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.

Trial registration: ClinicalTrials.gov NCT00523627 NCT00687115.

Figure 1.. Definition of thrifty and spendthrift metabolic phenotypes.

Human metabolic phenotypes can be revealed by measuring the short-term (24 hours) response to fasting and overfeeding (especially, low-protein overfeeding) from conditions of energy balance. Compared to metabolically spendthrift individuals, subjects with a thrifty metabolism demonstrate a greater decrease in 24-h energy expenditure from energy balance during fasting and smaller increase in energy expenditure during overfeeding (upper-left panel), thus showing relatively lower metabolic rates in both dietary conditions (upper-right panel). Subjects with a thrifty metabolism lose less weight during sustained caloric restriction (lower-left panel) and gain more weight during prolonged overfeeding (lower-right panel).

Figure 2.. Variability in energy sensing and its effects on weight change.

Positive linear relationship between energy intake and energy expenditure (EE) as determined by energy-sensing mechanisms (left graph). Inter-individual variability in the degree of energy sensing (i.e., over- vs. under-sensing) might explain the degree of susceptibility to weight gain or loss (right graph). Over the entire range of this energy-sensing relationship (e.g., low EE or high EE), there are subjects who normally sense their EE and eat accordingly (black circle), thus they can better maintain their weight over time. At any given point of the energy-sensing relationship, there are also subjects who over-sense their EE (solid square) and, as such, positively misconstrue their energy needs by consuming food as if they had higher EE (open circle), thus overeating relative to their energy needs and being more inclined to gain weight over time. Conversely, subjects that under-sense their EE (open square), eat less food than what they expend, thus are more prone to lose weight over time.