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The second installment in a 3-part series focusing on obesity was recently published in Biochemical Pharmacology, largely devoted to examining the evidence for the obesogen hypothesis, i.e., the proposal that environmental chemicals play a role in the growing overweight/obesity pandemic. This review specifically defines obesogens as chemicals that increase white adipose tissue mass (WAT) after exposure in vivo, and potential obesogens as those that induce differentiation of adipocytes in vitro but have not yet demonstrated an increase in WAT in vivo.
However, obesogens not only increase fat mass. They have also been implicated in multiple conditions with metabolic derangements, including diabetes, non-alcoholic fatty liver disease, and insulin resistance. Multiple mechanisms underlie these disturbances, including modifications to basal metabolic rate, the composition of the intestinal microbiota, as well as direct hormonal effects, such as inhibition of thyroid function. Obesogens have also been shown to interfere with glucose utilization in skeletal muscle, promote chronic inflammation, and induce mitochondrial dysfunction by increasing oxidative damage and interrupting normal signals for mitochondrial biogenesis and energy metabolism, such as PGC-1α and SIRT3, respectively. The effects of obesogens may also be epigenetic; this implies both transgenerational effects, as well as latency between exposure and the onset of related diseases. Currently pre-conception, pregnancy, and early childhood are thought to be the most vulnerable periods of exposure.
Obesogen Examples
Bisphenols: There are currently 24 analogs of bisphenol A (BPA), including bisphenol F, bisphenol S, etc., at least some of which have equal or greater obesogenic properties than BPA. Indeed, mixtures of bisphenols may have greater obesogenic effects than single compounds, a harsh reality that the approval process typically ignores, despite real-world continuous exposure to multiple toxins. In a meta-analysis of 15 studies with adult participants, 12 found a positive association between BPA and obesity. Two of these studies were prospective and found urinary BPA was linked to greater weight gain in women and abdominal obesity in men and women. While gestational BPA levels have been linked to an increase in girls’ central adiposity during childhood, most studies are limited by the use of only a single urinary sample, which is not likely to reflect the multiple and fluctuating exposures to a compound with a half-life of approximately 6 hours. Animal studies have demonstrated that BPA is associated with increased food intake, glucose intolerance, leptin resistance, an altered microbiome, fatty liver disease, etc.
Air pollution: PM2.5 is often used as a proxy for air quality, and mechanistically has been linked to diabetes and cardiovascular disease via a number of mechanisms, including endothelial and mitochondrial dysfunction, as well as insulin resistance. Air pollution has been associated in humans with greater obesity and abdominal adiposity in children, as well as impaired pancreatic β-cell function, with indications that prenatal exposure carries risks as well. It has been linked to metabolic disturbances including altered fatty acid metabolism, with a systematic review and meta-analysis concluding “that the air contaminants PM2.5, PM10, PM2.5absorbance, and NO2 play critical roles in childhood obesity.” National data from Korea also found an increased risk for not only obesity, but also for metabolic syndrome, hypertension, hyperglycemia, and dyslipidemia with each 10-μg/m3 PM2.5.
Per-and polyfluroalkyl substances (PFAS): Like other obesogens, PFAS exposure has been associated with a greater prevalence of metabolic syndrome, diabetes, and overweight/obesity. In children, PFAS exposure has been linked in metabolomic studies to changes related to energy production and catabolism. Quite strikingly, in a 2-year diet-induced weight-loss trial (the Pounds Lost trial), higher baseline plasma concentrations of PFASs in 621 overweight and obese men and women were associated with greater weight regain, primarily in women. On average, women in the highest tertile of PFAS concentrations regained 3.7–4.8 pounds more body weight than women in the lowest tertile. Additionally, PFASs (especially perfluorooctanesulfonic acid and perfluorononanoic acid) were linked with a greater decline in the resting metabolic rate (RMR) during the first 6 months as well as a lower increase in RMR during the period of weight regain. Given the difficulty of maintaining weight loss and the frequency of weight regain, this study shines a spotlight on the role of obesogens in the ongoing obesity epidemic.
The above examples are only a few from the long list of obesogens and potential obesogens identified in this thorough review, and the mechanisms for their effects are also provided in much greater detail. Given that exposure to these compounds occurs “in dust, water, food contamination, processed foods (including food additives), food packaging, food and storage containers, cosmetics and personal care products, furniture and electronics, air pollution, and solvents, disinfectants, pesticides, sunscreens, plastics and plasticizers, nonnutritive sweeteners, some antidepressants and antidiabetic drugs, and common household products,” the ability of most individuals to reduce exposure is limited, particularly without public health measures in place to do so. This emphasizes the importance of limiting exposure and enhancing detoxification/elimination of these ubiquitous compounds as key components of weight management, as well as addressing the damaged metabolic pathways they target.
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