Energy expenditure in the etiology of human obesity: spendthrift and thrifty metabolic phenotypes and energy-sensing mechanisms
The pathogenesis of human obesity is the result of dysregulation of the reciprocal relationship between food intake and energy expenditure (EE), which influences daily energy balance and ultimately leads to weight gain. According to principles of energy homeostasis, a relatively lower EE in a setting of energy balance may lead to weight gain; however, results from different study groups are contradictory and indicate a complex interaction between EE and food intake which may differentially influence weight change in humans. Recently, studies evaluating the adaptive response of one component to perturbations of the other component of energy balance have revealed both the existence of differing metabolic phenotypes (“spendthrift” and “thrifty”) resulting from overeating or underfeeding, as well as energy-sensing mechanisms linking EE to food intake, which might explain the propensity of an individual to weight gain. The purpose of this review is to debate the role that human EE plays on body weight regulation and to discuss the physiologic mechanisms linking EE and food intake. An increased understanding of the complex interplay between human metabolism and food consumption may provide insight into pathophysiologic mechanisms underlying weight gain, which may eventually lead to prevention and better treatment of human obesity.
KeywordsEnergy expenditure Adaptive thermogenesis Body weight regulation Metabolic phenotypes Energy sensing
The fundamental principle of energy balance applied to humans states that food intake and energy expenditure (EE) are the counterbalancing factors that determine body weight change. For instance, a persistent state of positive energy balance when food intake consistently exceeds EE leads to weight gain and eventually obesity onset, as the surplus energy is stored by the organism as predominantly body fat. Both food intake and EE are likely influenced by environmental and genetic factors; however, while food intake can vary largely from day to day due to psychological and social influences and it is hard to measure due to the episodic nature consisting in discrete feeding episodes, daily sedentary EE is largely determined by body size and composition and can be accurately measured via indirect calorimetry [1, 2]. As EE represents the more stable side of the energy balance equation, in the last 40 years it has been extensively studied to assess its effects on future weight change and to gain insight into the pathogenesis of human obesity. This review will focus on the role that EE on body weight regulation in humans. The physiologic mechanisms that may underlie the EE–food intake link will also be presented and discussed.
EE measured in energy balance as predictor of future weight change
Human EE can be continuously and precisely measured via indirect calorimetry methods [3, 4]. Typically, 24-h EE is measured inside a whole-room indirect calorimeter (also known as respiratory or metabolic chamber) in sedentary but physiologic conditions while trying to achieve perfect energy balance (i.e., energy equilibrium where EE equals food intake), namely providing subjects with the exact amount of energy from food they expend over the 24 h [5, 6]. Measuring EE in energy balance and weight stability is crucial as a subject’s EE depends on prior fluctuations in body weight and deviations from energy balance which may alter substrate oxidation (e.g., the preference of carbohydrate over fat oxidation), ultimately influencing the measured value of 24-h EE.
Known determinants of 24-h EE include body fat-free mass (FFM) and fat mass (FM), age, gender, ethnicity, glucose tolerance [1, 2, 7, 8, 9] but also familial relationships reflecting an underlying genetic background [10, 11, 12] (heritability = 0.52 ). Together, all the physiologic determinants explain more than 80% of the inter-individual variance in EE in a given population , leaving the remaining (unexplained) variance in EE after statistical adjustment for subjects’ characteristics as a potential predictor of future weight change based on the energy balance equation. Nevertheless, contradictory results on the role of EE on weight change have been reported in different studies. Concordant with the energy balance principles, a relatively low EE is a predictor of long-term weight gain in an American Indians population living in the Southwest of the USA [11, 13, 14]. Similarly, a reduced EE predicting increased adiposity was also observed in an Italian population  and in studies of infants  and children . Conversely, the opposite relationship was shown in a Nigerian population where a higher (instead of lower) EE was associated with increases in body weight over time . Lastly, several reports have shown no association between EE and weight change in humans [19, 20, 21, 22]. Potential explanations for these contradictory findings from different research groups may include population-specific body habitus, genetic and environmental factors. Variations in the research setting and differing length of the follow-up may also play role. For instance, an intrinsic deficit in daily EE carried for several years can lead to weight gain due to a sustained and persistent positive energy balance, even when daily food intake is set to achieve and maintain weight stability in the short-term period. In fact, in the context of the long-term longitudinal studies carried out in the Native American population living in Phoenix (Arizona, USA) where the large majority of individuals constantly gain weight over time during adulthood , a small but persistent positive daily energy balance due to a relatively lower EE may have a significantly greater impact in life-long body weight regulation in this population. By contrast, higher relative EE (as found in the study of Nigerian population) may result in a small negative daily energy balance that in turn may promote overeating in an effort to restore energy equilibrium, thereby inducing weight gain if the greater food intake is sustained over a longer period and consistently overcomes daily EE. Nonetheless, the strength of the association between EE measured during energy balance and future weight change (regardless of the directionality) is very small as it explains very little of the variance in weight change (R2 < 5%), indicating that food intake is a more potent determinant of daily energy balance thereby strongly influencing body weight change in humans.
