Enhanced Stat3 Activation in POMC Neurons Provokes Negative Feedback Inhibition of Leptin and InsulinSignaling in Obesity

Ernst, Marianne B.; Wunderlich, Claudia M.; Heß, Simon; Paehler, Moritz; Mesaros, Andrea; Koralov, Sergei B.; Kleinridders, André; Husch, Andreas; Münzberg, Heike; Hampel, Brigitte; Alber, Jens; Kloppenburg, Peter; Brüning, Jens C.; Wunderlich, Frank

doi:10.1523/jneurosci.5712-08.2009

Cited by 160 publications

(126 citation statements)

References 61 publications

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“…Our findings also suggest that leptin-responsive activation of Ob-Rb STAT3 signaling exerts important actions upon energy balance in young animals, but increased STAT3 activation in the long term may provoke increased adiposity at older ages with elevated levels of endogenous leptin (Table 1). This is in line with a recently reported study demonstrating through overexpression of a constitutively active form of STAT3 that chronically elevated basal STAT3 activation in the POMC neurons leads to obesity with attenuated leptin and insulin signaling due to increased SOCS3 expression (19). In addition, leptin is thought to act upon heterogeneous populations of Ob-Rb-expressing neurons, including those outside the ARC in the brain (34).…”

Section: Discussionsupporting

confidence: 90%

Signaling through Tyr⁹⁸⁵ of Leptin Receptor as an Age/Diet-Dependent Switch in the Regulation of Energy Balance

You

Jiang

et al. 2010

Molecular and Cellular Biology

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Leptin regulates energy homeostasis through central activation of multiple signaling pathways mediated byOb-Rb, the long form of leptin receptor. Leptin resistance underlies the pathogenic development of obesity, which is closely associated with environmental factors. To further understand the physiological function of leptin signaling mechanisms, we generated a knock-in line of mice (Y985F) expressing a mutant Ob-Rb with a phenylalanine substitution for Tyr 985 , one of the three intracellular tyrosines that mediate leptin's signaling actions. Surprisingly, whereas young homozygous Y985F animals were slightly leaner, they exhibit adult-onset or diet-induced obesity. Importantly, both age-dependent and diet-induced deterioration of energy balance was paralleled with pronounced leptin resistance, which was largely attributable to attenuation of leptin-responsive hypothalamic STAT3 activation as well as prominently elevated expression of hypothalamic SOCS3, a key negative regulator of leptin signaling. Thus, these results unmask distinct binary roles for Try 985 -mediated signaling in energy metabolism, acting as an age/diet-dependent regulatory switch to counteract age-associated or diet-induced obesity.As a component of the metabolic syndrome, obesity is closely associated with increased risk for the development of type 2 diabetes and cardiovascular disorders (16). Arising from a chronic imbalance between energy intake and expenditure, the pathogenic progression of obesity is attributable to the complex interactions between genetic factors and environmental influences. In mammals, energy balance is maintained through multiple homeostatic mechanisms that operate coordinately in response to hormonal and nutritional cues. Leptin is an adipose-secreted hormone (43) that plays a pivotal role in the regulation of energy metabolism. Acting through its activeform receptor Ob-Rb in distinct classes of leptin-responsive neurons (11,14,34), leptin activates multiple signaling pathways in the hypothalamus to regulate food intake and energy expenditure. Mice with deficiency in leptin (ob/ob) or its functional receptor (db/db) develop morbid obesity, hyperphagia, and diabetes (20). Impaired leptin responsiveness, i.e., leptin resistance (33), is a key characteristic of the metabolic defects that are responsible for disrupted energy control, presumably underlying the pathogenic development of human obesity (29). Although diminished leptin signaling has been found to occur in association with aging (21, 39) or feeding of a high-fat diet (HFD) (17, 18), the exact physiological mechanisms linking the environmental factors to the impairment in leptin-mediated regulation of energy metabolism remain largely elusive.Leptin binds to Ob-Rb and elicits an array of subsequent intracellular signaling cascades (7, 22) via Jak2 phosphorylation. The mouse Ob-Rb comprises three cytoplasmic tyrosine residues, Tyr 985 , Tyr 1077 , and Tyr 1138 , which are known to be phosphorylated and mediate leptin's physiological functions (22,26). The phosp...

