchers have 3 feasible options if the goal is understanding intake-disease relationships. The findings are useful for planning future nutrition studies that set policy priorities for populations and to understand the health impact of water. This trial was registered at clinicaltrials.gov as NCT03268577.

Greater anhedonia scores in healthy individuals are associated with less decline in 24-hour energy expenditure with fasting: Evidence for a link between behavioral traits and spendthrift phenotype.

Obesity rates are increasing and affecting mental health. It is important to understand how behavioral traits such as anhedonia are associated with physiologic traits that may predict weight-change in clinical and non-clinical populations. We studied whether 24-hour energy expenditure (24hEE) changes with fasting and overfeeding are associated with anhedonia in a healthy cohort. We performed behavioral assessments (physical anhedonia scale (PAS) and inventory for depressive symptoms (IDS)) followed by measures of 24hEE and urinary catecholamines in a whole-room indirect calorimeter (respiratory chamber) during energy balance, and then randomly during fasting and 2 different overfeeding diets. Participants (n=98) were medically healthy, between 18 and 55 years of age, with normal glucose regulation and weight-stable 6 months before admission. Women were premenopausal and not pregnant. Higher PAS was significantly associated with lesser decrease in 24hEE with fasting and higher urinary catecholamine excretion rates - consistent with spendthrift metabolism. As IDS increased, the association between anhedonia and the change in 24hEE from energy balance to fasting decreased (B-values were lower for change in EE). Here, higher PAS scores may reflect the ability to respond with appropriate homeostatic reactions which balance energy needs. IDS scores blunting this response may explain how anhedonia and depression can lead to weight gain.

Closed-loop control of air supply to whole-room indirect calorimeters to improve accuracy and standardize measurements during 24-hour dynamic metabolic studies.

OBJECTIVE: The aim of this study was to test proportional-integral-derivative (PID) control of air inflow rate in a whole-room indirect calorimeter to improve accuracy in measuring oxygen (O2 ) consumption ( V ̇ O 2 ) and carbon dioxide (CO2 ) production ( V ̇ CO 2 ). METHODS: A precision gas blender infused nitrogen (N2 ) and CO2 into the calorimeter over 24 hours based on static and dynamic infusion profiles mimicking V ̇ O 2 and V ̇ CO 2 patterns during resting and non-resting conditions. Constant (60 L/min) versus time-variant flow set by a PID controller based on the CO2 concentration was compared based on errors between measured versus expected values for V ̇ O 2 , V ̇ CO 2 , respiratory exchange ratio, and metabolic rate. RESULTS: Compared with constant inflow, the PID controller allowed both a faster rise time and long-term maintenance of a stable CO2 concentration inside the calorimeter, resulting in more accurate V ̇ CO 2 estimates (mean hourly error, PID: -0.9%, 60 L/min = -2.3%, p < 0.05) during static infusions. During dynamic infusions mimicking exercise sessions, the PID controller achieved smaller errors for V ̇ CO 2 (mean: -0.6% vs. -2.7%, p = 0.02) and respiratory exchange ratio (mean: 0.5% vs. -3.1%, p = 0.02) compared with constant inflow conditions, with similar V ̇ O 2 (p = 0.97) and metabolic rate (p = 0.76) errors. CONCLUSIONS: PID control in a whole-room indirect calorimeter system leads to more accurate measurements of substrate oxidation during dynamic metabolic studies.

Disinhibition augments thirst perception from two dehydrating stimuli in men.

Physiological systems controlling water and energy ingestion are coordinated. Whether maladaptive eating behavior and appetite for water are linked is unknown. Thus, we sought to investigate the association between maladaptive eating and both thirst and water drinking behavior with two dehydrating conditions. Twenty-two lean men and 20 men with obesity (mean age 32.3 ± 8.4 years and 30.0 ± 11.1 years, respectively) completed the Three-Factor Eating Questionnaire (TFEQ) and Gormally Binge Eating Scale. On separate days, volunteers were dehydrated by a 2-h hypertonic saline infusion and a 24-h water deprivation, and thirst was measured on a 100-mm visual analogue scale (VAS) during each procedure. After each dehydrating condition, ad libitum water intake was measured. In the saline infusion, higher Disinhibition on the TFEQ was associated with thirst in the lean group (ß = 4.2 mm VAS, p = 0.03) but not in the group with obesity (p = 0.51). In the water-deprivation condition, higher Disinhibition was also associated with thirst in the lean group (ß = 5.6 mm VAS, p = 0.01) with the strength of relationship being 3.5-fold stronger than that observed in the group with obesity (ß = 1.6 mm VAS, p = 0.0003). Hunger, Restraint, and binge-eating scores were not associated with thirst in either dehydrating condition (all p > 0.05). Maladaptive eating behaviors were not associated with ad libitum water intake (all p > 0.05). Disinhibition is associated with higher thirst perception in healthy weight individuals and may be attenuated in obesity. The characteristics of disinhibition which typically includes a heightened readiness to eat, may reflect a more general phenotype that also reflects a readiness to drink.

