Metabolic Determinants of Weight Gain in Humans

Abstract

One of the fundamental challenges in obesity research is to identify subjects prone to weight gain so that obesity and its comorbidities can be promptly prevented or treated. The principles of thermodynamics as applied to human body energetics demonstrate that susceptibility to weight gain varies among individuals as a result of interindividual differences in energy expenditure and energy intake, two factors that counterbalance one another and determine daily energy balance and, ultimately, body weight change. This review focuses on the variability among individuals in human metabolism that determines weight change. Conflicting results have been reported about the role of interindividual differences in energy metabolism during energy balance in relation to future weight change. However, recent studies have shown that metabolic responses to acute, short‐term dietary interventions that create energy imbalance, such as low‐protein overfeeding or fasting for 24 hours, may reveal the underlying metabolic phenotype that determines the degree of resistance to diet‐induced weight loss or the propensity to spontaneous weight gain over time. Metabolically “thrifty” individuals, characterized by a predilection for saving energy in settings of undernutrition and dietary protein restriction, display a minimal increase in plasma fibroblast growth factor 21 concentrations in response to a low‐protein overfeeding diet and tend to gain more weight over time compared with metabolically “spendthrift” individuals. Similarly, interindividual variability in the causal relationship between energy expenditure and energy intake (“energy sensing”) and in the metabolic response to cold exposure (e.g., brown adipose tissue activation) seems, to some extent, to be indicative of individual propensity to weight gain. Thus, an increased understanding and the clinical characterization of phenotypic differences in energy metabolism among individuals (metabolic profile) may lead to new strategies to prevent weight gain or improve weight‐loss interventions by targeted therapies on the basis of metabolic phenotype and susceptibility to obesity in individual persons.

Impaired Metabolic Flexibility to High-Fat Overfeeding Predicts Future Weight Gain in Healthy Adults

“…Yet, participants were recruited to be weight stable for at least 6 months before baseline admission and, on average, were also weight stable at each follow-up visit, suggesting that there were no substantial changes in physical activity or diet in this time period that might have confounded our results. While the strength of the relationship between impaired metabolic flexibility to HFOF and weight gain explained up to ∼15% of the interindividual variance in future weight change, this estimate can be considered a large effect size for a single metabolic parameter given that other metabolic determinants of weight change explain 5–10% of its variance ( 5 ).…”

“…Prolonged daily energy intake exceeding energy expenditure (EE) leads to an increase in body weight; however, even in highly controlled settings, some individuals are more prone to gain weight than others during sustained overfeeding (1,2) or, conversely, some individuals are more resistant to weight loss during caloric restriction (3,4) despite comparable dietary conditions among individuals. These results suggest that the individual metabolic response to overfeeding/underfeeding may partly determine the susceptibility to body weight change in conditions of persistent energy imbalance (5). Daily energy balance (EBL), which is the difference between 24-h energy intake and EE, is also reflective of macronutrient balances (i.e., proteins, fats, carbohydrates), which in turn play a major role in body weight regulation (6,7).…”

Low basal metabolic rate as a risk factor for development of insulin resistance and type 2 diabetes

“…Although several studies indicate that above average energy intake may constitute a significant risk factor for many diseases (eg, cardiovascular diseases and cancer) or general multimorbidity, the relation between basal/resting metabolism and propensity to weight gain and T2D development in humans is equivocal. 7 48 49 However, the majority of studies report phenotypic effects, usually in obese patients often with already diagnosed diabetes of each type. 14 18 39 The observed associations between BMR, weight gain, and T2D may be a result of condition-related pathologies (eg, glycosuria and increased protein turnover) rather than genetically determined variation in energy expenditures.…”

“…4 T2D development is underlined by both genetic and environmental factors affecting energy balance and leading to a nexus of weight gain and insulin resistance (IR). [5][6][7][8] In humans, no less than 70% of the total energy expenditures constitutes basal metabolic rate (BMR) or resting metabolic rate (RMR), which comprises of energy expended for vital functions in a resting, postabsorptive state. 9 It is therefore unsurprising that the link between variation in BMR/RMR and weight…”

Effects of Short-Term Fasting and Different Overfeeding Diets on Thyroid Hormones in Healthy Humans

“…The difference in the propensity to weight gain among individuals may depend on both environmental and genetic factors that influence the two components of daily energy balance. Among these factors, the ability to increase EE in response to overeating, namely the diet-induced thermogenesis (2), has been recently proposed to be a novel determinant of weight change (3). Dietary interventions such as 24-hour overfeeding or fasting lead to EE responses with a wide interindividual variability that characterizes thrifty versus spendthrift metabolic phenotypes (4).…”