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Section: Discussionsupporting

confidence: 90%

Signaling through Tyr⁹⁸⁵ of Leptin Receptor as an Age/Diet-Dependent Switch in the Regulation of Energy Balance

You

Jiang

et al. 2010

Molecular and Cellular Biology

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“…Indeed, negative feedback is well established in STAT3 signaling and can exist at many levels. In our mouse models, we may be observing the consequences of negative-feedback inhibition when tonic Stat3 hyperactivation exceeds a threshold, as previously observed (34)(35)(36). Furthermore, STAT3 signaling pathways are subject to significant crosstalk.…”

Section: Discussionmentioning

confidence: 57%

Loss of the tyrosine phosphatase PTPRD leads to aberrant STAT3 activation and promotes gliomagenesis

Ortiz

Fabius²,

Wu³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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PTPRD, which encodes the protein tyrosine phosphatase receptor-δ, is one of the most frequently inactivated genes across human cancers, including glioblastoma multiforme (GBM). PTPRD undergoes both deletion and mutation in cancers, with copy number loss comprising the primary mode of inactivation in GBM. However, it is unknown whether loss of PTPRD promotes tumorigenesis in vivo, and the mechanistic basis of PTPRD function in tumors is unclear. Here, using genomic analysis and a glioma mouse model, we demonstrate that loss of Ptprd accelerates tumor formation and define the oncogenic context in which Ptprd loss acts. Specifically, we show that in human GBMs, heterozygous loss of PTPRD is the predominant type of lesion and that loss of PTPRD and the CDKN2A/p16 INK4A tumor suppressor frequently co-occur. Accordingly, heterozygous loss of Ptprd cooperates with p16 deletion to drive gliomagenesis in mice. Moreover, loss of the Ptprd phosphatase resulted in phospho-Stat3 accumulation and constitutive activation of Stat3-driven genetic programs. Surprisingly, the consequences of Ptprd loss are maximal in the heterozygous state, demonstrating a tight dependence on gene dosage. Ptprd loss did not increase cell proliferation but rather altered pathways governing the macrophage response. In total, we reveal that PTPRD is a bona fide tumor suppressor, pinpoint PTPRD loss as a cause of aberrant STAT3 activation in gliomas, and establish PTPRD loss, in the setting of CDKN2A/p16 INK4A deletion, as a driver of glioma progression.G lioblastoma multiforme (GBM) is a devastating disease. It is the most common and aggressive type of glioma and outcomes remain poor despite current treatments (1). To increase our understanding of the genetic basis of this malignancy, several mutational survey studies examining GBM have been completed and provide a detailed view of the molecular changes underlying this cancer (2-4). Because GBM is a highly heterogeneous tumor, a challenge remains to determine which molecular alterations drive tumorigenesis and to understand the underlying mechanisms of action. Recent work by our group and others have identified inactivation of protein tyrosine phosphatase receptor-δ (PTPRD) as a frequent alteration in GBM and other tumors, and showed that PTPRD copy number loss correlates with poor prognosis (5-10). Despite the high prevalence of PTPRD inactivation in human tumors, it is not known whether loss of PTPRD can promote tumorigenesis. Furthermore, the mechanisms of action and the oncogenic context in which PTPRD acts remain obscure.PTPRD belongs to a family of protein-tyrosine phosphatases that collectively have been implicated in functions, including the regulation of receptor tyrosine kinases, growth, cell migration, and angiogenesis (11). Previously, we demonstrated that phosphorylated STAT3 (p-STAT3) is a substrate of PTPRD and that cancer-specific mutations in PTPRD abrogate the ability of the phosphatase to dephosphorylate STAT3 (5). Interestingly, accumulation of phosphorylated STAT3 and STAT3 hyper...

