Role of Energy Excretion in Human Body Weight Regulation

Abstract

Food intake and energy expenditure are the typical determinants of body weight. Yet, recent observations underscore that a third and often-neglected factor, fecal energy loss, can influence energy balance. Here, we explore how macronutrient excretion modulates human energy homeostasis and highlight its potential impact on the propensity to gain weight. Food intake and energy expenditure are the typical determinants of body weight. Yet, recent observations underscore that a third and often-neglected factor, fecal energy loss, can influence energy balance. Here, we explore how macronutrient excretion modulates human energy homeostasis and highlight its potential impact on the propensity to gain weight. Obesity develops as the result of a sustained positive energy balance. This etiological explanation surmises that calorie consumption must exceed calorie combustion for weight gain to occur. However, not all ingested nutrients are absorbed by the gastrointestinal tract. A fraction of food consumed ends up being excreted in feces. Moreover, even the nutrients that reach the circulation can still escape the body, such as by being filtered through the kidneys (Figure 1A ) [1.Southgate D.A. Durnin J.V. Calorie conversion factors. An experimental reassessment of the factors used in the calculation of the energy value of human diets.Br. J. Nutr. 1970; 24: 517-535Crossref PubMed Scopus (281) Google Scholar,2.Sanchez-Pena M.J. et al.Calculating the metabolizable energy of macronutrients: a critical review of Atwater’s results.Nutr. Rev. 2017; 75: 37-48Crossref PubMed Scopus (19) Google Scholar]. This collective excretion or loss of nutrients represents a frequently neglected component of energy balance regulation. Thus, more accurately: weight gain only occurs when the amount of absorbed (and retained) energy, exceeds the number of calories that are oxidized. The fact that calories from food can 'disappear' in feces (and urine) is an understudied component of overall energy balance [3.Jumpertz R. et al.Energy-balance studies reveal associations between gut microbes, caloric load, and nutrient absorption in humans.Am. J. Clin. Nutr. 2011; 94: 58-65Crossref PubMed Scopus (811) Google Scholar]. Moreover, it is potentially also a variable that protects some individuals from obesity while making others prone to weight gain [4.Webb P. Annis J.F. Adaptation to overeating in lean and overweight men and women.Hum. Nutr. Clin. Nutr. 1983; 37: 117-131PubMed Google Scholar,5.Basolo A. et al.Effects of underfeeding and oral vancomycin on gut microbiome and nutrient absorption in humans.Nat. Med. 2020; 26: 589-598Crossref PubMed Scopus (41) Google Scholar]. Overfeeding studies in humans show that weight gain varies substantially among individuals. As such, one classical study reported a weight gain range of 4.3–13.3 kg in 12 pairs of monozygotic twins who were overfed by a total of 84 000 kcal for a period of 100 days [6.Bouchard C. et al.The response to long-term overfeeding in identical twins.N. Engl. J. Med. 1990; 322: 1477-1482Crossref PubMed Scopus (1004) Google Scholar]. Two human phenotypes have more recently been proposed to explain this variability. While 'thrifty' individuals easily gain weight during times of caloric surplus, 'spendthrifty' individuals are less prone to adiposity, despite being exposed to the same obesogenic environment (Box 1) [7.Piaggi P. Metabolic determinants of weight gain in humans.Obesity (Silver Spring). 2019; 27: 691-699Crossref PubMed Scopus (46) Google Scholar,8.Johannsen D.L. et al.Metabolic adaptation is not observed after 8 weeks of overfeeding but energy expenditure variability is associated with weight recovery.Am. J. Clin. Nutr. 2019; 110: 805-813Crossref PubMed Scopus (15) Google Scholar].Box 1Human Thrifty versus Spendthrifty PhenotypesHumans inherit different susceptibilities to weight gain [6.Bouchard C. et al.The response to long-term overfeeding in identical twins.N. Engl. J. Med. 1990; 322: 1477-1482Crossref PubMed Scopus (1004) Google Scholar]. Although body weight regulation is biased towards weight gain, it is noticeable that a minor group of individuals are partly protected against overweight, even when exposed to highly obesogenic environments [7.Piaggi P. Metabolic determinants of weight gain in humans.Obesity (Silver Spring). 