et al . 2002 ). In DMH PrRP neurons, leptin activated signal transducer and activator of transcription protein 3 (STAT3) ( Takayanagi et al . 2008 ) while anorexigenic effect of leptin was impaired in PrRP- or GPR10-knockout mice ( Dodd & Luckman
Martina Holubová, Lucie Hrubá, Barbora Neprašová, Zuzana Majerčíková, Zdeňka Lacinová, Jaroslav Kuneš, Lenka Maletínská and Blanka Železná
I K Lund, J A Hansen, H S Andersen, N P H Møller and N Billestrup
hypothalamus, through which it exerts its key regulatory role by controlling the overall energy homeostasis, i.e. induction of reduced food intake and promotion of weight loss ( Ahima & Flier 2000 , Korner & Aronne 2003 ). Defective leptin signalling due to
Laura Marroquí, Alejandro Gonzalez, Patricia Ñeco, Ernesto Caballero-Garrido, Elaine Vieira, Cristina Ripoll, Angel Nadal and Ivan Quesada
different direct effects on the β-cell. Additionally, it has been proposed that alterations in leptin signaling in the β-cell might be involved in diabetes in obese individuals ( Seufert 2004 ). In the next sections we will focus on the different leptin
N Martínez-Micaelo, N González-Abuín, A Ardévol, M Pinent, E Petretto, J Behmoaras and M Blay
system ( Myers et al . 2008 ). In addition to its key role in the maintenance of energy homeostasis, leptin modulates both humoral and cell-mediated immunity ( La Cava & Matarese 2004 ). Leptin signalling is dependent on the presence of the long isoform
NM Morton, V Emilsson, P de Groot, AL Pallett and MA Cawthorne
Leptin is a cytokine secreted from adipose tissue at a rate commensurate with the size of the body's fat stores. In addition to its anorectic and thermogenic central actions, leptin is known to act on peripheral tissues, including the pancreatic beta-cell where it inhibits insulin secretion and reduces insulin transcript levels. However, the role of leptin signalling through its full-length receptor, OB-Rb, in the beta-cell remains unclear. In the present study, we show that leptin activates a signal transducer and activator of transcription (STAT)3 signalling mechanism in pancreatic islets and in a rat model of the pancreatic beta-cell, RINm5F. Leptin induced DNA binding to a STAT consensus oligonucleotide and resulted in transcriptional activation from STAT reporter constructs in a manner consistent with STAT3 activation. Western blot analysis confirmed activation of STAT3 in RINm5F and isolated rat islets. Conditions that mimic increased metabolic activity resulted in attenuation of leptin-mediated STAT DNA binding but had no significant effect on STAT3 tyrosine phosphorylation in RINm5F cells. In addition, leptin activated the mitogen activated protein (MAP) kinase pathway in RINm5F cells. The present study provides a framework for OB-Rb signalling mechanisms in the programming of the beta-cell by leptin and suggests that increased metabolic activity may modulate this function.
CP Briscoe, S Hanif, Arch JR and M Tadayyon
The effect of treatment with a 0.03% fatty acid (FA) cocktail on leptin-receptor-mediated STAT (signal transducers and activators of transcription) activation in the rat insulinoma cell line BRIN-BD11 was investigated. Leptin (10 nM) stimulated the tyrosine phosphorylation of STAT3 and STAT5b. Acute treatment with FAs prevented leptin-stimulated STAT3 tyrosine phosphorylation and significantly raised basal STAT5 phosphorylation. A chronic treatment (5 days) of BRIN-BD11 cells with FAs similarly attenuated leptin-stimulated STAT tyrosine phosphorylation. Chronic FA treatment also attenuated prolactin-stimulated STAT5b tyrosine phosphorylation but not interleukin-6-stimulated STAT3 tyrosine phosphorylation, suggesting that the effect is receptor/ligand specific. TaqMan analysis of gene expression following chronic FA treatment showed neither a decrease in the amount of leptin receptor (Ob-R) mRNA, nor an increase in the negative regulators of STAT signalling, SOCS3 (suppressors of cytokine signalling) or cytokine inducible sequence (CIS). These data demonstrate that FAs modulate leptin and prolactin signalling in beta-cells, implying that high levels of circulating FAs present in obese individuals affect the action of selective cytokines in beta-cell function.
N Hoggard, L Hunter, JS Duncan and DV Rayner
The central role of the melanocortin system in the regulation of energy balance has been studied in great detail. However, the functions of circulating melanocortins and the roles of their peripheral receptors remain to be elucidated. There is increasing evidence of a peripheral action of melanocortins in the regulation of leptin production by adipocytes. Here we investigate the interaction of alpha-melanocyte stimulating hormone (alpha-MSH) and agouti-related protein (AgRP) in the regulation of leptin secretion from cultured rat adipocytes and examine the changes in circulating alpha-MSH and AgRP in lean and obese rodents after hormonal and energetic challenge. Leptin secretion (measured by ELISA) and gene expression (by real-time quantitative PCR) of differentiated rat adipocytes cultured in vitro were inhibited by the administration of alpha-MSH (EC50=0.24 nM), and this effect was antagonised by antagonists of the melanocortin receptors MC4R and MC3R (AgRP and SHU9119). The presence of MC4R in rat adipocytes (RT-PCR and restriction digest) supports the involvement of this receptor subtype in this interaction. Leptin administered to ob/ob mice in turn increases the release of alpha-MSH into the circulation, suggesting a possible feedback loop between the site of alpha-MSH release and the release of leptin from the adipose tissue. However, the physiological significance of this putative feedback probably depends upon the underlying state of energy balance, since in the fasting state low plasma alpha-MSH is paralleled by low plasma leptin.
N T Lam, S D Covey, J T Lewis, S Oosman, T Webber, E C Hsu, A T Cheung and T J Kieffer
prevail causes insulin resistance and hyperglycemia which, if left untreated, may lead to diabetes mellitus. Leptin signaling is similarly regulated; signaling begins with phosphorylation and activation of janus kinase 2 (JAK2) ( Ghilardi & Skoda 1997
Lucia Kořínková, Martina Holubová, Barbora Neprašová, Lucie Hrubá, Veronika Pražienková, Michal Bencze, Martin Haluzík, Jaroslav Kuneš, Lenka Maletínská and Blanka Železná
fa/fa rats lacking functional leptin receptor signaling, negligible PrRP mRNA expression was detected ( Ellacott et al . 2002 ). Leptin deficiency in ob/ob mice causes obesity based on hyperphagia and decreased energy expenditure; in addition
M Gröschl, H-G Topf, J Kratzsch, J Dötsch, W Rascher and M Rauh
leptin ( Stallmeyer et al. 2001 , Goren et al. 2003 ). Other truncated isoforms, in particular the soluble receptor, seem to have a leptin-binding function rather than a signal-transducing function ( Lammert et al. 2001 ). Recently, functional Ob