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“…STAT3 activation in hypothalamic POMC-expressing neurons plays an important role in the maintenance of energy homeostasis (Xu et al, 2007). Additionally, enhanced STAT3 activation in POMC neurons may provoke a negative feedback inhibition of leptin and insulin signalling in obese animals (Ernst et al, 2009). Thus, we suggest that STAT3 activation in hypothalamic POMC neurons played a functional role in regulating the amphetamine-induced anorectic response.…”

Section: Figurementioning

confidence: 84%

Involvement of hypothalamic PI3K–STAT3 signalling in regulating appetite suppression mediated by amphetamine

Chu

Chen

Hsieh

et al. 2014

British J Pharmacology

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BACKGROUND AND PURPOSEAppetite suppression induced by amphetamine has been attributed to its inhibition of neuropeptide Y (NPY) neurons and activation of pro-opiomelanocortin (POMC) neurons in the hypothalamus. This study examined whether STAT3 was involved in these actions of amphetamine. EXPERIMENTAL APPROACHRats were given amphetamine daily for 4 days. Changes in the expression of NPY, POMC, melanocortin MC3 receptors, PI3K and STAT3 in the hypothalamus were assessed by RT-PCR and Western blotting. Antisense oligonucleotides to STAT3 were also used. KEY RESULTSExpression of NPY decreased with a maximum effect day 2 of amphetamine treatment. Expression of POMC, MC3 receptors, PI3K and STAT3 increased with a maximum response on day 2. Moreover, phosphorylation of STAT3 and its DNA binding activity increased and was expressed in a similar pattern. Infusion (i.c.v.) of STAT3 antisense at 60 min before amphetamine treatment, partly blocked amphetamine-induced anorexia and modulated expression of NPY, POMC, MC3 receptors and PI3K, indicating the involvement of STAT3 in amphetamine-treated rats. CONCLUSIONS AND IMPLICATIONSHypothalamic PI3K-STAT3 signalling participated in the regulation of NPY-and POMC-mediated appetite suppression. These findings may contribute to a better understanding of anorectic drugs.

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Enhanced Stat3 Activation in POMC Neurons Provokes Negative Feedback Inhibition of Leptin and InsulinSignaling in Obesity

Abstract: Leptin-stimulated Stat3 activation in proopiomelanocortin (POMC)-expressing neurons of the hypothalamus plays an important role in

Cited by 160 publications

References 61 publications

Signaling through Tyr⁹⁸⁵ of Leptin Receptor as an Age/Diet-Dependent Switch in the Regulation of Energy Balance

Signaling through Tyr⁹⁸⁵ of Leptin Receptor as an Age/Diet-Dependent Switch in the Regulation of Energy Balance

Loss of the tyrosine phosphatase PTPRD leads to aberrant STAT3 activation and promotes gliomagenesis

Involvement of hypothalamic PI3K–STAT3 signalling in regulating appetite suppression mediated by amphetamine

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Enhanced Stat3 Activation in POMC Neurons Provokes Negative Feedback Inhibition of Leptin and InsulinSignaling in Obesity

Abstract: Leptin-stimulated Stat3 activation in proopiomelanocortin (POMC)-expressing neurons of the hypothalamus plays an important role in

Cited by 160 publications

References 61 publications

Signaling through Tyr985 of Leptin Receptor as an Age/Diet-Dependent Switch in the Regulation of Energy Balance

Signaling through Tyr985 of Leptin Receptor as an Age/Diet-Dependent Switch in the Regulation of Energy Balance

Loss of the tyrosine phosphatase PTPRD leads to aberrant STAT3 activation and promotes gliomagenesis

Involvement of hypothalamic PI3K–STAT3 signalling in regulating appetite suppression mediated by amphetamine

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Product

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Signaling through Tyr⁹⁸⁵ of Leptin Receptor as an Age/Diet-Dependent Switch in the Regulation of Energy Balance

Signaling through Tyr⁹⁸⁵ of Leptin Receptor as an Age/Diet-Dependent Switch in the Regulation of Energy Balance