2019; 27: 691-699Crossref PubMed Scopus (46) Google Scholar]. In humans, predisposition to weight gain spans a wide continuum, but two markedly different phenotypes have been proposed to exist at the outermost ends [7.Piaggi P. Metabolic determinants of weight gain in humans.Obesity (Silver Spring). 2019; 27: 691-699Crossref PubMed Scopus (46) Google Scholar,8.Johannsen D.L. et al.Metabolic adaptation is not observed after 8 weeks of overfeeding but energy expenditure variability is associated with weight recovery.Am. J. Clin. Nutr. 2019; 110: 805-813Crossref PubMed Scopus (15) Google Scholar]. As such, humans who are susceptible to obesity have been proposed to be equipped with a 'thrifty' phenotype compared with more obesity-resistant subjects with a 'spendthrifty' phenotype [7.Piaggi P. Metabolic determinants of weight gain in humans.Obesity (Silver Spring). 2019; 27: 691-699Crossref PubMed Scopus (46) Google Scholar,8.Johannsen D.L. et al.Metabolic adaptation is not observed after 8 weeks of overfeeding but energy expenditure variability is associated with weight recovery.Am. J. Clin. Nutr. 2019; 110: 805-813Crossref PubMed Scopus (15) Google Scholar]. Thrifty subjects tend to conserve energy both during underfeeding and overfeeding. As a consequence, they have a natural propensity for weight gain and, in addition, find it difficult to lose weight [7.Piaggi P. Metabolic determinants of weight gain in humans.Obesity (Silver Spring). 2019; 27: 691-699Crossref PubMed Scopus (46) Google Scholar,8.Johannsen D.L. et al.Metabolic adaptation is not observed after 8 weeks of overfeeding but energy expenditure variability is associated with weight recovery.Am. J. Clin. Nutr. 2019; 110: 805-813Crossref PubMed Scopus (15) Google Scholar]. By contrast, individuals with a spendthrifty phenotype waste more energy both when dieting and when eating in excess. Therefore, they find it not only easier to lose weight, but also more difficult to gain weight. From an evolutionary point of view, the thrifty phenotype might have been advantageous because it favored survival by saving energy and increasing fat deposition during periods of limited food availability [8.Johannsen D.L. et al.Metabolic adaptation is not observed after 8 weeks of overfeeding but energy expenditure variability is associated with weight recovery.Am. J. Clin. Nutr. 2019; 110: 805-813Crossref PubMed Scopus (15) Google Scholar].Identifying these two phenotypes in overfeeding studies has been challenging due to the low sample size often used in such studies [8.Johannsen D.L. et al.Metabolic adaptation is not observed after 8 weeks of overfeeding but energy expenditure variability is associated with weight recovery.Am. J. Clin. Nutr. 2019; 110: 805-813Crossref PubMed Scopus (15) Google Scholar]. Yet, another strategy to map obesity susceptibility and resistance has been to place individuals in metabolic chambers and subject them to acute, short-term fasting and (low-protein) overfeeding, respectively [7.Piaggi P. Metabolic determinants of weight gain in humans.Obesity (Silver Spring). 2019; 27: 691-699Crossref PubMed Scopus (46) Google Scholar,8.Johannsen D.L. et al.Metabolic adaptation is not observed after 8 weeks of overfeeding but energy expenditure variability is associated with weight recovery.Am. J. Clin. Nutr. 2019; 110: 805-813Crossref PubMed Scopus (15) Google Scholar]. Also, studies have started to explore whether endocrine factors and/or metabolic tissues (e.g., leptin, FGF21, skeletal muscle, and brown fat) mediate individual metabolic responses [7.Piaggi P. Metabolic determinants of weight gain in humans.Obesity (Silver Spring). 2019; 27: 691-699Crossref PubMed Scopus (46) Google Scholar,8.Johannsen D.L. et al.Metabolic adaptation is not observed after 8 weeks of overfeeding but energy expenditure variability is associated with weight recovery.Am. J. Clin. Nutr. 2019; 110: 805-813Crossref PubMed Scopus (15) Google Scholar]. However, the exact contribution from these factors has not been clearly defined. It also remains unknown whether, and to what extent, energy loss in feces and urine contributes to the physiological differences between thrifty and spendthrifty phenotypes (Figure I). Humans inherit different susceptibilities to weight gain [6.Bouchard C. et al.The response to long-term overfeeding in identical twins.N. Engl. J. Med. 1990; 322: 1477-1482Crossref PubMed Scopus (1004) Google Scholar]. Although body weight regulation is biased towards weight gain, it is noticeable that a minor group of individuals are partly protected against overweight, even when exposed to highly obesogenic environments [7.Piaggi P. Metabolic determinants of weight gain in humans.Obesity (Silver Spring). 