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

Discussion

In the setting of carefully controlled CR in an inpatient setting we found evidence of a thrifty phenotype among obese individuals. This phenotype was defined by a relatively larger decrease in 24h-EE with fasting and a smaller increase in 24h-EE with overfeeding. These characteristics were associated with smaller weight loss during CR, and a more spendthrift phenotype was related to a greater weight loss and rate of calculated energy deficit accumulated over 42 days.

Wide interindividual variability in the amount and rate of weight loss during CR is common and has been repeatedly demonstrated in underfeeding studies.^[5,20–22] Our aim was to identify and quantify possible physiologic causes of this variability. To date, differences in the physiology of energy expenditure have not been able to explain why some people lose weight with less difficulty than others when dieting. Despite the lack of reliable methods to measure food intake (both in a metabolic ward and more so under free-living conditions), excess caloric intake is suspected to be the main cause of obesity.^[1,23] The variability and reproducibility of the energy expenditure changes during CR and overfeeding make these physiological measurements interesting candidates when trying to understand individual differences in success during dietary weight loss interventions.^[15]

The mean 24h-EE response to short-term fasting and overfeeding in our subjects confirmed previously reported values from human studies.^{[11,15,24–26]} Weyer et al.^[11] reported a correlation between the metabolic responses to short-term fasting and overfeeding in humans, such that individuals with the smallest decrease in 24h-EE in response to fasting had the greatest increase in 24h-EE in response to overfeeding. Importantly, this was shown in a mixed group of both lean and obese individuals, indicating that, despite weight gain, certain obese individuals retain a more spendthrift energy expenditure phenotype. We have described for the first time that obese individuals with a spendthrift phenotype lost the most weight during 6 weeks of CR. A 1% smaller 24h-EE decrease during fasting (range −5.3% to −12.1%) led to a larger energy deficit of 124 kcal/day, or a greater cumulative energy loss of more than 5,000 kcal over the 6-week time period. A 124-kcal/day smaller energy deficit in the thrifty phenotype is equivalent to the amount of energy expenditure reduction caused by a melanocortin 4 receptor (MC4R) gene mutation in Pima Indians (~110–140 kcal/day),^[26] which predisposes these individuals to obesity.^[27]

The data indicate that only 24h-EE changes in response to fasting, not changes in sleeping energy expenditure (an approximate surrogate for resting metabolic rate) during fasting, were associated with the observed weight changes over 42 days of CR, indicating that resting energy expenditure is unlikely to be involved in the observed difference between individuals the thrifty and spendthrift phenotypes. Thus the differences are likely the result of variation in the energy expenditure response to CR. This may be related to diet-induced thermogenesis, which may convey resistance to weight gain during overfeeding.

The identification of the two phenotypes before the caloric deficit–induced weight loss differentiates our findings from those of previous work,^[28,29] where the concurrent occurrence of changes in energy expenditure and weight loss/gain was observed during or after caloric deficit/excess interventions. As noted above, because we are demonstrating a metabolic adaptation to CR that is measurable before and during weight loss under CR, it is plausible that this adaptation has an influence on diet-related energy metabolism. The accelerated accumulation of the calculated energy deficit is important because calculated energy deficit was positively correlated with weight loss. This indicates as well that further understanding of these phenotypes requires meticulous measurement of both energy intake (accounting for waste) and energy expenditure.

Even though there was no continuous association between baseline weight and percentage weight loss, when we dichotomized our study population by the energy expenditure response to fasting, the thrifty phenotype had a lower body weight at baseline. One possible explanation for their greater 24h-EE response to fasting might be that effects of prior dieting lead to the more preservative thrifty phenotype. In general, mechanisms that might lead to the thrifty versus spendthrift phenotype are not clear. Individual responses of the sympathetic nervous system,^[30–32] thyroid hormones,^[32–34] and leptin and ghrelin,^[35] among others, are likely to have a major influence. It is possible that our subjects had variable volumes of brown adipose tissue, which influences human energy expenditure.^[36] The variability in weight loss after the same relative CR over 6 weeks is a result of changes in diet-related energy metabolism and especially the interindividual variability of those changes during CR. Variation in the amount of brown adipose tissue might (at least in part) account for the observed weight loss variability via its effect on diet-related energy metabolism. However, brown adipose tissue activation was not measured in our study. While the relationship of the predictors of weight loss during CR was dominated by the metabolic response to fasting, the statistically significant response to overfeeding might have an even more important role in preventing or limiting weight gain. Although sedentary time was a statistically independent negative predictor of weight loss, even after adjusting for 24h-EE response to fasting and overfeeding, age, sex, race, and baseline weight, it was physiologically less relevant.

Our finding that only the calculated energy deficit (kilocalories), not values based on the caloric contents of body composition changes (measured by DXA), accurately represent the weight loss percentage indicates the importance of energy balance measuring techniques when examining metabolic changes during CR. One of the underlying assumptions of DXA—a constant hydration of lean body mass—is not provided during the early phase of voluntary weight loss because of glycogen, sodium, protein, and fluid shifts^[37] and therefore might explain the diverging results between the two methods, especially with this small number of individuals. In addition, in the calculation of assumed energy deficit, FFM is treated as one value, which is likely not the case given the wide variety of tissue it represents. A comparison of the assumed and measured energy did, however, show a moderate but nonsignificant (because of the small sample size) association between the two methods. In combination with the resulting 14 ± 452 kcal/day measurement difference, the two methods can be considered in fair agreement.

The pervasive rule that an energy deficit of 3,500 kcal is required to lose 1 lb of body weight is based on calculations assuming that dietary weight loss is mostly a result of energy-dense FM loss.^[38] We found considerably lower values and wide interindividual variation in the caloric cost of losing 1 lb body mass in both thrifty and spendthrift subjects (mean 2,239 kcal/lb, range 1,558–2,993 kcal/lb), with no statistically significant difference between the two groups. However, our DXA measures before and after CR (weight-stable conditions) revealed that both FM and FFM were reduced, confirming earlier findings by Forbes.^[39,40]

Our study is limited by a few missing 24h-EE assessments during CR, which are missing at random. DXA measurements are complete and were performed in the same week but not always on analogous days during the study. Further, to calculate the energy deficit based on body composition changes measured by DXA, we used estimates of energy content of FM (38.91 MJ/kg) and FFM (4.27 MJ/kg); we acknowledge that these values are population averages and might differ interindividually. In addition, possible differences in the amount of standing versus sitting time and spontaneous muscle contraction (all of which are components of "non exercise activity thermogenesis"^[41]), for example, that used for maintaining posture, which cannot be measured as precisely with the accelerometers used in this study,^[42] might explain at least part of the larger energy deficit in subjects with the spendthrift phenotype. We acknowledge the small sample size as a limitation of this study. Our use of repeated measure analyses, however, thereby increasing measurement precision and statistical power, enabled us to adjust for multiple confounders.^[18,19]

In conclusion, using detailed measures of actual energy intake (as measured by bomb calorimetry) and energy expenditure (using whole-room indirect calorimetry and activity monitoring) during carefully monitored prolonged inpatient studies, we clearly determined that there is variation in the extent of weight loss in obese humans during 50% CR that is not the result of a lack of adherence but is caused by real biologic interindividual variation in energy expenditure responses to the same energy deficits, that is, thrifty and spendthrift phenotypes. Whether identification of these phenotypes can be harnessed to prevent weight gain in humans remains to be established.

Diabetes. 2015;64(8):2859-2867. © 2015  American Diabetes Association, Inc.