Recharacterizing the Metabolic State of Energy Balance in Thrifty and Spendthrift Phenotypes

Abstract

Purpose: The human thrifty phenotype hypothesis presupposes that lower 24-hour (24h) energy expenditure (24EE) during famine preserves body mass and promotes survival. The prevailing view defines thrifty individuals as having a lower 24EE during fasting. However, it is also plausible that the greater decline in 24EE during fasting in thrifty individuals is due to higher 24EE during energy balance conditions (ENBAL). Herein, we provide evidence that this is indeed the case.

Methods: In 108 healthy subjects, 24EE was measured in a whole-room indirect calorimeter both during ENBAL and 24h fasting conditions. Subjects were categorized as thrifty or spendthrift based on the median value (-162 kcal/day) of the difference in 24EE (adjusted for body composition) between fasting and ENBAL conditions. Concomitant 24h urinary catecholamines were assessed by liquid chromatography-mass spectrometry.

Results: Compared to ENBAL, 24EE decreased during 24h fasting by 172 kcal/day (standard deviation = 93; range, -470 to 122). A greater-than-median decrease in 24EE ("thriftier" phenotype) was due to higher 24EE during ENBAL (+124 kcal/day; P < 0.0001) but not to lower 24EE during fasting (P = 0.35). Greater fasting-induced increase in epinephrine was associated with concomitant lower decrease in 24EE (r = 0.27; P = 0.006).

Main conclusion: The greater decrease in 24EE during acute fasting (which characterizes the thrifty phenotype) is not due to reduced metabolic rate during fasting but to a relatively higher 24EE during feeding conditions, and this decrease in 24EE during fasting is accompanied by a smaller increase in epinephrine. These results recharacterize the prevailing view of the short-term 24EE responses that define the human metabolic phenotypes. Clinical Trials: NCT00523627, NCT00687115, NCT02939404.

Keywords: FGF21; energy balance; energy expenditure; epinephrine; fasting; thrifty phenotype.

Published by Oxford University Press on behalf of the Endocrine Society 2020.

Figures

Figure 1.

Original concept of the human metabolic phenotypes, where differences in the decrease in 24EE during 24h fasting between spendthrift and thrifty subjects are due to a lower 24EE during fasting in thrifty subjects compared with spendthrift subjects.

Figure 2.

Close association between 24h food intake and 24EE during energy balance inside the calorimeter. The slope of the regression line is 0.99 (95% CI, 0.93, 1.04) and its X- and Y-intercepts are 8 (CI, −123, 125) and −8 (CI, −130, 114), respectively. Abbreviations: 24EE, 24h energy expenditure; CI, confidence interval.

Figure 3.

Relatively higher EE during energy balance (thrifty phenotype) is associated with greater decrease in EE during 24h fasting. Relationships between adjusted 24EE (panel A) and adjusted SLEEP (panel C) during ENBAL (x-axis) and during fasting (y-axis). Adjusted 24EE and SLEEP values were calculated via linear regression models including age, sex, ethnicity, fat mass (FM), fat-free mass (FFM), spontaneous physical activity (SPA) (only 24EE analyses), ambient temperature, and calorimeter room (Room 1 or 2) as covariates in the regression models. Comparison of changes in adjusted 24EE (panel B) and in adjusted SLEEP (panel D) from ENBAL during 24h fasting between thrifty and spendthrift subjects. Classification of subjects as either spendthrift or thrifty is based on the median value of the adjusted decrease in 24EE from ENBAL during 24h fasting, such that thrifty subjects were identified as those with a greater-than-median decrease in adjusted 24EE (< −162 kcal/day). Black bars denote the average 24EE or SLEEP during ENBAL while grey bars denote the average 24EE or SLEEP during 24h fasting. The distance between the black and the grey bars denotes the fasting-induced changes in 24EE or SLEEP. Error bars denote the 95% confidence interval. Statistical significance between metabolic groups was determined by Student unpaired t tests. Average 24h time courses of minute-by-minute energy expenditure in thrifty and spendthrift subjects during ENBAL and during 24h fasting (panel E). Minute-by-minute adjusted energy expenditure values of each time course were calculated from a linear mixed model to account for repeated measures over the 24h with covariates age, sex, ethnicity, FM, FFM, SPA, ambient temperature, and calorimeter room. Four subjects had a 24EE during fasting greater than that during ENBAL. In this case, we substituted the 24EE values during FST of these 4 subjects with their corresponding 24EE value during ENBAL to avoid positive, nonphysiological values for the decrease in 24EE during fasting. In a sensitivity analysis, similar results were obtained after removing these 4 subjects from the analysis. In the scatterplot shown in panel C, 3 subjects can be considered outliers as they have a very high adjusted SLEEP during ENBAL but a very low adjusted SLEEP during fasting. In a sensitivity analysis, similar results were obtained after removing these 3 subjects from the analysis (slope: 0.73; 95% CI, 0.56–0.90). Abbreviations: 24EE, 24h energy expenditure; CI, confidence interval; EE, energy expenditure; ENBAL, energy balance; SLEEP, sleeping metabolic rate.