2019; 27: 691-699Crossref PubMed Scopus (46) Google Scholar]. In humans, predisposition to weight gain spans a wide continuum, but two markedly different phenotypes have been proposed to exist at the outermost ends [7.Piaggi P. Metabolic determinants of weight gain in humans.Obesity (Silver Spring). 2019; 27: 691-699Crossref PubMed Scopus (46) Google Scholar,8.Johannsen D.L. et al.Metabolic adaptation is not observed after 8 weeks of overfeeding but energy expenditure variability is associated with weight recovery.Am. J. Clin. Nutr. 2019; 110: 805-813Crossref PubMed Scopus (15) Google Scholar]. As such, humans who are susceptible to obesity have been proposed to be equipped with a 'thrifty' phenotype compared with more obesity-resistant subjects with a 'spendthrifty' phenotype [7.Piaggi P. Metabolic determinants of weight gain in humans.Obesity (Silver Spring). 2019; 27: 691-699Crossref PubMed Scopus (46) Google Scholar,8.Johannsen D.L. et al.Metabolic adaptation is not observed after 8 weeks of overfeeding but energy expenditure variability is associated with weight recovery.Am. J. Clin. Nutr. 2019; 110: 805-813Crossref PubMed Scopus (15) Google Scholar]. Thrifty subjects tend to conserve energy both during underfeeding and overfeeding. As a consequence, they have a natural propensity for weight gain and, in addition, find it difficult to lose weight [7.Piaggi P. Metabolic determinants of weight gain in humans.Obesity (Silver Spring). 2019; 27: 691-699Crossref PubMed Scopus (46) Google Scholar,8.Johannsen D.L. et al.Metabolic adaptation is not observed after 8 weeks of overfeeding but energy expenditure variability is associated with weight recovery.Am. J. Clin. Nutr. 2019; 110: 805-813Crossref PubMed Scopus (15) Google Scholar]. By contrast, individuals with a spendthrifty phenotype waste more energy both when dieting and when eating in excess. Therefore, they find it not only easier to lose weight, but also more difficult to gain weight. From an evolutionary point of view, the thrifty phenotype might have been advantageous because it favored survival by saving energy and increasing fat deposition during periods of limited food availability [8.Johannsen D.L. et al.Metabolic adaptation is not observed after 8 weeks of overfeeding but energy expenditure variability is associated with weight recovery.Am. J. Clin. Nutr. 2019; 110: 805-813Crossref PubMed Scopus (15) Google Scholar]. Identifying these two phenotypes in overfeeding studies has been challenging due to the low sample size often used in such studies [8.Johannsen D.L. et al.Metabolic adaptation is not observed after 8 weeks of overfeeding but energy expenditure variability is associated with weight recovery.Am. J. Clin. Nutr. 2019; 110: 805-813Crossref PubMed Scopus (15) Google Scholar]. Yet, another strategy to map obesity susceptibility and resistance has been to place individuals in metabolic chambers and subject them to acute, short-term fasting and (low-protein) overfeeding, respectively [7.Piaggi P. Metabolic determinants of weight gain in humans.Obesity (Silver Spring). 2019; 27: 691-699Crossref PubMed Scopus (46) Google Scholar,8.Johannsen D.L. et al.Metabolic adaptation is not observed after 8 weeks of overfeeding but energy expenditure variability is associated with weight recovery.Am. J. Clin. Nutr. 2019; 110: 805-813Crossref PubMed Scopus (15) Google Scholar]. Also, studies have started to explore whether endocrine factors and/or metabolic tissues (e.g., leptin, FGF21, skeletal muscle, and brown fat) mediate individual metabolic responses [7.Piaggi P. Metabolic determinants of weight gain in humans.Obesity (Silver Spring). 