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.
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