Ghrelin induces leptin resistance by activation of suppressor of cytokine signaling 3 expression in male rats: implications in satiety regulation
Authors: Chung Owyang
Yuanxu Lu
Gintautas Grabauskas
Xiaoyin Wu
ShiYi Zhou
Il Song
Andrea Heldsinger
Journal: Endocrinology (2014)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: leptin; ghrelin; vagal afferent pathways; Epac; SOCS3
Affiliations: Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48019.

Abstract:  The anorexigenic adipocyte-derived hormone leptin and the orexigenic hormone ghrelin act in opposition to regulate feeding behavior via the vagal afferent pathways. The mechanisms by which ghrelin exerts its inhibitory effects on leptin are unknown. We hypothesized that ghrelin activates the exchange protein activated by cAMP (Epac), inducing increased SOCS3 expression, which negatively affects leptin signal transduction and neuronal firing in nodose ganglia (NG) neurons. We showed that 91 ± 3% of leptin receptor (LRb) -bearing neurons contained ghrelin receptors (GHS-R1a) and that ghrelin significantly inhibited leptin-stimulated STAT3 phosphorylation in rat NG neurons. Studies of the signaling cascades used by ghrelin showed that ghrelin caused a significant increase in Epac and suppressor of cytokine signaling 3 (SOCS3) expression in cultured rat NG neurons. Transient transfection of cultured NG neurons to silence SOCS3 and Epac genes reversed the inhibitory effects of ghrelin on leptin-stimulated STAT3 phosphorylation. Patch-clamp studies and recordings of single neuronal discharges of vagal primary afferent neurons showed that ghrelin markedly inhibited leptin-stimulated neuronal firing, an action abolished by silencing SOCS3 expression in NG. Plasma ghrelin levels increased significantly during fasting. This was accompanied by enhanced SOCS3 expression in the NG and prevented by treatment with a ghrelin antagonist. Feeding studies showed that silencing SOCS3 expression in the NG reduced food intake evoked by endogenous leptin. We conclude that ghrelin exerts its inhibitory effects on leptin-stimulated neuronal firing by increasing SOCS3 expression. The SOCS3 signaling pathway plays a pivotal role in ghrelin's inhibitory effect on STAT3 phosphorylation, neuronal firing, and feeding behavior. 

Retracted: No

PubPeer comments:
 Fig 6  Silencing of SOCS3 prevents the inhibitory action of ghrelin on leptin-stimulated nodose neuronal activity in vivo. A, Response of NG neuron electroporated with control siRNA to the administration of leptin (225 u03bcg kg, iv). I am concerned about the repeated section of neuronal recording. Is this normal for this technique? ![file] , 
 Fig 6  Silencing of SOCS3 prevents the inhibitory action of ghrelin on leptin-stimulated nodose neuronal activity in vivo. ... D, Silencing the expression of SOCS3 ... abolished the inhibitory action of ghrelin (25 u03bcg kg) on leptin stimulation . What intrigues me here is the vertical symmetry of the baseline between nerve spikes... every positive excursion of noise is mirrored by an identical negative excursion. This does not seem to be normal for the technique. ![file] , 
 #2 Agreed with Hoya, it is not normally possible for a baseline trace to be perfectly symmetrical. , 
 The symmetry is odd, but it depends a bit on what interference is generating that noise. I wouldn t say impossible. , 
 #4 Perhaps not impossible, but have you ever seen traces with such symmetry before? and have you seen the other issues in the traces from the same group? https: pubpeer.com search?q=owyang , 
 #1 To answer #1 question, the two traces shown in the orange rectangle are very likely from the same sweep of recording. ,