Impaired Metabolic Flexibility to High-Fat Overfeeding Predicts Future Weight Gain in Healthy Adults.

The ability to switch fuels for oxidation in response to changes in macronutrient composition of diet (metabolic flexibility) may be informative of individuals' susceptibility to weight gain. Seventy-nine healthy, weight-stable participants underwent 24-h assessments of energy expenditure and respiratory quotient (RQ) in a whole-room calorimeter during energy balance (EBL) (50% carbohydrate, 30% fat) and then during 24-h fasting and three 200% overfeeding diets in a crossover design. Metabolic flexibility was defined as the change in 24-h RQ from EBL during fasting and standard overfeeding (STOF) (50% carbohydrate, 30% fat), high-fat overfeeding (HFOF) (60% fat, 20% carbohydrate), and high-carbohydrate overfeeding (HCOF) (75% carbohydrate, 5% fat) diets. Free-living weight change was assessed after 6 and 12 months. Compared with EBL, RQ decreased on average by 9% during fasting and by 4% during HFOF but increased by 4% during STOF and by 8% during HCOF. A smaller decrease in RQ, reflecting a smaller increase in lipid oxidation rate, during HFOF but not during the other diets predicted greater weight gain at both 6 and 12 months. An impaired metabolic flexibility to acute HFOF can identify individuals prone to weight gain, indicating that an individual's capacity to oxidize dietary fat is a metabolic determinant of weight change.

Effects of Short-Term Fasting and Different Overfeeding Diets on Thyroid Hormones in Healthy Humans.

Background: A greater decrease in 24-hour energy expenditure (EE) during fasting and a smaller increase in 24-hour EE during low-protein overfeeding (metabolic "thrifty" phenotype) predict weight gain. As thyroid hormones (TH) are implicated in energy intake and metabolism, we assessed whether: (i) TH concentrations are altered by 24-hour fasting or overfeeding diets with varying protein content and (ii) diet-related changes in TH correlate with concomitant changes in EE. Methods: Fifty-eight euthyroid healthy subjects with normal glucose regulation underwent 24-hour dietary interventions including fasting, eucaloric feeding, and five overfeeding diets in a crossover design within a whole-room indirect calorimeter to measure the 24-hour EE. Overfeeding diets (200% of energy requirements) included three diets with 20% protein, one diet with 3% protein (low-protein overfeeding diet [LPF]: 46% fat), and one diet with 30% protein (high-protein overfeeding diet [HPF]: 44% fat, n = 51). Plasma free thyroxine (fT4), free triiodothyronine (fT3), and fibroblast growth factor 21 (FGF21) concentrations were measured after overnight fast the morning of and after each diet. Results: On average, fT4 increased by 8% (+0.10 ng/dL, 95% confidence interval [CI 0.07-0.13], p < 0.0001) and fT3 decreased by 6% (-0.17 pg/mL [CI -0.27 to -0.07], p = 0.001) after 24-hour fasting, whereas both fT4 and fT3 decreased by 5% (-0.07 ng/dL [CI -0.11 to -0.04], p < 0.0001) and 4% (-0.14 pg/mL [CI -0.24 to -0.04], p = 0.008) following HPF, respectively. Greater decreases in fT3 after HPF are associated with larger decreases in FGF21 (r = 0.40, p = 0.005). Following LPF, the mean fT3 increased by 6% (+0.14 pg/mL [CI 0.05-0.2], p = 0.003) with no change in fT4 (p = 0.7). No changes in TH were observed after normal-protein overfeeding diets (all p > 0.1). No associations were observed between TH concentrations and diet-related changes in 24-hour EE during any diet (all p > 0.07). Conclusions: Acute (200%) short-term (24 hours) changes in food intake induce small changes in TH concentrations only after diets with low (0% fasting and 3% protein overfeeding) or high (30% protein overfeeding) protein content. The fT3-FGF21 association after high-protein overfeeding suggests a role for TH in inhibiting FGF21 secretion by the liver during protein excess. These results indicate that TH are involved in protein metabolism; however, they do not mediate the short-term EE response to diets that characterize the metabolic phenotypes and determine the individual susceptibility to weight gain.

Core body temperature, energy expenditure, and epinephrine during fasting, eucaloric feeding, and overfeeding in healthy adult men: evidence for a ceiling effect for human thermogenic response to diet.

