Obesity I: Overview and molecular and biochemical mechanisms

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 YY_3-36) 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.

Keywords: Adipose tissue; Energy balance; Hormone receptors; Metabolism; Microbiome; Obesity.

Figure 1.. Endocrine control of Metabolism

The main tissues involved in controlling metabolism are shown along with the main endocrine and paracrine modulators of metabolic function. Many positive and negative control points in the tissues and the brain are integrated to control metabolism and body weight. The homeostatic pathway is the largest and most complex and likely regulates the set point for metabolism via control of the appetite and satiety centers in the brain. The hedonic center controls emotional eating and food addiction which can override the homeostatic system.

Figure 2.. The interplay between leptin and insulin signaling pathways.

The insulin receptor and the leptin receptor recruit the low-abundance-message insulin receptor substrate-2. Lack of available insulin receptor substrate 2 for the leptin receptor due to hyperinsulinemia could result in defective leptin signal transduction. Alternatively, insulin induction of suppressor of cytokine signaling-3 could inactivate the leptin receptor through alterations in tyrosine phosphorylation. Abbreviations, Agrp: Agouti-Related Neuropeptide; Akt: AKR Thymoma, protein kinase B; eIF-4E: Eukaryotic translation Initiation Factor 4E; ERK: Extracellular signal-regulated Kinase; Foxo: Forkhead box; Grb2: Growth factor receptor-Bound protein 2; GSK3β: Glycogen Synthase Kinase 3-beta; IRS2: Insulin Receptor Substrate 2; JAK2: Janus Kinase 2; MEK: MAPK/ERK Kinase; mTOR: mammalian Target Of Rapamycin; PDE Phosphodiesterase; PI3K: PhosphatidylInositol 3-Kinase; pomc: Proopiomelanocortin; Ptp1b: Protein-Tyrosine Phosphatase 1B; RAF: Rapidly Accelerated Fibrosarcoma kinase; RAS: Rat Sarcoma virus protein; S6: S6 ribosomal protein; Shc: Src homology 2 domain-containing; SHP2: Src Homology region 2-containing Protein tyrosine phosphatase 2; SOCS3: Suppressor Of Cytokine Signaling 3; STAT3: Signal Transducer and Activator of Transcription 3