Obesity represents a complex chronic disease; likewise, its pathogenesis is characterized by a multifactorial, intricate interplay between environmental, genetic, and epigenetic factors. A sedentary lifestyle together with an excess calories intake set on a genetic predisposing background, which can be further modulated through epigenetic modifications. Among genetic mutations, the most important FTO region was found to correlate with obesity and its complications development, together with several other genes involved in food intake and body weight regulation. Moreover, the concept of a circadian clock disruption, induced by the gradual change in lifestyle habits, seems to strongly contribute to those metabolic and endocrine alterations which favor obesity development.
The mechanisms regulating hunger and satiety in our body are extremely complex, involving several organs and systems which in turn interact with the external environment integrating different kind of inputs. The central nervous system (CNS) communicates to the peripheral organs, sending and receiving a whole range of signals including mechanic, hormonal, and nervous stimuli, which mediate a cross-talk not just with the central brain but also between lower systems. In the CNS, the main regions involved in food intake regulation are located in the hypothalamus; the mesolimbic hedonic pathway carries out a different kind of food intake control which involves the more instinct drivings. Several hormones secreted by gastrointestinal tract, adipose tissue, and pancreatic-liver axis, such as glucagon-like peptide (GLP-1), leptin, and insulin, are well-known factors acting on this fine regulation system. Other central regulators, identified more recently, are represented by the big family of the skeletal muscle produced hormones, the myokines, and the gut microbiota, whose alteration seems to be crucial in obesity development.
Adiposity does not represent a pathologic condition per se; indeed, the concept of “sick fat” refers to all those local modifications occurring in adipose tissue and gradually involving the body systemically, which set at the cell site, and finally lead to disease. Adiposopathy is typically characterized at the cell level by adipose cell hypertrophy, visceral fat accumulation, tissue fibrosis, and low-grade inflammation. These alterations could lead to the preferential challenging of fatty free acids (FFA) towards other organs outside adipose tissue with an ectopic lipid and fat accumulation, a phenomenon called lipotoxicity which is strongly related to the appearance or worsening of insulin resistance. At this final step, the obesity-associated complications develop. Indeed, pathological obesity typically correlates with metabolic syndrome, i.e., type 2 diabetes mellitus, hypertension, dyslipidemia, nonalcoholic fatty liver disease (NAFLD), and cardiovascular complications.
KeywordsObesity pathogenesis Multiorgan cross-talk Adiposopathy
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