Figure 4.

Adjusted values of 24h energy expenditure and sleeping metabolic rate of the top 10 thriftiest and top 10 most spendthrift subjects during ENBAL and 24h fasting. Classification of the 10 thriftiest / 10 most spendthrift subjects was based on the decrease in adjusted 24EE from ENBAL during 24h fasting, such that the 10 thriftiest subjects were those who had the greatest decrease in adjusted 24EE during 24h fasting, whereas the 10 most spendthrift subjects were those who had the smallest decrease (or increase) in adjusted 24EE during fasting (panel A). Adjusted 24EE (or SLEEP) values were calculated by adding the average 24EE (or SLEEP) value calculated in the whole cohort to the residual values obtained from a linear regression model with covariates age, sex, ethnicity, fat mass, fat-free mass, spontaneous physical activity (only 24EE), ambient temperature, and calorimeter room. Abbreviations: 24EE, 24-h energy expenditure; ENBAL, energy balance; SLEEP, sleeping metabolic rate.

Figure 5.

Thrifty subjects have a higher 24EE at any level of fat-free mass than spendthrift subjects Relationships between fat-free mass and 24EE during (A) 24h energy balance and during (B) 24h fasting, separated by metabolic groups. Thrifty subjects are denoted in red, spendthrift subjects are denoted in green. In a linear regression analysis including the phenotypic group (thrifty vs spendthrift) and fat-free mass as determinants, thrifty subjects had higher 24EE than spendthrift subjects at any level of fat-free mass during energy balance (+101 kcal/day, 95% CI, +29, +173; P = 0.006) but not during fasting conditions (P = 0.67). Classification of subjects as either spendthrift or thrifty is based on the median value of the adjusted decrease in 24EE from ENBAL during 24h fasting, such that thrifty subjects were identified as those with a greater-than-median decrease in adjusted 24EE (< −162 kcal/day). Abbreviations: 24EE, 24-h energy expenditure.

Figure 6.

A greater decrease in 24EE during 24h fasting is associated with less increase in urinary epinephrine excretion rate. Association of fasting-induced changes in (panel A) 24h urinary epinephrine excretion rate, (panel C) plasma leptin, and (panel D) plasma FGF21 concentrations with the concomitant decrease in adjusted 24EE during fasting. Comparison of fasting-induced changes in (panel B) 24h urinary epinephrine excretion rate, (panel D) plasma leptin, and (panel F) plasma FGF21 between thrifty and spendthrift subjects. Classification of subjects as spendthrift or thrifty is based on the median value of adjusted decrease in 24EE from ENBAL during fasting, such that thrifty subjects were those with a greater-than-median decrease in 24EE. Adjusted 24EE values were calculated by adding the average 24EE value calculated in the whole cohort to the residual values obtained from a linear regression model with covariates age, sex, ethnicity, FM, FFM, spontaneous physical activity, ambient temperature, and calorimeter room. In the bar charts, black bars denote mean hormonal concentration during ENBAL, and grey bars denote mean hormonal concentration during 24h fasting. Error bars denote the 95% confidence interval of the respective mean. Abbreviations: 24EE, 24h energy expenditure; FGF21, fibroblast growth factor 21.

Figure 7.

Less decrease in plasma FGF21 concentration after 24h fasting is associated with less decrease in SLEEP and greater urinary epinephrine excretion rate. The y-intercept of the regression line of panel A is 11 (95% confidence interval, −15 to 36). Abbreviations: FGF21, fibroblast growth factor 21; SLEEP, sleeping energy expenditure.

Figure 8.

Redefined concept of the human thrifty and spendthrift phenotypes, where the greater decrease in adjusted 24EE in thrifty subjects is a result of higher EE requirements during energy balance and characterized by greater decreases both in daytime thermogenesis (red bold arrows) and in sleeping metabolic rate (blue bold arrows). Conversely, spendthrift subjects decrease 24EE less during fasting as they are able to increase their sleeping metabolic rate while also showing smaller decrease in daytime thermogenesis. The fasting-induced changes in sleeping metabolic rate might be mediated by a hormonal pathway including FGF21 and epinephrine (light blue arrows). Abbreviations: 24EE, 24h energy expenditure; FGF21, fibroblast growth factor 21.