Energy expenditure measurements are reproducible in different whole-room indirect calorimeters in humans.

OBJECTIVE: This study aimed to evaluate the agreement of commonly reported energy metabolism measurements obtained from two different whole-room indirect calorimeters (WRICs). METHODS: Nine healthy adult volunteers were evaluated over four separate 24-hour periods in a crossover design, twice in two different WRICs of different sizes, each operated according to the Room Indirect Calorimetry Operating and Reporting Standards published in 2020. The reproducibility of repeated measurements was quantified by the coefficient of variation (CV) and intraclass correlation coefficient (ICC). RESULTS: The CVs between and within each WRIC for average 24-hour carbon dioxide production rate (VCO2 ) and oxygen consumption rate (VO2 ), 24-hour energy expenditure (EE), and respiratory exchange ratio ranged from 1.5% to 3.6%, whereas sleep EE ranged from 3.1% to 5.5%. CVs for macronutrient oxidation rates and spontaneous physical activity were higher, ranging from 9.2% to 38.1%. ICCs of VCO2 , VO2 , 24-hour EE, and energy expenditure at zero activity were >0.95, indicating excellent reproducibility, whereas ICCs for lipid oxidation, awake and fed thermogenesis, and sleep EE ranged from 0.55 to 0.92, indicating moderate to high reproducibility. ICCs for respiratory exchange ratio and carbohydrate and protein oxidation rates were lower (<0.70). Spontaneous physical activity showed high reproducibility within chambers (ICC = 0.88) but differed substantially between chambers (ICC = 0.23). CONCLUSIONS: Cross-chamber reproducibility is high for common outcome measures assessed in the respiratory chamber. The results support efforts to promote standardization across WRICs to allow multicenter studies.

Water intake, thirst, and copeptin responses to two dehydrating stimuli in lean men and men with obesity.

OBJECTIVE: Physiological systems responsible for water homeostasis and energy metabolism are interconnected. This study hypothesized altered responses to dehydration including thirst, ad libitum water intake, and copeptin in men with obesity. METHODS: Forty-two men (22 lean and 20 with obesity) were stimulated by a 2-hour hypertonic saline infusion and a 24-hour water deprivation. In each dehydrating condition, thirst, ad libitum water intake after dehydration, and urinary and hormonal responses including copeptin were assessed. RESULTS: After each dehydration condition, ad libitum water intake was similar between both groups (p > 0.05); however, those with obesity reported feeling less thirsty (p < 0.05) and had decreased copeptin response and higher urinary sodium concentrations when stressed (p < 0.05). Angiotensin II, aldosterone, atrial and brain natriuretic peptides, and apelin concentrations did not differ by adiposity group and did not explain the different thirst or copeptin responses in men with obesity. However, leptin was associated with copeptin response in lean individuals during the hypertonic saline infusion (p < 0.05), but the relationship was diminished in those with obesity. CONCLUSIONS: Diminished thirst and copeptin responses are part of the obesity phenotype and may be influenced by leptin. Adiposity may impact pathways regulating thirst and vasopressin release, warranting further investigation.

Food insecurity is associated with higher respiratory quotient and lower glucagon-like peptide 1.

