Review
Obesity I: Overview and molecular and biochemical mechanisms

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Highlights

  • There is an expanding global obesity and non-communicable disease pandemic.

  • Obesity is a multifactorial, multi-organ, multi-hormone, and multi-mechanism disease.

  • Genetic and environmental influences control adiposity and weight gain.

  • Understanding the tissues/organs, hormones, and mechanisms involved in obesity set the stage for understanding the evidence for the obesogen hypothesis.

Abstract

Obesity is a chronic, relapsing condition characterized by excess body fat. Its prevalence has increased globally since the 1970s, and the number of obese and overweight people is now greater than those underweight. Obesity is a multifactorial condition, and as such, many components contribute to its development and pathogenesis. This is the first of three companion reviews that consider obesity. This review focuses on the genetics, viruses, insulin resistance, inflammation, gut microbiome, and circadian rhythms that promote obesity, along with hormones, growth factors, and organs and tissues that control its development. It shows that the regulation of energy balance (intake vs. expenditure) relies on the interplay of a variety of hormones from adipose tissue, gastrointestinal tract, pancreas, liver, and brain. It details how integrating central neurotransmitters and peripheral metabolic signals (e.g., leptin, insulin, ghrelin, peptide YY3-36) is essential for controlling energy homeostasis and feeding behavior. It describes the distinct types of adipocytes and how fat cell development is controlled by hormones and growth factors acting via a variety of receptors, including peroxisome proliferator-activated receptor-gamma, retinoid X, insulin, estrogen, androgen, glucocorticoid, thyroid hormone, liver X, constitutive androstane, pregnane X, farnesoid, and aryl hydrocarbon receptors. Finally, it demonstrates that obesity likely has origins in utero. Understanding these biochemical drivers of adiposity and metabolic dysfunction throughout the life cycle lends plausibility and credence to the “obesogen hypothesis” (i.e., the importance of environmental chemicals that disrupt these receptors to promote adiposity or alter metabolism), elucidated more fully in the two companion reviews.

Section snippets

Introduction and secular trends

Obesity is a chronic, relapsing condition characterized by excess body fat [1], [2]. It is among the most critical global health issues and a growing pandemic affecting adults, children, and infants [3], [4], [5]. Obesity rates have tripled since the 1970s, and the prevalence of adult obesity in the U.S. increased from 30.5% in 2000 to 42.4% in 2018, a 40% increase in frequency in less than two decades [6]. Currently, there are more obese individuals globally than those who are underweight [7],

The relationship between obesity and non-communicable disease

Obesity is thought to be unhealthy primarily because it is associated with what are known collectively as non-communicable diseases (NCDs), including hypertension [11], type 2 diabetes (T2D) [12], [13], dyslipidemia, [14], nonalcoholic fatty liver disease (NAFLD) [15], and cardiovascular disease (CVD) [16]. Currently, 54% of adults greater than 60 years of age manifest one or more of these diseases [17]. Obesity is also associated with increased prevalence of and mortality from at least

Adipose tissue development and function

Adipose tissue grows by increased cell number and size during in utero life, childhood, and adolescence; after that, the number of adipocytes remains stable if weight remains stable. In humans, adipose tissue appears between the 14th and 24th week of gestation, and in mice, adipose tissue is apparent between postnatal days one and seven [69]. Adipose tissue depots are highly dynamic and plastic organs. Changes resulting from weight gain or loss involve coordinating multiple cell types,

Receptors involved in the control of energy metabolism

MSCs differentiate into mature white adipocytes (WAT) under the control of various cellular receptors which act as transcription factors (Table 1) to control four physiological processes: proliferation mitotic cloning early differentiation and terminal differentiation. Other liver-based receptors alter liver metabolism to direct energy disposition into adipose tissue for storage [94]. Lastly systemic hormones that bind to their receptors in the liver brain and adipose tissue alter food intake

Homeostatic mechanisms

Regulation of energy balance, and hence weight status, relies on integrating peripheral hunger and satiety signals by the central nervous system (CNS) controlling feeding behavior and activity [225], [226]. Feeding behavior is often dichotomized as homeostatic or hedonic [227]. Homeostatic feeding is defined as that which is required to meet physiological/survival needs and is based on increasing the motivation to eat when energy stores are depleted. In contrast, hedonic feeding is driven by

Heterogeneous nature of control of weight and adiposity

As noted above, energy metabolism, and thus weight as a secondary metric, is tightly controlled by an integrated system of organs and hormones dependent on genetics and the environment. The complex changes in metabolism that result in obesity account for the difficulty in understanding, controlling, and treating obesity: no two patients have the same genetic backgrounds and environmental stimuli. It also illustrates that the pathogenesis of obesity involves more than just overeating and lack of

Insulin resistance and obesity

Insulin resistance is defined as the decreased tissue response to insulin-mediated cellular actions. It has been proposed that insulin resistance results from reduced glucose transport, particularly impairment of GLUT4, which may be due to increased reactive oxygen species (ROS) from fatty acid oxidation via an unknown mechanism [300]. As stated earlier, while obesity and insulin resistance overlap, they are not the same, as some patients are obese without being insulin resistant, and some are

Fetal origins of obesity

Excessive weight gain can start at any time across the lifespan. Still, the prenatal and neonatal environment has long been considered a critical period for the origins of obesity and cardio-metabolic disease in humans, as described in the Developmental Origins of Health and Disease (DOHaD) hypothesis [365]. For example, undernutrition during pregnancy leads to a low birth weight linked to an increased incidence of obesity, CVD and T2D later in life [366]. Substantial evidence from animal and

Conclusions

This review focused on the tissues/organs, hormones, pathways, and mechanisms that play key roles in metabolism to induce adipose tissue, resulting in obesity. Obesity is a multi-functional, multi-tissue, multi-hormone, multi-receptor, and multi-mechanism disease. When obesity results from increased VAT or liver fat with large fat cells, inflammation, and insulin and leptin resistance, it is also associated with several metabolic disorders, including T2D, NAFLD, CVD and some cancers. On the

Funding

Christopher Kassotis, NIH, R00ES030405.

Dominique Lagadic-Gossman, European Union Horizon 2020 Research and Innovation Program, Oberon #825712.

Vesna Munic Kos, Swedish Research Council for Sustainable Development (FORMAS) #2019-00375.

Troy Roepke, NIH, R01MH12 3544, P30ES005022, USDA/NIFA NJ6195.

Jan Vondracek, Czech Science Foundation #21-005335, Institute of Biophysics of the Czech Academy of Science, RVO-68081707.

Robert Barouki, European Union Horizon 2020 Research and Innovation Program,

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