BACKGROUND: In homeothermic animals, approximately 50% of daily energy expenditure (EE) is spent to maintain a consistent core body temperature (CBT). In humans, little is known about CBT responses to feeding and overfeeding and their relationship to diet-related changes in EE. OBJECTIVE: To study the effects of feeding and overfeeding on CBT and its association with diet-induced thermogenesis (DIT). DESIGN: Fifty-three healthy men with normal glucose regulation and a wide range of body composition (mean ±â€¯SD, body fat: 25 ±â€¯8%, range: 7-43%) had 24-h EE assessed during fasting in a whole-room indirect calorimeter with concomitant CBT measurement by ingestible capsules and 24-h urinary collection for catecholamine measurements. Changes in 24-h EE (DIT) and CBT compared to fasting were assessed during three normal-protein (20%) diets using a cross-over design: one eucaloric diet (EBL, 50% carbohydrate, n = 37) and two overfeeding diets with 200% energy requirements: a high-fat (FNP, 60% fat, n = 25) and a high-carbohydrate (CNP; 75% carbohydrate, n = 24) diet. RESULTS: The average 24-h CBT (avgCBT) during fasting was 36.81 ±â€¯0.14 °C (inter-individual CV = 0.4%) and positively correlated with 24-h urinary epinephrine (r = 0.61, p < 0.001), but not with body composition measures (p > 0.05). AvgCBT increased during EBL (Δ = 0.06 ±â€¯0.11 °C, p = 0.002), FNP (Δ = 0.13 ±â€¯0.14 °C, p < 0.001), and CNP (Δ = 0.19 ±â€¯0.13 °C, p < 0.001) and associated with increased DIT during EBL (r = 0.43, p = 0.01, ß = 31 kcal/day/0.1 °C) and FNP (r = 0.60, p = 0.002, ß = 43 kcal/day/0.1 °C), but not CNP (p = 0.47). A ceiling effect for the increase in CBT, but not in DIT, was observed during feeding and, particularly, overfeeding. CONCLUSIONS: CBT increases with feeding and is moderately associated with DIT to a different degree depending on the macronutrient composition of the overfeeding diet. There is a ceiling effect such that individuals with a higher CBT during fasting have limited capacity to increase CBT with feeding. Because of body thermoregulatory mechanisms that maintain a constant CBT, these results indicate that CBT has a limited role in the inter-individual variability in DIT.

FGF21 Is a Hormonal Mediator of the Human "Thrifty" Metabolic Phenotype.

Fibroblast growth factor 21 (FGF21) regulates energy expenditure (EE) and influences weight change during low-protein overfeeding in rodent models. The change in EE after a low-protein overfeeding diet is a predictor of weight change in humans and a feature of the "thrifty" metabolic phenotype. However, there are no studies showing an association between circulating FGF21 and diet-related EE in humans. We assessed the changes in plasma FGF21 concentrations after 24 h of seven dietary interventions with different macronutrient content while in a whole-room indirect calorimeter in 64 healthy subjects with normal glucose regulation. Plasma FGF21 concentration consistently increased by threefold only after the two low-protein (3%) overfeeding diets, one high in carbohydrate (75%) and the other high in fat (46%), with larger increases in FGF21 being associated with greater increases in 24-h EE. Subjects with smaller increases in FGF21 after the low-protein high-fat diet gained more weight after 6 months in free-living conditions. Therefore, the individual predisposition to weight gain over time can be assessed by 24-h overfeeding a low-protein diet and measurements of plasma FGF21 concentrations. Individuals with a blunted FGF21 response to a low-protein diet have a thrifty metabolism and are at risk for future weight gain.

Norepinephrine and T4 Are Predictors of Fat Mass Gain in Humans With Cold-Induced Brown Adipose Tissue Activation.

Context: In healthy adults with detectable cold-induced brown adipose tissue activation (CIBA), the relationships between sympathetic nervous system (SNS) or thyroid activity during energy balance (EBL) with CIBA and body composition change are undetermined. Objective: To investigate the relationships between CIBA and thermoneutral catecholamines and thyroid hormones measured during EBL and to determine if CIBA, catecholamines, or thyroid hormones predict body composition changes. Design, Setting, Participants, and Interventions: Twelve healthy volunteers (seven male and five female) with positive CIBA [>2 standardized uptake value (g/mL)] had 24-hour energy expenditure (24hEE) assessed during EBL via whole-room indirect calorimetry while residing on a clinical research unit. Positron emission tomography/computed tomography scans were performed after exposure to 16°C for 2 hours to quantify CIBA. Main Outcome Measures: CIBA, 24hEE during EBL, and thermoneutrality with concomitant measurement of urinary catecholamines and plasma free T3 and free T4. Body composition at baseline and 6 months by dual-energy X-ray absorptiometry. Results: Lower urinary norepinephrine and free T4 were associated with higher CIBA (r = -0.65, P = 0.03; and r = -0.75, P < 0.01, respectively), but CIBA was not associated with 24hEE at thermoneutrality (P = 0.77). Lower CIBA (ß = -3.5 kg/standardized uptake value; P < 0.01) predicted fat mass gain, whereas higher urinary norepinephrine and free T4 predicted future fat mass gain at 6 months (ß = 3.0 kg per twofold difference in norepinephrine, P = 0.03; and ß = 1.2 kg per 0.1-ng/dL difference in free T4, P = 0.03, respectively). Conclusion: Lower SNS and free thyroid measurements at baseline indicate a greater capacity for CIBA, which may be predictive against fat mass gain.