OBJECTIVE: Food insecurity is known to be associated with obesity, but its association with physiological measures is unclear. Therefore, it was hypothesized that, compared with food-secure individuals, those with food insecurity would have higher 24-hour energy expenditure (EE [kilocalories per day]) and 24-hour respiratory quotient (RQ [ratio]). Subsequently, hormones involved in appetite regulation, substrate oxidation, and EE were explored. METHODS: A total of 113 healthy participants without diabetes (75 men; mean [SD], age 40 [12] years; BMI 30 [8] kg/m2 ) were included in this analysis. Participants completed the Food Security Short Form, underwent a dual-energy x-ray absorptiometry scan, and spent 24 hours in a human respiratory chamber following a weight-maintaining diet. RESULTS: Compared with individuals with food security, participants with food insecurity had no difference in 24-hour EE. However, they had higher carbohydrate oxidation rates (p = 0.03) and lower lipid oxidation rates (p = 0.02), resulting in higher 24-hour RQ (p < 0.01). They also had lower fasting glucagon-like peptide 1 (p = 0.03) concentrations. CONCLUSIONS: Food insecurity is associated with higher 24-hour RQ and lower fasting glucagon-like peptide 1 concentrations, metabolic and hormonal differences previously shown to drive greater calorie intake in the setting of unrestricted food availability. These findings therefore provide new insight into the paradoxical link between restricted food access and increased adiposity.

Trends in spontaneous physical activity and energy expenditure among adults in a respiratory chamber, 1985 to 2005.

OBJECTIVE: Fidgeting, a type of spontaneous physical activity (SPA), has substantial thermogenic potential. This research aims to examine secular trends in SPA and energy expenditure (EE) inside a respiratory chamber. METHODS: From 1985 to 2005, healthy adults (n = 678; mean age: 28.8 years; men: 60%; 522 Indigenous American, 129 White, and 27 Black) had a 24-hour stay in the respiratory chamber equipped with radar sensors. Body composition, glucose tolerance, fasting insulin, insulin action (hyperinsulinemic-euglycemic clamp), and insulin secretion (intravenous glucose tolerance test) were measured as covariates. RESULTS: SPA, adjusted for age, sex, race, and body composition, declined (r = -0.30, p < 0.0001), with a concomitant rise in the energy cost of SPA (r = 0.30, p < 0.0001). The 24-hour EE adjusted for covariates increased (r = 0.31, p < 0.0001), which was reflected in increases in EE during sleep (r = 0.18, p < 0.0001) and during the awake, fed condition (r = 0.28, p < 0.0001). The secular trends in SPA or 24-hour EE were unchanged with adjustment for measures related to glucose metabolism. CONCLUSIONS: Secular trend analyses showed a decline in fidgeting. However, this decline in SPA was partially counterbalanced by an increase in energy cost of this activity and a rise in EE. Nevertheless, our results support public health efforts to promote small but sustained changes in these behaviors.

Reduced Albumin Concentration Predicts Weight Gain and Higher Ad Libitum Energy Intake in Humans.

Objective: Circulating albumin is negatively associated with adiposity but whether it is associated with increased energy intake, lower energy expenditure or weight gain has not been examined. Methods: In study 1 (n=238; 146 men), we evaluated whether fasting albumin concentration was associated with 24-h energy expenditure and ad libitum energy intake. In study 2 (n=325;167 men), we evaluated the association between plasma albumin and change in weight and body composition. Results: After adjustment for known determinants of energy intake lower plasma albumin concentration was associated with greater total daily energy intake (ß= 89.8 kcal/day per 0.1 g/dl difference in plasma albumin, p=0.0047). No associations were observed between plasma albumin concentrations and 24-h energy expenditure or 24-h respiratory quotient (p>0.2). Over 6 years, volunteers gained on average 7.5 ± 11.7 kg (p<0.0001). Lower albumin concentrations were associated with greater weight [ß=3.53 kg, p=0.039 (adjusted for age, sex, follow up time), CI 0.16 to 6.21 per 1 g/dl difference albumin concentration] and fat mass (ß=2.3 kg, p=0.022), respectively, but not with changes in fat free mass (p=0.06). Conclusions: Lower albumin concentrations were associated with increased ad libitum food intake and weight gain, indicating albumin as a marker of energy intake regulation. Clinical Trial Registration: ClinicalTrials.gov, identifiers NCT00340132, NCT00342732.

Lower insulin clearance is associated with increased risk of type 2 diabetes in Native Americans.

