Time to Consider the "Exposome Hypothesis" in the Development of the Obesity Pandemic

Abstract

The obesity epidemic shows no signs of abatement. Genetics and overnutrition together with a dramatic decline in physical activity are the alleged main causes for this pandemic. While they undoubtedly represent the main contributors to the obesity problem, they are not able to fully explain all cases and current trends. In this context, a body of knowledge related to exposure to as yet underappreciated obesogenic factors, which can be referred to as the "exposome", merits detailed analysis. Contrarily to the genome, the "exposome" is subject to a great dynamism and variability, which unfolds throughout the individual's lifetime. The development of precise ways of capturing the full exposure spectrum of a person is extraordinarily demanding. Data derived from epidemiological studies linking excess weight with elevated ambient temperatures, in utero, and intergenerational effects as well as epigenetics, microorganisms, microbiota, sleep curtailment, and endocrine disruptors, among others, suggests the possibility that they may work alone or synergistically as several alternative putative contributors to this global epidemic. This narrative review reports the available evidence on as yet underappreciated drivers of the obesity epidemic. Broadly based interventions are needed to better identify these drivers at the same time as stimulating reflection on the potential relevance of the "exposome" in the development and perpetuation of the obesity epidemic.

Keywords: antibiotics; brown adipose tissue; endocrine disruptors; environment; epigenetics; microbiota; obesogens; sleep; thermogenesis; viral infection; “exposome”.

Figure 1

Schematic diagram of the factors involved in energy homeostasis. The classical Venn diagram shows how in obesity the intersection between increased food intake, nutrient absorption, and fat accumulation, together with decreased energy expenditure, the main factors determining energy homeostasis, are simultaneously under the broader influence of the environment as well as genetics and epigenetics.

Figure 2

Conventional versus critical window “exposome” views in assessment of health risk in humans. The comprehensive portrait of an individual’s “exposome” evolves throughout the lifetime with the possibility of prioritized exposure factors, during specific time-points or critical windows as opposed to a standard, random or linear exposure. The diagram emphasizes the relevance of measurements at different time-points (modified from Fang et al. [131]).

Figure 3

Characterization of the “exposome”. The “exposome” of a given person represents the combined exposures from all external sources that reach the internal chemical environment. Specific biomarkers or potential signatures of the “exposome” might be detected in the bloodstream.

Figure 4

Factors influencing the resposome. Schematic diagram on how the genetic predisposition (genome) interacts with the environmental exposure (“exposome”) to influence an individual’s genetic and acquired susceptibility shaping its responses (resposome) that yield the ultimate health outcome as regards body weight control.

Figure 5

Evolution of the individual’s genetic and environmental framework across the lifespan. Over a lifetime, genetic and environmental influences may change reciprocally with acute and chronic exposures translating into a specific information with predictive interest as well as effective biomarkers that may provide mechanistic insight of pragmatic application.

Figure 6

Multidimensional view of the complex interaction of the main drivers involved in excess weight development and obesity-associated comorbidities. OSA, obstructive sleep apnea; MAFLD, metabolic-associated fatty liver disease; T2D, type 2 diabetes; CVD, cardiovascular diseases.