2019; 27: 691-699Crossref PubMed Scopus (46) Google Scholar,8.Johannsen D.L. et al.Metabolic adaptation is not observed after 8 weeks of overfeeding but energy expenditure variability is associated with weight recovery.Am. J. Clin. Nutr. 2019; 110: 805-813Crossref PubMed Scopus (15) Google Scholar]. However, the exact contribution from these factors has not been clearly defined. It also remains unknown whether, and to what extent, energy loss in feces and urine contributes to the physiological differences between thrifty and spendthrifty phenotypes (Figure I). Alterations in energy dissipation, such as heat-producing processes, have traditionally been used to explain why humans respond differently to perturbations in energy balance. Yet, after several decades of research, scientists still debate to what extent weight gain is counteracted by so-called 'Luxuskonsumption', that is, an adaptive increase in energy expenditure that exceeds that expected by the obligatory needs of a greater body mass [4.Webb P. Annis J.F. Adaptation to overeating in lean and overweight men and women.Hum. Nutr. Clin. Nutr. 1983; 37: 117-131PubMed Google Scholar,8.Johannsen D.L. et al.Metabolic adaptation is not observed after 8 weeks of overfeeding but energy expenditure variability is associated with weight recovery.Am. J. Clin. Nutr. 2019; 110: 805-813Crossref PubMed Scopus (15) Google Scholar]. In a recent study, it was reported that 8 weeks of overfeeding (40% above baseline energy needs), only triggered a small induction of 24-h energy expenditure of 23 kcal/day, on average. Hence, the authors concluded that metabolic adaptation was ‘unlikely to confer strong resistance to weight gain’ [8.Johannsen D.L. et al.Metabolic adaptation is not observed after 8 weeks of overfeeding but energy expenditure variability is associated with weight recovery.Am. J. Clin. Nutr. 2019; 110: 805-813Crossref PubMed Scopus (15) Google Scholar]. Additionally, a counterintuitive observation was made by analyzing the individual responses: the subjects with the greatest induction in energy expenditure were those who gained the largest amount of weight during overfeeding [8.Johannsen D.L. et al.Metabolic adaptation is not observed after 8 weeks of overfeeding but energy expenditure variability is associated with weight recovery.Am. J. Clin. Nutr. 2019; 110: 805-813Crossref PubMed Scopus (15) Google Scholar]. These findings both support that Luxuskonsumption is not an essential protective mechanism against experimentally induced adiposity and suggest the existence of other weight gain-defense systems. In 2011, an inpatient feeding study used bomb calorimetry to show that, on average, ~5% and ~0.5% of ingested energy are lost in feces and urine [3.Jumpertz R. et al.Energy-balance studies reveal associations between gut microbes, caloric load, and nutrient absorption in humans.Am. J. Clin. Nutr. 2011; 94: 58-65Crossref PubMed Scopus (811) Google Scholar]. An interindividual variation in fecal energy loss of 2–9% was reported [3.Jumpertz R. et al.Energy-balance studies reveal associations between gut microbes, caloric load, and nutrient absorption in humans.Am. J. Clin. Nutr. 2011; 94: 58-65Crossref PubMed Scopus (811) Google Scholar]. The same group recently confirmed these findings in adults with obesity who underwent two 3-day interventions with a total energy intake of 150% and 50% of their weight maintenance energy needs [5.Basolo A. et al.Effects of underfeeding and oral vancomycin on gut microbiome and nutrient absorption in humans.Nat. Med. 2020; 26: 589-598Crossref PubMed Scopus (41) Google Scholar]. Here, Baloso, Hohenadel, and Ang et al. showed that relative fecal energy loss was on average 6% during overfeeding and 9% during underfeeding (the absolute fecal energy loss was accordingly highest in the overfeeding intervention). Similar observations were made for urinary energy loss, which averaged around 1% and 2% for overfeeding and underfeeding, respectively [5.Basolo A. et al.Effects of underfeeding and oral vancomycin on gut microbiome and nutrient absorption in humans.Nat. Med. 2020; 26: 589-598Crossref PubMed Scopus (41) Google Scholar]. These numbers are in line with previous reports. A study that aimed to define energy absorption reference values for healthy free-living volunteers showed that the 95% confidence interval for energy absorption was 87.7–91.0%. Yet, the total individual variability in fecal energy absorption ranged from 80% to 94.8% [9.Wierdsma N.J. et al.Bomb calorimetry, the gold standard for assessment of intestinal absorption