Linking To And Excerpting From Nature’s “Obesogens: a unifying theory for the global rise in obesity”

• Abstract
• Introduction and Background
• Ontogeny of obesity
• Current models of obesity
• The Energy Balance Model (EBM)
• The Carbohydrate-Insulin Model (CIM)
• The Energy Reduction-Oxidation Model (REDOX)
• The Obesogen Model (OBS)
• Proposed Integrated Model
• Summary
• Future directions
• References
• Funding
• Author information
• Ethics declarations
• Additional information
• Rights and permissions
• About this article

Abstract

Despite varied treatment, mitigation, and prevention efforts, the global prevalence and severity of obesity continue to worsen. Here we propose a combined model of obesity, a unifying paradigm that links four general models: the energy balance model (EBM), based on calories as the driver of weight gain; the carbohydrate-insulin model (CIM), based on insulin as a driver of energy storage; the oxidation-reduction model (REDOX), based on reactive oxygen species (ROS) as a driver of altered metabolic signaling; and the obesogens model (OBS), which proposes that environmental chemicals interfere with hormonal signaling leading to adiposity. We propose a combined OBS/REDOX model in which environmental chemicals (in air, food, food packaging, and household products) generate false autocrine and endocrine metabolic signals, including ROS, that subvert standard regulatory energy mechanisms, increase basal and stimulated insulin secretion, disrupt energy efficiency, and influence appetite and energy expenditure leading to weight gain. This combined model incorporates the data supporting the EBM and CIM models, thus creating one integrated model that covers significant aspects of all the mechanisms potentially contributing to the obesity pandemic. Importantly, the OBS/REDOX model provides a rationale and approach for future preventative efforts based on environmental chemical exposure reduction.

Introduction and Background

Obesity continues to increase at an alarming rate across the globe despite an increase in the number of diets and drugs [1]. The etiology of obesity is still not understood, as evidenced by the following statements from recent articles:

1. 1.In 2017, an Endocrine Society Scientific Statement [2] noted, “The current lack of consensus regarding obesity pathogenesis has resulted in competing and poorly justified claims both from within and outside the scientific community. These inconsistencies erode public trust and confidence in the scientific process concerning obesity and its treatment, further supporting nonscientific ideologies and products.”
2. 2.A recent perspective noted that we do not have a clear explanation for the obesity epidemic [3]. Notably, the national data do not support higher energy consumption as a driver of the obesity epidemic since 2000. “This lack of adequate attention and investment in understanding the root causes of the obesity epidemic … may at least partly owe to the belief that the foundational causes are already known” [3].
3. 3.A recent scientific meeting organized at the Royal Society in London by Profs. Speakman, Sørensen, Hall, and Allison focused on “Causes of obesity: theories, conjectures and evidence” [4]. Despite numerous symposia, guidelines, and punditry, the attendees were no closer to a unifying theory for the global rise in obesity.

Ontogeny of obesity

Obesity is a neuroendocrine disease [2]. Body weight is highly regulated by various systems and hormones from many tissues integrated by the brain to regulate food intake and metabolism [5]. Key questions include, what has changed over the last 50 years that led to the obesity epidemic? What has been imposed on or removed from society that led to the obesity epidemic?

Before examining the various models of obesity, it is essential to understand when obesity starts (ontogeny), as that aspect of etiology must be integrated into any model. Obesity, like other non-communicable diseases, can have at least some of its origins in utero and early childhood and may manifest itself at any time across the lifespan. Both under and over-nutrition in utero are associated with obesity in the offspring later in life [6,7,8,9,10]. Mothers or fathers who are overweight during pregnancy may have overweight offspring [11]. In a rodent study, maternal exercise during pregnancy promoted physical activity in adult offspring, suggesting that the propensity to exercise may also be programmed during development [12]. The strongest perinatal predictor of childhood obesity is reported to be maternal pre-pregnancy obesity [13]. In a rodent study, gestational exposure to a Western diet predisposes to a high fat and sugar diet in later life to promulgate obesity [14]. Developmental programming can also affect intergenerational obesity in humans [15, 16], and transgenerational epigenetic inheritance of obesity is seen in animal models [17]. Altered epigenetic regulation of gene expression during development due to nutrition, stress, or environmental chemicals can interfere with the control of food intake and metabolism, including metabolic efficiency via effects on the development of the adipose tissue, pancreas, liver, gastrointestinal tract, brain and/or muscle, thereby resulting in an altered body weight set point or sensitivity for developing obesity across the lifespan and generations [18]. In utero and early development may be a highly sensitive time for the programming of fat storage due to permanent effects on gene expression and adipose tissue differentiation. Consequently, nutrition, stress, and environmental chemicals can all have the potential to alter metabolic signaling at this stage, leading to excessive adipose tissue growth and energy storage throughout life.

Current models of obesity

Two of the major models of obesity include the energy balance model (EBM) reviewed in [5, 19], which emphasizes overeating and sedentary activity, and the carbohydrate-insulin model (CIM) reviewed in [20], which emphasizes energy storage due to hyperinsulinemia’s effect on adipocytes. The reduction-oxidation model (REDOX) is an additional lesser-known model reviewed in [21, 22]. The REDOX model emphasizes that many substances, including processed foods and environmental exposures, can cause obesity by generating false and misleading information about energy status. This misinformation is driven by changes in the oxidation-reduction potential of metabolites that circulate and communicate to organs throughout the body. A fourth model, the obesogen model (OBS) reviewed in [18], posits that exposure to environmental chemicals, especially during critical developmental periods, but also across the lifespan, can affect long-term metabolism via hormonal changes, increasing susceptibility to obesity.