FIGURE 15 Effects of leptin in leptin-deficient mice. Body weights of female obese mice treated with saline (control) or 270 pg of leptin/day were compared to body weights of obese mice treated with saline, but fed an amount of food equal to that consumed by the leptin-treated mice (pair-fed). Note that the loss of body weight produced by leptin was not accounted for simply by decreased food intake. (From Levin N, Nelson C, Gurney A, Vandlen R, de Sauvage F. Pair-feeding studies provide compelling evidence that the ob protein exerts adipose-reducing effects in excess of those induced by reductions in food intake. Proc Natl Acad Sci USA 1996;93:1726-1730.)



FIGURE 16 Leptin concentrations in blood plasma correlate with body fat content in 500 human subjects. (From Caro JF, Sinha MK, Kolaczynski JW, Zhang PL, Considine RV. Leptin: The tale of an obesity gene. Diabetes 1996;45:1455-1462.)

receptors that signals by activation of the cytosolic tyrosine kinase JAK2 (see Chapter 2). Multiple splice variants of leptin receptor mRNA give rise to different isoforms, including one that circulates as a soluble protein. Other isoforms have truncated cytoplasmic domains, but only the form with the full-length cytoplasmic tail appears to be capable of signaling. Truncated forms, which are expressed in vascular endothelium and the choroid plexus, may serve a transport function to facilitate passage of leptin across blood vessels in the brain to breech the blood-brain barrier and thus deliver leptin to target cells in the central nervous system.

The principal targets for leptin are neurons in the arcuate nuclei of the hypothalamus, but leptin receptors are also found in neurons of the paraventri-cular, ventromedial, and dorsomedial nuclei and neurons in the lateral hypothalamus. Neuropeptide transmitters of some of these neurons have been identified along with their receptors, and the sites of their expression have been located. These neurons project to hypothalamic and brain-stem autonomic integrating centers. Neurons from the arcuate and paraventricular nuclei project to the median eminence of the hypothalamus where they release hypophysio-tropic hormones into the hypophysial-portal circulation (see Chapter 38). Through these neural connections, leptin integrates nutritional status with adrenal, gona-dal, and thyroidal function and with GH and prolactin secretion. Some of the relevant neuropeptides are as follows:

• Neuropeptide Y (NPY) is a 36-amino-acid peptide that is abundantly expressed in neurons of the arcuate nuclei of the hypothalamus whose axons project to the paraventricular nuclei and the lateral hypothalamic area. Its expression is increased during fasting. When administered into the hypothalamus of rodents, NPY stimulates food intake, lowers energy expenditure, and with continued administration may produce obesity. Expression of NPY is increased in leptin deficiency; production, and transcription and release of NPY are suppressed by leptin administration.

• Pro-opiomelanocortin (POMC), the precursor of ACTH in anterior pituitary cells, is also expressed in the arcuate nucleus of the hypothalamus where

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