In other words, leptin levels in circulation are rather stable on a short-term basis (i.e., meal to meal) and require (under normal physiological conditions) hours rather than minutes/seconds to respond to numerous metabolic stimuli. of leptin generated great enjoyment in the metabolism field (1,2). Along with leptin, the identification of the second important adipocyte-derived hormone, adiponectin (3), fundamentally changed our view of adipose tissue and its communication with other organs in the mid-1990s. Adipose tissue was no longer merely considered an energy sink; rather, we began to appreciate its role as a highly active endocrine organ. The early studies also highlighted the importance of adipose tissue per se as a key regulator of systemic energy metabolism. Leptin, the Mouse monoclonal to ERBB3 product of the gene, is usually a 167-residue peptide hormone. It is primarily secreted by adipose tissue. Functional inactivation of the gene prospects to undetectable levels of leptin in blood circulation (4). Once released by adipose tissue into the bloodstream, leptin reaches its targets, including the hypothalamus, through different mechanisms (5). Though the mechanisms are still somewhat unclear, leptin has been reported to reach the brain via direct transport through circumventricular organs, saturable transport through the blood-brain barrier (6), and uptake into the brain parenchyma and choroid plexus (7). Leptin binding to the long form of its receptor (LepRb) activates a well-characterized downstream signaling pathway, which regulates food intake and energy expenditure (8). The central melanocortin system is usually a target of leptin to regulate energy and GSK726701A glucose homeostasis (9). This system consists of intermingled neurons expressing pro-opiomelanocortin (POMC) and neurons generating agouti-related protein (AgRP), which are respectively activated and inhibited by leptin. In particular, LepR-expressing POMC neurons regulate hepatic glucose homeostasis (9), while LepR-expressing AgRP neurons regulate food intake and energy expenditure (10). Unlike insulin, which is usually stored in granules for immediate release in response to a proper stimulus (11), the rate of leptin release is usually primarily dependent on the rate of gene GSK726701A transcription and translation. The adipocyte lacks a classical brought on exocytic pathway and, at best, responds in an inducible fashion by releasing factors that are withheld at the level of the endoplasmic reticulum within a 15- to 30-min delay. In other words, leptin levels in blood circulation are rather stable on a short-term basis (i.e., meal to meal) and require (under normal physiological GSK726701A conditions) hours rather than minutes/seconds to respond to numerous metabolic stimuli. Similarly, it remains quite puzzling how leptin regulates food intake on a day-to-day GSK726701A basis. Elevated insulin and glucocorticoid levels are strong stimulators of leptin secretion. In contrast, the sympathetic nervous system, through activation of adrenergic receptors, significantly represses leptin release (9). Acute and chronic administration of recombinant leptin into slim individuals or mice (either wild-type or leptin-deficient mice) yields a number of responses, such as reducing food intake and body weight (12). This and other observations formed the basis for leptin therapy for the U.S. Food and Drug AdministrationCapproved treatment of individuals with leptin deficiency and generalized lipodystrophy (13). Originally, there was the expectation that leptin therapy would have the same successful potential for the treatment of diet-induced obesity as insulin has for diabetes (14). However, it was rapidly established that the vast majority of obese individuals do not have a shortage of leptin. Rather, most common forms of obesity are associated with excessive circulating levels of leptin (coined hyperleptinemia), which results in a still ill-defined state of leptin resistance (15). The most accepted definition of leptin resistance is the failure of pharmacological doses of leptin to suppress food intake and body weight. However, selective leptin resistance is also.