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( Leptin)
 The effects of leptin were observed by studying mutant obese mice that arose at random within a mouse colony at the Jackson Laboratory in 1950. These mice were massively obese and hyperphagic. Leptin itself was discovered in 1994 by Jeffrey M. Friedman and colleagues at the Rockefeller University through the study of those mutant mice. The Ob(Lep) gene (Ob for obese and Lep for leptin) is located on chromosome 7 in humans. Leptin is produced by adipose tissue and interacts with six types of receptor (LepRa–LepRf). LepRb is the only receptor isoform that contains active intracellular signaling domains. This receptor is present in a number of hypothalamic nuclei, where it exerts its effects. Importantly, leptin binds to the ventromedial nucleus of the hypothalamus, known as the "appetite center." Binding of leptin to this nucleus signals to the brain that the body has had enough to eat—a sensation of satiety. A very small group of humans possess homozygous mutations for the leptin gene which lead to a constant demand for food, resulting in severe obesity. This condition can be successfully treated by the administration of recombinant human leptin.[1] Thus, circulating leptin levels give the brain a reading of energy storage for the purposes of regulating appetite and metabolism. Leptin works by inhibiting the activity of neurons that contain neuropeptide Y (NPY) and agouti-related peptide (AgRP), and by increasing the activity of neurons expressing a-melanocyte-stimulating hormone (a-MSH). The NPY neurons are a key element in the regulation of appetite; small doses of NPY injected into the brains of experimental animals stimulates feeding, while selective destruction of the NPY neurons in mice causes them to become anorexic. Conversely, a-MSH is an important mediator of satiety, and differences in the gene for the receptor at which a-MSH acts in the brain are linked to obesity in humans. Leptin is also regulated (downward) by melatonin during the night.[2] Brazilian researchers found in 2004 that, in the presence of insulin, "melatonin interacts with insulin and upregulates insulin-stimulated leptin expression."[3]
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