capacity: normative values in healthy ambulant adults.J. Hum. Nutr. Diet. 2014; 27: 57-64Crossref PubMed Scopus (24) Google Scholar]. The physiological importance of this variation is obvious and can be exemplified by a female participant who lost the energetic equivalent of half a liter of sugar-sweetened soft drink in her feces (i.e., a loss of 53 g/day carbohydrate) [9.Wierdsma N.J. et al.Bomb calorimetry, the gold standard for assessment of intestinal absorption capacity: normative values in healthy ambulant adults.J. Hum. Nutr. Diet. 2014; 27: 57-64Crossref PubMed Scopus (24) Google Scholar]. However, this study was not designed to include strict dietary control and dietary records were used for estimating total energy intake. This limitation could have inflated the ranges, especially given that women, who have a wider absorption range compared with men, tend to underestimate their true energy intake [9.Wierdsma N.J. et al.Bomb calorimetry, the gold standard for assessment of intestinal absorption capacity: normative values in healthy ambulant adults.J. Hum. Nutr. Diet. 2014; 27: 57-64Crossref PubMed Scopus (24) Google Scholar]. During the early 1980s, Heymsfield et al. demonstrated that humans without malabsorption diseases extracted 89–99% of ingested energy [10.Heymsfield S.B. et al.Energy malabsorption: measurement and nutritional consequences.Am. J. Clin. Nutr. 1981; 34: 1954-1960Crossref PubMed Scopus (37) Google Scholar]. This finding fits with the 2–10% fecal energy loss reported in the controlled study by Baloso and coworkers [5.Basolo A. et al.Effects of underfeeding and oral vancomycin on gut microbiome and nutrient absorption in humans.Nat. Med. 2020; 26: 589-598Crossref PubMed Scopus (41) Google Scholar]. Scrutinizing the individual values reported by Baloso et al. reveals two subjects with fecal energy losses of ~80 kcal/day and ~500 kcal/day, respectively. They can be regarded as examples of the two opposite ends of the healthy energy absorption spectrum. Given data on their absolute energy intake, we can estimate how widely different fecal energy losses affect overall energy balance. Thus, the subject with a fecal energy loss of ~80 kcal/day (corresponding to 2%) was, in reality, overfed by ~147%. By contrast, for the subject with the pronounced fecal energy waste (~500 kcal/day, corresponding to 10%) the degree of overfeeding was in reality (only) ~135% [5.Basolo A. et al.Effects of underfeeding and oral vancomycin on gut microbiome and nutrient absorption in humans.Nat. Med. 2020; 26: 589-598Crossref PubMed Scopus (41) Google Scholar] (Figure 1B). The potential long-term implications of such differences must be emphasized. If these data are representative and, importantly, if it turns out that the calories excreted in stools during periods of positive energy balance correlate closely with longitudinal weight gain, fecal energy loss could in fact explain a large proportion of the population-wide weight gain variation. In other words, an important component of human obesity resistance might reside in the gut – unrelated to the release of classical satiety hormones, but reflective of a lower energy harvest in lean humans. It is intriguing to speculate further and consider that energy excretion might be elevated in individuals with constitutional thinness (CTs). This condition is characterized by a normal body fat percentage but a very low body weight [body mass index (BMI) <18 kg/m2]. These subjects report a desire to gain weight and data indicate that they ingest the same absolute amount of energy as those of normal body weight [11.Ling Y. et al.Persistent low body weight in humans is associated with higher mitochondrial activity in white adipose tissue.Am. J. Clin. Nutr. 2019; 110: 605-616Crossref PubMed Scopus (15) Google Scholar,12.Ling Y. et al.Resistance to lean mass gain in constitutional thinness in free-living conditions is not overpassed by overfeeding.J. Cachexia Sarcopenia Muscle. 