Spendthrift and thrifty metabolic phenotypes
Among the daily components of 24-h EE including sleeping metabolic rate (the minimum energy required by a subject to maintain normal body metabolic functions), the cost of being awake and the thermic effect of food (collectively named “awake and fed” thermogenesis ) and the energy cost of physical activity , the thermic effect of food represents the EE component that underlies the link between food intake and EE. The thermic effect of food, defined as the increase in EE after meals consumption  and representing approximately 10% of 24-h EE measured in energy balance , is composed of the obligatory costs of metabolizing the ingested nutrients, as well as a proposed variable facultative component that might explain the different response of individuals to excess or reduced food intake that may ultimately determine weight change. In a small pilot cross-over study done in 14 men (7 whites and 7 Native Americans) undergoing 48-h fasting and overfeeding with a balanced diet twice their energy requirements inside a metabolic chamber, it was shown that on average 24-h EE decreased of about 10% from its baseline value (i.e., during energy balance) with fasting and increased by a similar amount with overfeeding . Very interestingly, in this same study the individual EE responses to fasting and overfeeding both showed a wide inter-subject variability and were closely related to each other, such as the subjects showing larger decreases in EE when fasting tended to have smaller increases in EE when being overfed (i.e., metabolically thrifty individuals) as opposed to subjects showing smaller decreases in EE with fasting and larger increases in EE with overfeeding (i.e., metabolically spendthrift individuals). These results indicated the existence of two human metabolic phenotypes potentially uncovered by dietary manipulations: a more metabolically efficient type that does not expend as much energy when either being overfed or fasting (thrifty) as the type that, even when overeating or fasting, expends energy at comparatively higher metabolic rates (spendthrift). The results from the pilot study identifying these thrifty and spendthrift metabolic phenotypes based on the EE responses to fasting and overfeeding  were recently replicated in two other independent studies including subjects from different ethnic groups [28, 29]. More importantly, these two longitudinal studies showed for the first time the effects of these intrinsic metabolic characteristics on weight change.
In the other independent study  (ClinicalTrials.gov #NCT00687115), 12 obese but otherwise healthy individuals had 24-h measures of EE inside a metabolic chamber during energy balance (100% of weight-maintaining energy needs), overfeeding a balanced diet (200% of weight-maintaining energy needs) and fasting in random order, followed by a 6-week 50% caloric restriction period in a carefully monitored inpatient study. More metabolic thrifty individuals (i.e., those subjects with a larger decrease in 24-h EE with fasting at baseline) showed a smaller weight loss after the caloric restriction period as compared to more spendthrift individuals (i.e., those subjects who showed a smaller decrease in EE during fasting at baseline) who instead lost the greatest amount of weight after 6 weeks  (Fig. 3b).
Taken together, the results from the three above-mentioned studies provide supporting evidence about the existence of well-defined human EE phenotypes related to body weight maintenance which exist in both lean and obese individuals: an energy-efficient (“thrifty”) phenotype denoted by a lower 24-h EE, which has more propensity to spontaneous weight gain and/or smaller weight loss during caloric restriction as compared to a more “spendthrift” phenotype.
The physiologic mechanisms underlying the EE responses to dietary intervention which identify these two metabolic profiles found in the human population are still yet to be elucidated but may include percent body fat  and fat distribution , core body temperature , hormonal mediators such as appetitive hormones , sympathetic nervous system tone  and genetic polymorphisms.
