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COMPLEMENTARY HYPOTHESES ON CONTRIBUTORS TO THE OBESITY EPIDEMIC

Increased rates of obesity have occurred within virtually every race, age, sex, ethnicity, and economic group. Despite substantial punditry on the issue, the exact reasons are incompletely known. The two most common factors cited as contributing to the obesity epidemic and those whose causal influence on increasing obesity levels in the population are often presumed unequivocally, are food marketing practices and institutionally-driven reductions in physical activity. Previously, we have taken to calling these “the big two.” In this commentary, we build on previous writings in this area to introduce additional factors that may contribute to the obesity epidemic. Here we simply emphasize that there may be other factors working in combination with “the big two,” influencing body fatness through effects on energy intake, energy expenditure, and/or nutrient partitioning.


Introduction
Most readers have witnessed the profoundly increased prevalence of obesity illustrated on CDC maps. The two factors most commonly cited as having an unequivocal, causal influence on population obesity levels are food marketing practices and institutionally-driven declines in physical activity. Previously, we labeled these "the big two." Here we update our previous writings and introduce other putative contributors.
Our questioning of "the big two" as the sole causes of obesity in no way dismisses them as contributors to population obesity levels. We simply emphasize that additional factors may be involved, and expand on current evidence for each in Table 1. We also emphasize the importance of not conflating "the big two" with energy intake and energy expenditure. The laws of thermodynamics are not in question and we maintain the belief that changes in body energy stores, largely manifested as changes in body fat, result from the difference between energy intake and expenditure. Thus, "the big two" almost assuredly influence adiposity.
Good scientists simultaneously maintain both healthy skepticism and open-mindedness. Hence, we are open to speculation and conjectures on many "outside the box" contributors. We also recognize that speculation and conjecture are not proof, and we and the reader should remain skeptical concerning the extent to which these factors impact obesity.

Sleep Debt
Behavioral factors change with culture, environment, and technology. Over the last several decades, Americans have been sleeping less 1 . In both model organism studies and short-term human experiments, sleep deprivation affects energy intake and expenditure 1,2 . Over long periods, this can lead to increased adiposity. Conversely, helping individuals sleep more might attenuate weight gain. Randomized controlled trials testing such interventions are necessary and underway.

Decreased Smoking
Cigarette smoking and nicotine have anorexigenic effects and increase resting metabolic rate 1 . Generally, individuals who quit smoking gain weight. Thus, decreased smoking rates in the last half-century likely contributed to the obesity epidemic. Nevertheless, we emphasize in the strongest possible terms that the negative health effects of smoking are profound and we recommend continued smoking cessation.

Increased Atmospheric CO 2
A creative hypothesis in the early exploratory stages concerns rising atmospheric CO 2 levels. CO 2 has been documented as a contributor to oceanic acidification and may similarly shift organismal pH. Reductions in pH are sensed by neurons within the lateral hypothalamus, leading to secretion of orexin, which promotes wakefulness and increased energy intake 3 . Combined with increased feeding, the effects of orexin on arousal could promote sleep debt and subsequent weight gain.

Ambient Temperature
Thermoneutrality refers to the ambient temperature at which the energy required to maintain core body temperature is minimized. Human and animal studies have shown that exposure to temperatures above or below this zone result in increased metabolic rate, and therefore potential weight reduction 1,2 . Over the last 30 years, use and efficiency of home heating and cooling systems has risen, and vocational work requiring environmental exposure outside thermoneutrality has declined, potentially leading to weight gain 1 .

Technology
Use of electronic media and technology has increased, particularly among children and adolescents. Greater screen time is associated with increased appetite, reduced physical activity, and higher obesity rates 4 .

Suspected Endocrine Disruptors
Manufactured chemicals hypothesized to disrupt endocrine function have increased in the environment, the food chain, and humans 1 . These substances include commonly used plastic-hardeners, pesticides, solvents, heavy metals, and phthalates. Binding of these chemicals to nuclear receptors for estrogen, PPARγ, and retinoic acid X may increase adiposity by promoting adipocyte differentiation, which could lead to increased rates of obesity in the presence of positive energy balance. Additionally, certain chemicals may dysregulate lipid metabolism or act as antiandrogens, resulting in increased fat deposition 1,2 .

Pharmaceutical Iatrogenesis
The use of pharmaceuticals known to cause weight gain (psychotropic medications, antidiabetics, antihypertensives, steroid hormones and contraceptives, antihistamines, and protease inhibitors) has drastically increased 1,2 . In fact, the incidences of diagnosed anxiety and depression, type 2 diabetes, and hypertension, along with associated medications, match climbing obesity rates.

Infections
While conflicting results exist, adenovirus 36 (Adv36) and other microbial infections have been associated with human obesity. In both cell culture and model organisms, Adv36 infection accelerated the differentiation and proliferation of preadipocytes into lipid-laden adipocytes 2 .

The Gut Microbiome
Multiple mechanisms have been considered to explain how dysbiosis of gut microbiota may be involved in obesity. Excess body fat may alter populations of gut bacteria, which could impact metabolism through impaired gut signaling pathways governing inflammation, insulin sensitivity, and adiposity 5 . This is an en vogue topic, yet it must be acknowledged that cause and effect is uncertain.

Social-Psychological Factors
Economic disparity and insecurity may produce both physiological and behavioral changes resulting in increased energy intake 6 . Delay discounting, or how the value of a reward decreases as the time until reward receipt increases, has also been studied in human diet and physical activity adherence 7 . Humans typically prefer smaller immediate rewards, presenting the possibility of little value in maintaining or achieving a healthy weight. The last two decades of research in this area have produced abundant evidence of higher reward discounting in drug-dependent individuals, gamblers, and persons prone to obesity 7 . Finally, greater cognitive demand, with resulting hyperphagia and poor dietary choices, may impact body weight 8 .

Reproductive Factors
Humans assortatively mate for adiposity, and higher BMI has been associated with having more offspring 1,2 . These two factors combined would be expected to increase the frequency of genotypes susceptible to obesity. In utero, energetic factors can lead to obesogenic effects passed down over generations 1,2 . These effects could be amplified with higher gravida age, as more women delay reproduction beyond age 30 1,2 . A more recent concept is that of fetal drive, whereby the offspring's genotype drives the physiology and behavior of the mother, potentially impacting her obesity risk beyond pregnancy 9 .

Conclusions
While our discussion of potential contributors to the obesity epidemic is not exhaustive, it seems likely that, not one, but a combination of factors is responsible for the increased rates of obesity. Additionally, these factors are ever-changing, requiring a multifactorial approach to reducing population obesity levels and present exciting opportunities for new discovery. May result in lower blood pH, activation of orexin neurons in the lateral hypothalamus, and increased appetite and food intake.