2020; (Published online April 10, 2020. https://doi.org/10.1002/jcsm.12572)Crossref PubMed Scopus (8) Google Scholar]. Moreover, both resting and total energy expenditure appear to be similar to those of control subjects when correcting for differences in fat-free mass [11.Ling Y. et al.Persistent low body weight in humans is associated with higher mitochondrial activity in white adipose tissue.Am. J. Clin. Nutr. 2019; 110: 605-616Crossref PubMed Scopus (15) Google Scholar]. CTs and controls do not differ with regard to fecal fat excretion [11.Ling Y. et al.Persistent low body weight in humans is associated with higher mitochondrial activity in white adipose tissue.Am. J. Clin. Nutr. 2019; 110: 605-616Crossref PubMed Scopus (15) Google Scholar] but, to our knowledge, it is unknown whether an altered excretion of other macronutrients partly explains this phenotype. Given that interindividual variation in carbohydrate and protein absorption appears to vary more than fat absorption [1.Southgate D.A. Durnin J.V. Calorie conversion factors. An experimental reassessment of the factors used in the calculation of the energy value of human diets.Br. J. Nutr. 1970; 24: 517-535Crossref PubMed Scopus (281) Google Scholar,9.Wierdsma N.J. et al.Bomb calorimetry, the gold standard for assessment of intestinal absorption capacity: normative values in healthy ambulant adults.J. Hum. Nutr. Diet. 2014; 27: 57-64Crossref PubMed Scopus (24) Google Scholar], it would be worthwhile investigating whether total fecal energy loss differs between CTs and control subjects. Interestingly, a recent metabolomics analysis of urine from subjects with CT indicated that a higher 24-h urinary excretion of amino acids and intermediary metabolites might contribute to their weight gain resistance [12.Ling Y. et al.Resistance to lean mass gain in constitutional thinness in free-living conditions is not overpassed by overfeeding.J. Cachexia Sarcopenia Muscle. 2020; (Published online April 10, 2020. https://doi.org/10.1002/jcsm.12572)Crossref PubMed Scopus (8) Google Scholar]. This underscores that a thorough investigation of urine energy content using bomb calorimetry is also warranted. Given the findings discussed earlier, we wonder whether many dietary, pharmacological, and genetic manipulations that alter energy balance might do so, in part, by impacting fecal and urinary energy loss, but that this has gone unnoticed so far. As an illustrative example, oral supplementation with polyphenols in male New Zealand black mice attenuated high-fat diet-induced obesity partly by increasing fecal energy loss [13.Klaus S. et al.Epigallocatechin gallate attenuates diet-induced obesity in mice by decreasing energy absorption and increasing fat J. PubMed Scopus Google Scholar]. Moreover, human to energy intestinal or show but on body weight R. et of for obesity with weight loss and a review and PubMed Scopus Google et loss associated with a review of and Rev. PubMed Scopus Google Scholar]. Also, the of and obesity was by a that fecal energy excretion to a that that of malabsorption [10.Heymsfield S.B. et al.Energy malabsorption: measurement and nutritional consequences.Am. J. Clin. Nutr. 1981; 34: 1954-1960Crossref PubMed Scopus (37) Google Scholar]. it is that the metabolizable energy, or of varies between individuals M.J. et al.Calculating the metabolizable energy of macronutrients: a critical review of Atwater’s results.Nutr. Rev. 2017; 75: 37-48Crossref PubMed Scopus (19) Google Scholar]. food and food such as and all affect food [1.Southgate D.A. Durnin J.V. Calorie conversion factors. An experimental reassessment of the factors used in the calculation of the energy value of human diets.Br. J. Nutr. 1970; 24: 517-535Crossref PubMed Scopus (281) Google Scholar,2.Sanchez-Pena M.J. et al.Calculating the metabolizable energy of macronutrients: a critical review of Atwater’s results.Nutr. Rev. 2017; 75: 37-48Crossref PubMed Scopus (19) Google Scholar]. Moreover, factors such as and consumption might also influence the amount of energy that is extracted from M.J. et al.Calculating the metabolizable energy of macronutrients: a critical review of Atwater’s results.Nutr. Rev. 2017; 75: 37-48Crossref PubMed Scopus (19) Google Scholar]. Given the the fecal and urinary energy loss, nutrient and calorie excretion have as two that potentially affect human body weight. Thus, the regulation of energy excretion and the relative impact on energy homeostasis are important for is by a from the which is by the number from the and the number This also from the the and to for Metabolic is an at the of and by an from the number were with

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