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

Martin Reinhardt; Marie S. Thearle; Mostafa Ibrahim; Maximilian G. Hohenadel; Clifton Bogardus; Jonathan Krakoff; Susanne B. Votruba


Diabetes. 2015;64(8):2859-2867. 

In This Article


Predictors of Weight Loss

In response to fasting and overfeeding 24h-EE decreased by 9.4% ± 1.8% (range −12.1 to −5.3%; 218 ± 43 kcal/day; P < 0.001) and increased by 7.6% ± 4.6% (range −0.1 to 13.6; 188 ± 123 kcal/day; P < 0.001), respectively. Subjects with the smallest reduction in 24h-EE in response to fasting lost the most weight (r = −0.84; P < 0.001 [Fig. 3B]; changes in sleeping energy expenditure during fasting: r = 0.07; P = 0.83). This relationship was still true after adjusting for age, sex, and race in a mixed model (β = −0.66 kg; P = 0.001). Subjects with the greatest 24h-EE increases with overfeeding tended to lose the most weight (r = −0.38; P = 0.22, Spearman rank correlation), and this became significant in a mixed model using all data points and adjusting for age, sex, and race (β = −0.43 kg; P = 0.01). There was no association of baseline weight with percentage of weight lost (r = −0.38; P = 0.22, Spearman rank correlation). Dichotomizing our obese population by the 24h-EE response to fasting, individuals below the median (thrifty phenotype) weighed less at baseline (98.0 ± 15.8 vs. 119.1 ± 7.3 kg; P = 0.02). Weighted AST did not differ between days spent inside and outside of the calorimeter (P = 0.87, paired t test). Weighted AST was positively related to weight change; more sedentary subjects lost less weight (r = 0.62; P = 0.04, Spearman rank correlation [n = 11]; Fig. 3C). After adjusting for age, sex, and race in a mixed model, weighted AST had a small influence on the daily rate of weight loss (β = 0.000096 kg/day; P = 0.02), and each 10% increase in sedentary time resulted in 0.001 kg less weight loss per day (0.04 kg less weight loss over 42 days). In a full model adjusting for age, sex, race, and baseline weight and accounting for repeated measures, weighted AST (β = 0.000059 kg/day; P = 0.02) and 24h-EE response to fasting (β = −0.55 kg; P < 0.001) and overfeeding (β = −0.083 kg; P = 0.02) were independent predictors of weight loss. Anthropometric and metabolic characteristics at baseline and changes after CR are given in Table 1 and Table 2, respectively.

Figure 3.

A: Individual percent weight loss curves. Baseline weight (Day 0) was set as the weight from the initial DXA scan during the weight stabilization period, and final weight was from the last day of CR (Day 42). Weight increases in 3 individuals between Day 0 and Day 1 are due to weight variations during the stabilization period. C, Caucasian; H, Hispanic; NA, Native American. B: Correlation between 24h-EE response to fasting and percent weight change during CR (r = −0.84; P ≤ 0.001; n = 12). C: Correlation between percent sedentary time during CR and percent weight loss (r = 0.63; P = 0.04; n = 11). ○, Female volunteer; ▴, male volunteer.

Calculated Energy Deficit

There was a positive association between weight loss and the calculated energy deficit (summed over 42 days; r = 0.75; P = 0.009, Spearman rank correlation) (Fig. 4A). That is, individuals with the greatest weight loss had the greatest calculated energy deficit. The 24h-EE reduction in response to fasting and the calculated energy deficit were negatively associated (r = −0.73; P = 0.01, Spearman rank correlation; Fig. 4C); those with the smallest reduction in 24h-EE in response to fasting had the greatest calculated energy deficit. In the multivariate mixed models adjusted for age, sex, race, and baseline weight, 24h-EE responses to fasting (β = −124 kcal/day; P < 0.0001) and overfeeding (β = −37 kcal/day; P < 0.0001) predicted a greater daily cumulative energy deficit over time (Fig. 4B). The mean energy deficit required to lose 1 kg of body weight was 4,935 kcal (2,239 kcal/lb; range 3,434–6,600 kcal/kg and 1,558–2,993 kcal/lb).

Figure 4.

A: Correlation between summed calculated energy deficit over 42 days and percent weight loss during CR (r = 0.7; P = 0.02; n = 11). B: Daily cumulative (42 days) calculated energy deficit by categorization of thrifty (gray line) and spendthrift (black line) phenotypes, based on the median of 24h-EE response to fasting; thrifty phenotype n = 6; spendthrift phenotype n = 5. Error bars represent standard deviations. C: Correlation between percent decrease in 24h-EE in response to fasting and summed calculated energy deficit over 42 days (r = −0.66; P = 0.03; n = 11). D: Daily cumulative calculated energy deficit over 42 days with assumed energy deficit data points superimposed. The upper and lower dashed lines represent the 95% CI of the means of the calculated energy deficit. Vertical error bars associated to the closed squares represent the standard deviation of the assumed energy deficit. ○, Female volunteer; ▴, male volunteer.

Assumed Energy Deficit From DXA

There were no significant associations between percentage weight loss (r = 0.45; P = 0.16), percentage of 24h-EE in response to fasting (r = −0.38; P = 0.3) or overfeeding (r = −0.018; P = 0.96), and the assumed energy deficit from DXA measurements. When comparing the calculated and assumed energy deficits, we found a mean difference of 571 ± 19,002 kcal over 6 weeks, or 14 ± 452 kcal/day, between methods (P = 0.3; Fig. 4D). There was a moderate association between the assumed and calculated energy deficit (r = 0.49; P = 0.13, Spearman rank correlation).