Abstract
Leptin is secreted into the digestive tract and contributes to the absorption of dietary molecules by regulating transporters activity. Here, we studied the effect of luminal leptin on the intestinal transport of L-glutamate, an important component of human diet. We examined the effect of leptin on L-glutamate uptake in rat intestine in vitro measuring glutamate-induced short-circuit current (Isc) in Ussing chambers and L-[3H (U)]-glutamate uptake in jejunal everted rings. Glutamate-induced Isc was only observed in Na+-free conditions. This Isc was concentration (1–60 mmol L−1) and pH dependent. Luminal leptin increased glutamate Isc (∼100 %). Dose-response curve showed a biphasic pattern, with maximal stimulations observed at 10−13 and 10−10 mmol L−1, that were sensitive to leptin receptor antagonist. In everted rings, two glutamate transport mechanisms were distinguished: a Na+-dependent, H+-independent, that was inhibited by leptin (∼20 %), and a Na+-independent but H+-dependent, that was enhanced by leptin (∼20 %), in line with data obtained in Ussing chambers. Altogether, these data reveal original non-monotonic effect of luminal leptin in the intestine and demonstrate a new role for this hormone in the modulation of L-glutamate transport, showing that luminal active gut peptides can influence absorption of amino acids.
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Akiba Y, Watanabe C, Mizumori M, Kaunitz JD (2009) Luminal L-glutamate enhances duodenal mucosal defense mechanisms via multiple glutamate receptors in rats. Am J Physiol Gastrointest Liver Physiol 297:G781–G791
Auger C, Attwell D (2000) Fast removal of synaptic glutamate by postsynaptic transporters. Neuron 28:547–558
Bado A, Levasseur S, Attoub S et al (1998) The stomach is a source of leptin. Nature 394:790–793
Bannai S (1986) Exchange of cystine and glutamate across plasma membrane of human fibroblasts. J Biol Chem 261:2256–2263
Barrenetxe J, Barber A, Lostao MP (2001) Leptin effect on galactose absorption in mice jejunum. J Physiol Biochem 57:345–346
Barrenetxe J, Villaro AC, Guembe L, Pascual I, Munoz-Navas M, Barber A, Lostao MP (2002) Distribution of the long leptin receptor isoform in brush border, basolateral membrane, and cytoplasm of enterocytes. Gut 50:797–802
Bassi MT, Gasol E, Manzoni M et al (2001) Identification and characterisation of human xCT that co-expresses, with 4F2 heavy chain, the amino acid transport activity system xc. Pflugers Arch 442:286–296
Beyreuther K, Biesalski HK, Fernstrom J et al (2007) Consensus meeting: monosodium glutamate—an update. Eur J Clin Nutr 61:304–313
Blachier F, Boutry C, Bos C, Tomé D (2009) Metabolism and functions of L-glutamate in the epithelial cells of the small and large intestines. Am J Clin Nutr 90:814S–821S
Broer S (2008) Amino acid transport across mammalian intestinal and renal epithelia. Physiol Rev 88:249–286
Burdo J, Dargusch R, Schubert D (2006) Distribution of the cystine/glutamate antiporter system xc—in the brain, kidney, and duodenum. J Histochem Cytochem 54:549–557
Buyse M, Berlioz F, Guilmeau S et al (2001) PepT1-mediated epithelial transport of dipeptides and cephalexin is enhanced by luminal leptin in the small intestine. J Clin Invest 108:1483–1494
Cammisotto PG, Renaud C, Gingras D, Delvin E, Levy E, Bendayan M (2005) Endocrine and exocrine secretion of leptin by the gastric mucosa. J Histochem Cytochem 53:851–860
Christensen HN (1984) Organic ion transport during seven decades. The amino acids. Biochim Biophys Acta 779:255–269
Cinti S, Matteis RD, Pico C et al (2000) Secretory granules of endocrine and chief cells of human stomach mucosa contain leptin. Int J Obes Relat Metab Disord 24:789–793
De Matteis R, Dashtipour K, Ognibene A, Cinti S (1998) Localization of leptin receptor splice variants in mouse peripheral tissues by immunohistochemistry. Proc Nutr Soc 57:441–448
Dray C, Sakar Y, Vinel C et al (2013) The intestinal glucose-apelin cycle controls carbohydrate absorption in mice. Gastroenterology 144:771–780
Ducroc R, Guilmeau S, Akasbi K, Devaud H, Buyse M, Bado A (2005) Luminal leptin induces rapid inhibition of active intestinal absorption of glucose mediated by sodium-glucose cotransporter 1
Ducroc R, Sakar Y, Fanjul C, Barber A, Bado A, Lostao MP (2010) Luminal leptin inhibits L-glutamine transport in rat small intestine: involvement of ASCT2 and B0AT1. Am J Physiol Gastrointest Liver Physiol 299:G179–G185
Elinav E, Niv-Spector L, Katz M et al (2009) Pegylated leptin antagonist is a potent orexigenic agent: preparation and mechanism of activity. Endocrinology 150:3083–3091
Fanjul C, Barrenetxe J, Inigo C, Sakar Y, Ducroc R, Barber A, Lostao MP (2012) Leptin regulates sugar and amino acids transport in the human intestinal cell line Caco-2. Acta Physiol (Oxf) 205:82
