Other studies have also demonstrated that HFD induces SOCS3 expression by leptin in POMC and AgRP neurons ( 20, 21). In this context, suppressor of cytokine signaling 3 (SOCS3) seems to be a key protein in central leptin resistance because its loss of function in the hypothalamus confers protection to high-fat diet (HFD)-induced obesity ( 19). Another proposed mechanism is the disruption of leptin signal transduction as several proteins are able to inhibit the signaling from cytokine receptors ( 17, 18). In addition, a more recent study has shown that BBB impairment can also be attributed to higher plasmatic levels of cytokines and fatty acids in obese subjects ( 16). As the hypothalamus mediates the anti-obesity actions of leptin, one of the models proposed a decrease in leptin transport across the BBB ( 15). Although the mechanisms behind the development of leptin resistance are still unclear, several models have been proposed. Nevertheless, it has been described that the effect of leptin treatment on the control of body weight through the regulation of both food intake and energy expenditure is differently exerted in lean and obese humans, suggesting different sensitivity to the hormone ( 14). The concept of leptin resistance is used to define states where hyperleptinemia is combined to lack of response to the hormone, with consequent maintenance of body weight excess and increased food consumption ( 13). This effect has been coined as leptin resistance. However, in most obese subjects, despite its high serum levels, leptin fails to perform its physiological functions and consequently fails to reduce weight ( 11, 12). Besides acting on the hypothalamus to suppress appetite, leptin also induces lipolysis in WAT and thermogenesis in brown adipose tissue (BAT) and browning of WAT, via the activation of the sympathetic nervous system (SNS) ( 10). Specifically, leptin modulates the activity of two types of neurons to inhibit appetite, through production of anorexigenic peptides by the pro-opiomelanocortin (POMC) neurons ( 8) and suppression of the orexigenic agouti-related protein (AgRP) neurons ( 9). Hence, leptin is released by adipocytes in proportion to the size of fat depots, enters the circulation, and reaches the central nervous system by crossing the blood-brain barrier (BBB) through receptor-mediated endocytosis ( 6) in which it acts mainly through the arcuate nucleus of the hypothalamus to mediate most of its actions ( 7). The effect of leptin on body weight is attributed to its action in a specific brain region, the hypothalamus. Leptin has a central role in body weight homeostasis due to its inhibition of food intake inhibition and stimulation of energy expenditure. The circulating levels of leptin are proportional to the amount of fat and function as the afferent signal in a negative feedback loop that seeks to maintain body fat in a very narrow range of variation ( 5). Obesity is typically characterized by excessive amounts of the hormone leptin, a cytokine-like molecule produced in white adipose tissue (WAT) that is secreted into the systemic circulation ( 4). Consequently, it places a large financial burden on the economy due to the increased morbidity and mortality, as well as the reduced quality of life and development of chronic diseases ( 3). The worldwide prevalence of obesity is rapidly increasing and has nearly doubled between 19 ( 2). Obesity is a public health concern affecting both genders at all ages around the world ( 1).
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