The metabolic conditioning of obesity: A review of the pathogenesis of obesity and the epigenetic pathways that “program” obesity from conception

Abstract

Understanding the developmental origins of health and disease is integral to overcome the global tide of obesity and its metabolic consequences, including atherosclerotic cardiovascular disease, type 2 diabetes, hyperlipidemia, and nonalcoholic fatty liver disease. The rising prevalence of obesity has been attributed, in part, to environmental factors including the globalization of the western diet and unhealthy lifestyle choices. In this review we argue that how and when such exposures come into play from conception significantly impact overall risk of obesity and later health outcomes. While the laws of thermodynamics dictate that obesity is caused by an imbalance between caloric intake and energy expenditure, the drivers of each of these may be laid down before the manifestation of the phenotype. We present evidence over the last half-century that suggests that the temporospatial evolution of obesity from intrauterine life and beyond is, in part, due to the conditioning of physiological processes at critical developmental periods that results in maladaptive responses to obesogenic exposures later in life. We begin the review by introducing studies that describe an association between perinatal factors and later risk of obesity. After a brief discussion of the pathogenesis of obesity, including the systemic regulation of appetite, adiposity, and basal metabolic rate, we delve into the mechanics of how intrauterine, postnatal and early childhood metabolic environments may contribute to adult obesity risk through the process of metabolic conditioning. Finally, we detail the specific epigenetic pathways identified both in preclinical and clinical studies that synergistically “program” obesity.

Water Intake and Adiposity Outcomes among Overweight and Obese Individuals: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

“…First, among the trials that recommended replacing artificially sweetened beverages with water, increased adiposity was suggested. This finding may likely be due to chance, considering the small number of trials (only two trials), the predominant weight given to one trial [20], the inconsistency in the statistical significance of a positive association across measures of adiposity (body weight and WC), and the known adverse effects of artificially sweetened beverages on gut microbiota diversity [46][47][48] and metabolic regulation [49], both of which are considered etiologic factors of obesity. Nevertheless, the true benefit of artificially sweetened beverages over water on adiposity control cannot be ruled out.…”

Exploring Maternal Diet-Epigenetic-Gut Microbiome Crosstalk as an Intervention Strategy to Counter Early Obesity Programming

“…However, the response becomes maladaptive in the context of a mismatch between the expected environment and nutritional exposures across the lifespan. Maternal undernutrition can therefore influence a "thrifty phenotype", with the result that offspring develop obesity later in life following exposure to a high-calorie diet [42].…”

New Mediators in the Crosstalk between Different Adipose Tissues

“…Obesity can be regulated through multiple interactions between endocrine tissues and the nervous system. We are now aware of the importance of AT in metabolic homeostasis and of the fact that its accumulation leads to chronic inflammation [20]. WAT is one of the main regulators of metabolism, controlling energy storage, inflammation, and immunity.…”