Guilmeau S, Buyse M, Tsocas A, Laigneau JP, Bado A (2003) Duodenal leptin stimulates cholecystokinin secretion: evidence of a positive leptin-cholecystokinin feedback loop. Diabetes 52:1664–1672
Haddad N, Howland R, Baroody G, Daher C (2006) The modulatory effect of leptin on the overall insulin production in ex-vivo normal rat pancreas. Can J Physiol Pharmacol 84:157–162
Hindlet P, Bado A, Deloménie C et al (2009) Reduced intestinal absorption of dipeptides via PepT1 in mice with diet-induced obesity is associated with leptin receptor down-regulation. J Biol Chem 284:6601–6608
Iñigo C, Barber A, Lostao MP (2004) Leptin effect on intestinal galactose absorption in ob/ob and db/db mice. J Physiol Biochem 60:93–97
Iñigo C, Patel N, Kellett GL, Barber A, Lostao MP (2007) Luminal leptin inhibits intestinal sugar absorption in vivo. Acta Physiol (Oxf) 190:303–310
Kanai Y, Hediger MA (2004) The glutamate/neutral amino acid transporter family SLC1: molecular, physiological and pharmacological aspects. Pflugers Arch 447:469–479
Krimi RB, Letteron P, Chedid P, Nazaret C, Ducroc R, Marie JC (2009) Resistin-like molecule-beta inhibits SGLT-1 activity and enhances GLUT2-dependent jejunal glucose transport. Diabetes 58:2032–2038
Lostao MP, Urdaneta E, Martinez-Anso E, Barber A, Martinez JA (1998) Presence of leptin receptors in rat small intestine and leptin effect on sugar absorption. FEBS Lett 423:302–306
Margetic S, Gazzola C, Pegg GG, Hill RA (2002) Leptin: a review of its peripheral actions and interactions. Int J Obes Relat Metab Disord 26:1407–1433
Munck BG, Munck LK (1999) Effects of pH changes on systems ASC and B in rabbit ileum. Am J Physiol 276:G173–G184
Pallett AL, Morton NM, Cawthorne MA, Emilsson V (1997) Leptin inhibits insulin secretion and reduces insulin mRNA levels in rat isolated pancreatic islets. Biochem Biophys Res Commun 238:267–270
Rasmussen BA, Breen DM, Duca FA, Cote CD, Tahmasebi MZ, Filippi BM, Lam TK (2013) Jejunal leptin-PI3K signaling lowers glucose production. Cell Metab
Schultz SG, Alvarez OO, Curran PF, Yu-Tu L (1970) Dicarboxylic amino acid influx across brush border of rabbit ileum. Effects of amino acid charge on the sodium-amino acid interaction. J Gen Physiol 56:621–639
Shpilman M, Niv-Spector L, Katz M et al (2011) Development and characterization of high affinity leptins and leptin antagonists. J Biol Chem 286:4429–4442
Sweeney G (2002) Leptin signalling. Cell Signal 14:655–663
Uotani S, Bjorbaek C, Tornoe J, Flier JS (1999) Functional properties of leptin receptor. Diabetes 48:279–286
Utsunomiya-Tate N, Endou H, Kanai Y (1996) Cloning and functional characterization of a system ASC-like Na+-dependent neutral amino acid transporter. J Biol Chem 271:14883–14890
Vandenberg LN, Colborn T, Hayes TB et al (2012) Hormones and endocrine-disrupting chemicals: low-dose effects and non-monotonic dose responses. Endocr Rev 33:378–455
Wadiche JI, Arriza JL, Amara SG, Kavanaugh MP (1995) Kinetics of a human glutamate transporter. Neuron 14:1019–1027
Xiao W, Feng Y, Holst JJ, Hartmann B, Yang H, Teitelbaum DH (2014) Glutamate prevents intestinal atrophy via luminal nutrient sensing in a mouse model of total parenteral nutrition. FASEB J 28:2073–2087
Zhang HH, Kumar S, Barnett AH, Eggo MC (1999) Intrinsic site-specific differences in the expression of leptin in human adipocytes and its autocrine effects on glucose uptake. J Clin Endocrinol Metab 84:2550–2556
Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM (1994) Positional cloning of the mouse obese gene and its human homologue. Nature 372:425–432
Acknowledgments
We thank Asunción Redín for her unconditional technical assistance; Ana Barber, Maude Le Gall, and Katia Marazova for their helpful comments.
This work was supported by the “Ministerio de Educación y Ciencia”, Spain (Grant BFU2007-60420/BFI) and the “Fundación Marcelino Botín”. The Spanish group is member of the Network for Cooperative Research on Membrane Transport Proteins (REIT), co-funded by the “Ministerio de Educación y Ciencia”, Spain and the European Regional Development Fund (ERDF) (Grant BFU2007-30688-E/BFI). C. Fanjul has been a recipient of a pre-doctoral fellowship from the “Asociación de Amigos”, University of Navarra.
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No conflicts of interest, financial or otherwise, are declared by the authors.
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María Pilar Lostao and Robert Ducroc contributed equally to this work.
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Fanjul, C., Barrenetxe, J., Lostao, M.P. et al. Modulation of intestinal L-glutamate transport by luminal leptin. J Physiol Biochem 71, 311–317 (2015). https://doi.org/10.1007/s13105-015-0414-z
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DOI: https://doi.org/10.1007/s13105-015-0414-z