AIMS/HYPOTHESIS: Impaired insulin clearance is implicated in the pathogenesis of type 2 diabetes, but prospective evidence remains limited. Therefore, we sought to identify factors associated with the metabolic clearance rate of insulin (MCRI) and to investigate whether lower MCRI is associated with increased risk of incident type 2 diabetes. METHODS: From a longitudinal cohort, 570 adult Native Americans without diabetes living in the Southwestern United States were characterised at baseline and 448 participants were monitored over a median follow-up period of 7.9 years with 146 (32%) incident cases of diabetes identified (fasting plasma glucose ≥7.0 mmol/l, 2 h plasma glucose [2-h PG] ≥11.1 mmol/l, or clinical diagnosis). At baseline, participants underwent dual-energy x-ray absorptiometry or hydrodensitometry to assess body composition, a 75 g OGTT, an IVGTT to assess acute insulin response (AIR), and a hyperinsulinaemic-euglycaemic clamp to assess MCRI and insulin action (M). RESULTS: In adjusted linear models, MCRI was inversely associated with body fat percentage (r = -0.35), fasting plasma insulin (r = -0.55) and AIR (r = -0.22), and positively associated with M (r = 0.17; all p < 0.0001). In multivariable Cox proportional hazard models, lower MCRI was associated with an increased risk of diabetes after adjustment for age, sex, heritage, body fat percentage, AIR, M, fasting plasma glucose, 2-h PG, and fasting plasma insulin (HR per one-SD difference in MCRI: 0.77; 95% CI 0.61, 0.98; p = 0.03). CONCLUSIONS/INTERPRETATION: Lower MCRI is associated with an unfavourable metabolic phenotype and is associated with incident type 2 diabetes independent of established risk factors. CLINICAL TRIAL REGISTRATION NUMBERS: ClinicalTrials.gov NCT00339482; NCT00340132.

Thigh Adipocyte Size is Inversely Related to Energy Intake and Respiratory Quotient in Healthy Women.

OBJECTIVE: The relationship between adipocyte size and ad libitum energy intake has not been previously examined. This study hypothesized an inverse relationship between adipocyte size and daily energy intake (DEI). METHODS: Seventy healthy adults (39 men and 31 women; BMI 30.0 [SD 6.3]) underwent dual-energy x-ray absorptiometry and subcutaneous fat biopsies from the abdomen and thigh. Osmium-fixed adipocytes were sized with a Coulter counter. Volunteers self-selected food from a vending machine paradigm as the only source of energy intake over 3 days as inpatients. Volunteers also had 24-hour respiratory quotient (RQ) measured in a whole-room indirect calorimeter. RESULTS: In women, the large cell peak diameter of the thigh depot was greater than that of the abdominal depot (Δ = +15.8 µm; P < 0.0001). In women, thigh peak diameter was inversely associated with DEI (ß = -264.7 kcal/d per 10-µm difference; P = 0.03) after adjusting for demographics and body composition. The thigh peak diameter in women was associated with 24-hour RQ (r = -0.47, P = 0.04) after adjusting for demographics, body composition, and 24-hour energy balance. These associations did not extend to men or the abdominal depot. CONCLUSIONS: In women, thigh adipocyte size was associated with reduced DEI and 24-hour RQ, indicating a special role for thigh fat in women. This depot-specific sexual dimorphism indicates common regulation of energy intake and adipocyte size in the thigh region of women.

Metabolic Responses to 24-Hour Fasting and Mild Cold Exposure in Overweight Individuals Are Correlated and Accompanied by Changes in FGF21 Concentration.

A greater decrease in 24-h energy expenditure (24 EE) during 24-h fasting defines a "thriftier" metabolic phenotype prone to weight gain during overfeeding and resistant to weight loss during caloric restriction. As the thermogenic response to mild cold exposure (COLD) may similarly characterize this human phenotype identified by acute fasting conditions, we analyzed changes in 24 EE and sleeping metabolic rate (SLEEP) in a whole-room indirect calorimeter during 24-h fasting at thermoneutrality (24°C) and during energy balance both at thermoneutrality (24°C) and mild cold (19°C) in 20 healthy volunteers (80% male; aged 36.6 ± 11.4 years; percentage body fat 34.8 ± 10.5%). Greater decrease in 24 EE during fasting (thriftier phenotype) was associated with less increase in 24 EE during COLD (i.e., less cold-induced thermogenesis). Greater decreases in plasma fibroblast growth factor 21 (FGF21) after 24-h fasting and after COLD were highly correlated and associated with greater decreases in SLEEP in both conditions. We conclude that the metabolic responses to short-term fasting and COLD are associated with and mediated by the liver-derived hormone FGF21. Thus, the 24 EE response to COLD further identifies the "thrifty" versus "spendthrift" phenotype, providing an additional setting to investigate the physiological mechanisms underlying the human metabolic phenotype and characterizing the individual susceptibility to weight change.