Energy-sensing mechanisms: the putative link between EE and food intake
Research studies evaluating the adaptive response of one component (EE or food intake) to perturbations of the other component of energy balance have revealed both the existence of differing metabolic phenotypes resulting from overeating or underfeeding, as well as energy-sensing mechanisms linking EE to food intake, which might explain the propensity of an individual to weight gain. An increased understanding of the complex interplay between human metabolism and food consumption may provide insight into pathophysiologic mechanisms underlying weight gain, which may eventually lead to prevention and better treatment of human obesity.
Studies #NCT00523627, #NCT00687115 and #NCT00342732 were supported by the Intramural Research Program of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
The protocols were approved by the Institutional Review Board of the National Institute of Diabetes and Digestive and Kidney Diseases.
All volunteers were fully informed of the nature and purpose of the studies (#NCT00523627, #NCT00687115 and #NCT00342732), and written informed consent was obtained.
- 5.Lam YY, Redman LM, Smith SR, Bray GA, Greenway FL, Johannsen D, Ravussin E (2014) Determinants of sedentary 24-h energy expenditure: equations for energy prescription and adjustment in a respiratory chamber. Am J Clin Nutr 99(4):834–842. doi: 10.3945/ajcn.113.079566 CrossRefPubMedPubMedCentralGoogle Scholar
- 12.Piaggi P, Masindova I, Muller YL, Mercader J, Wiessner GB, Chen P, Consortium STD, Kobes S, Hsueh WC, Mongalo M, Knowler WC, Krakoff J, Hanson RL, Bogardus C, Baier LJ (2017) A genome-wide association study using a custom genotyping array identifies variants in GPR158 associated with reduced energy expenditure in American Indians. Diabetes. doi: 10.2337/db16-1565 Google Scholar
- 20.Weinsier RL, Nelson KM, Hensrud DD, Darnell BE, Hunter GR, Schutz Y (1995) Metabolic predictors of obesity. Contribution of resting energy expenditure, thermic effect of food, and fuel utilization to 4-year weight gain of post-obese and never-obese women. J Clin Investig 95(3):980–985. doi: 10.1172/JCI117807 CrossRefPubMedPubMedCentralGoogle Scholar
- 26.Thearle MS, Pannacciulli N, Bonfiglio S, Pacak K, Krakoff J (2013) Extent and determinants of thermogenic responses to 24 h of fasting, energy balance, and five different overfeeding diets in humans. J Clin Endocrinol Metab 98(7):2791–2799. doi: 10.1210/jc.2013-1289 CrossRefPubMedPubMedCentralGoogle Scholar
- 31.Vinales KL, Schlogl M, Piaggi P, Hohenadel M, Graham A, Bonfiglio S, Krakoff J, Thearle MS (2017) The consistency in macronutrient oxidation and the role for epinephrine in the response to fasting and overfeeding. J Clin Endocrinol Metab 102(1):279–289. doi: 10.1210/jc.2016-3006 PubMedGoogle Scholar
- 32.Caudwell P, Finlayson G, Gibbons C, Hopkins M, King N, Naslund E, Blundell JE (2013) Resting metabolic rate is associated with hunger, self-determined meal size, and daily energy intake and may represent a marker for appetite. Am J Clin Nutr 97(1):7–14. doi: 10.3945/ajcn.111.029975 CrossRefPubMedGoogle Scholar
- 34.Blundell JE, Caudwell P, Gibbons C, Hopkins M, Naslund E, King NA, Finlayson G (2012) Body composition and appetite: fat-free mass (but not fat mass or BMI) is positively associated with self-determined meal size and daily energy intake in humans. Br J Nutr 107(3):445–449. doi: 10.1017/S0007114511003138 CrossRefPubMedGoogle Scholar
- 35.Piaggi P, Thearle MS, Krakoff J, Votruba SB (2015) Higher daily energy expenditure and respiratory quotient, rather than fat-free mass, independently determine greater ad libitum overeating. J Clin Endocrinol Metab 100(8):3011–3020. doi: 10.1210/jc.2015-2164 CrossRefPubMedPubMedCentralGoogle Scholar
- 39.Weise CM, Thiyyagura P, Reiman EM, Chen K, Krakoff J (2013) Fat-free body mass but not fat mass is associated with reduced gray matter volume of cortical brain regions implicated in autonomic and homeostatic regulation. NeuroImage 64:712–721. doi: 10.1016/j.neuroimage.2012.09.005 CrossRefPubMedGoogle Scholar