ReviewObesity I: Overview and molecular and biochemical mechanisms
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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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