Leptin and Other Peptide Systems
Peripheral Leptin administration results in activation of hypothalamic neurones expressing the Leptin receptor suggesting a hypothalamic mediation of Leptin effects on satiety. Leptin receptors are expressed in NPY and POMC producing neurones J Neurosci. 1998 Jan 1;18(1):559-72 as well as orexin producing neurones. J Neurosci. 1999 Feb 1;19(3):1072-87. Leptin receptors are co-expressed with POMC mRNA and Gal-mRNA in the Arcuate nucleus (ARC). Peripheral Leptin might enter the CNS through active uptake or through blood brain barrier deficient areas.
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Leptin interacts with almost all other neuropeptides in the brain which are involved in regulation of food intake. Thus while inhibiting the orexigenic Neuropeptide Y andAgRP neurones, Leptin stimulates the expression of POMC/CART peptides which are strongly anorexigenic. Leptin increases CRH expression in the paraventricular nucleus of the hypothalamus. Leptin also interacts with other pathways involving GLP-1, and Galanin. Endocr Rev. 1999 Feb;20(1):68-100 In the hypothalamic arcuate nuclei, Leptin facilitates satiety through inhibition of the NPY/AgRP neurones while stimulating POMC neurones Front Neuroendocrinol. 2003 Dec;24(4):225-53 CRH J Clin Invest. 1996 Sep 1;98(5):1101-6. and CART. Nature. 1998 May 7;393(6680):72-6. Leptin suppressed NPY induced feeding acutely and on a long term basis in rats. Endocrinology. 1998 Feb;139(2):466-73 as well as the feeding induced by Galanin and MCH. Endocrinology. 1998 Nov;139(11):4739-42. At the same time, NPY deficient mice still demonstrated Leptin induced suppression of feeding, suggesting the importance of other pathways in Leptin's action. Nature. 1996 May 30;381(6581):415-21. Blockade of MC4 (melanocortin4) receptors reduced the ability of Leptin to inhibit food intake suggesting that the melanocortin pathway has a major role in mediating Leptin effects. Nature. 1997 Nov 27;390(6658):349 GLP-1 neurones express the Leptin receptor OB-Rb. Exendin 4 (9-39) which is a (GLP-1 antagonist) blocks the effects of Leptin. FEBS Lett. 1997 Sep 29;415(2):134-8. These could suggest that Leptin may act via GLP-1 neurones. |
Leptin and OTHER SYSTEMS
Leptin can directly regulate CD4+ proliferation and Th1 cytokine production during fasting, Nature. 1998 Aug 27;394(6696):897-901. and thus may provide a link between nutritional status and immune function. In keeping with this, leptin deficient ob/ob mice have decreased cytokine production from Th1 cells and CD4+ proliferation . Leptin may also have a role in the maturation of the reproductive axis as shown by its ability to accelerate puberty in wild-type mice, and to restore puberty and fertility in ob/ob mice. While it can help maturation of the reproductive system in rodents, loss of the normal diurnal rhythm Proc Natl Acad Sci U S A. 1998 Mar 3;95(5):2541-6. with reduced Leptin levels in female athletes has been associated with amenorrhea. J Clin Endocrinol Metab. 1997 Jan;82(1):318-21. Leptin can also regulate glucose and lipid metabolism independent of its effects on appetite and body weight through stimulation of lipolysis and gluconeogenesis, J Biol Chem. 1997 Oct 31;272(44):27758-63. with suppression of glycolysis while increasing the energy expenditure through sympathetic stimulation of brown adipose tissue and the adrenal gland. Hypertension. 1997 Sep;30(3 Pt 2):619-23. Leptin may also regulate hematopoiesis Proc Natl Acad Sci U S A. 1996 Dec 10;93(25):14564-8. and myelination of neurones. Endocrinology. 1999 Jun;140(6):2755-62. Although Leptin is predominantly secreted from fat, up to 25% of circulating Leptin seems to be derived from the fundic P cells and pepsinogen secreting chief cells of the stomach. Nature. 1998 Aug 20;394(6695):790-3; Gut. 2000 Aug;47(2):178-83. An exocrine and endocrine component have been described with chief cells co secreting Leptin and pepsinogen, while endocrine cells of the stomach secrete only Leptin. J Histochem Cytochem. 2005 Jul;53(7):851-60. Leptin receptors are demonstrable in the enterocytes of the duodenum jejunum and ileum forming a gastro-enteric axis. The significance of gastric Leptin is not known. Insulin increases gastric Leptin secretion into the stomach lumen through vagal mechanisms, Gastroenterology. 2002 Feb;122(2):259-63. while CCK increases leptin synthesis and release. Biochem Biophys Res Commun. 2003 Oct 24;310(3):681-4 |