Leptin Stimulates Both JAK2-dependent and JAK2-independent Signaling Pathways

Jiang, Lin; Li, Zhiqin; Rui, Liangyou

doi:10.1074/jbc.m805545200

Cited by 78 publications

(78 citation statements)

References 45 publications

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“…Moreover, in studies with human breast carcinoma cells, it was shown that Stat-3 can not only be activated via the classical JAK/Stat-pathway, but also by src kinases, because an inhibition of these tyrosine kinases was accompanied by a dose-dependent blocking of Stat-3 signaling (Garcia et al 2001). Src-specific inhibitors such as pp2 significantly attenuated leptinstimulated tyrosine phosphorylation of Stat-3 in both fibroblast and neurons (Jiang et al 2008). We can approve this correlation, because incubation of the cells with leptin in combination with pp2, resulted in a significant decrease of Stat-3 activation (Fig.…”

Section: Discussionmentioning

confidence: 64%

Leptin stimulates the migration of colon carcinoma cells by multiple signaling pathways

Ratke

Entschladen²,

Niggemann³

et al. 2010

Endocrine-Related Cancer

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Active migration of tumor cells is a prerequisite for the development of metastasis and tumor progression, and is regulated by a variety of extracellular ligands. Epidemiological studies have shown that obesity increases the risk of colon cancer by 1.5-to 2-fold with obesity-associated colon cancer accounting for 14-35% of total incidence. In obese individuals, serum levels of leptin are markedly increased, and therefore, we have investigated the impact of this adipocytokine on the migration of various human colon carcinoma cell lines such as SW480, SW620, and HCT116. Leptin significantly enhanced the migratory activity of all three cell lines, and the strongest effect was observed in SW480 cells, which increased their locomotor activity from 28% spontaneously locomoting cells to 50%. The intracellular signal transduction regulating this pro-migratory effect involves the activation of the transcription factor signal transducer and activator of transcription-3 via Janus kinases, but also the activity of src tyrosine kinases, focal adhesion kinase, exclusively protein kinase Cd, and the phosphatidyl-inositol-3-kinase, as proven by the use of particular inhibitors and target-specific small interfering RNAs. Herein, we deliver new evidence for a modulatory role of leptin in the regulation of colon cancer progression by stimulating tumor cell migration. Thus, our findings have potential clinical implications, because understanding the impact of leptin on tumor cell migration and the underlying signal transduction mechanisms is mandatory for future development of novel therapeutics to treat obesity-associated colorectal cancer.

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Section: Discussionmentioning

confidence: 64%

Leptin stimulates the migration of colon carcinoma cells by multiple signaling pathways

Ratke

Entschladen²,

Niggemann³

et al. 2010

Endocrine-Related Cancer

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“…LepRb cells were cultured in F-12K medium with 12% horse serum and 3% fetal bovine serum (20). Cells were fixed by 4% PFA for 5 to 10 min.…”

Section: Generation Of Shp2mentioning

confidence: 99%

Shp2 Controls Female Body Weight and Energy Balance by Integrating Leptin and Estrogen Signals

Zhang

Meng

et al. 2012

Molecular and Cellular Biology

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In mammals, leptin regulates food intake and energy balance mainly through the activation of LepRb in the hypothalamus, and estrogen has a leptin-like effect in the hypothalamic control of metabolism. However, it remains to be elucidated how estrogen signaling is intertwined with the leptin pathway. We show here that Shp2, a nonreceptor tyrosine phosphatase, acts to integrate leptin and estrogen signals. The expression of a dominant-active mutant (Shp2 D61A ) in forebrain neurons conferred female, but not male, transgenic mice resistance to high-fat diet (HFD)-induced obesity and liver steatosis, accompanied by improved insulin sensitivity and glucose homeostasis. Fed with either HFD or regular chow food, Shp2 D61A female mice showed dramatically enhanced leptin sensitivity. Microinjection of Shp2 D61A -expressing adeno-associated virus into mediobasal hypothalamus elicited a similar antiobese effect in female mice. Biochemical analyses showed a physical association of Shp2 with estrogen receptor alpha, which is necessary for the synergistic and persistent activation of Erk by leptin and estrogen. Together, these results elucidate a mechanism for the direct cross talk of leptin and estrogen signaling and offer one explanation for the propensity of postmenopausal women to develop obesity.

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“…Leptin is the key signaling molecule responsible for long term satiety and energy balance; mutations that cause defective leptin secretion or abnormal leptin receptor signaling result in obesity in ob/ob mice (9, 10) and in humans (11). The leptin receptor belongs to the IL-6 receptor family of class 1 cytokine receptors and mediates the biological effects of leptin via the Janus kinase 2-signal transducer and activator of transcription 3 (JAK2/STAT3) pathway (12)(13)(14). Several splice variants of the leptin receptor exist; however, the LRb isoform mediates the leptin effect on satiety (4).…”

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confidence: 99%

Synergistic Interaction between Leptin and Cholecystokinin in the Rat Nodose Ganglia Is Mediated by PI3K and STAT3 Signaling Pathways

Heldsinger

Grabauskas

Song

et al. 2011

Journal of Biological Chemistry

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Research has shown that the synergistic interaction between vagal cholecystokinin-A receptors (CCKARs) and leptin receptors (LRbs) mediates short term satiety. We hypothesize that this synergistic interaction is mediated by cross-talk between signaling cascades used by CCKARs and LRbs, which, in turn, activates closure of K ؉ channels, leading to membrane depolar- Leptin, the product of the ob gene, is secreted primarily from white adipocyte tissue; its level in the circulation correlates with the degree of adiposity (1, 2). Circulating leptin crosses the blood-brain barrier via a receptor-mediated transport system (3, 4) and acts on the long form of the leptin receptor (LRb) 2 in the medial hypothalamus to regulate feeding behavior and energy balance (5). Leptin is secreted from several other sites, including the gastric mucosa, brown adipocyte tissue, placenta, mammary gland, ovarian follicles, and brain (5, 6). Leptin mRNA and leptin protein have also been detected in human stomach mucosa (7) and rat gastric fundus (8). Leptin levels in the stomach are altered by nutritional state and by cholecystokinin (CCK) administration. CCK is not, however, a stimulus for leptin release from isolated adipocytes (8). Leptin is the key signaling molecule responsible for long term satiety and energy balance; mutations that cause defective leptin secretion or abnormal leptin receptor signaling result in obesity in ob/ob mice (9, 10) and in humans (11). The leptin receptor belongs to the IL-6 receptor family of class 1 cytokine receptors and mediates the biological effects of leptin via the Janus kinase 2-signal transducer and activator of transcription 3 (JAK2/STAT3) pathway (12-14). Several splice variants of the leptin receptor exist; however, the LRb isoform mediates the leptin effect on satiety (4). CCK is an endogenous peptide found in the gastrointestinal tract and the brain. It is released into the circulation after a meal and acts on neurons both centrally and peripherally (15). The satiety action of CCK appears to be mediated by low affinity CCK-A receptors (CCKARs) on vagal afferent neurons (16). Systemic administration of CCK inhibits food intake in several species, including rats and humans (17), giving credence to the hypothesis that peripheral CCK acts as a satiety signal. CCK cannot penetrate the blood-brain barrier; therefore, systemically administered CCK likely acts at a peripheral site to inhibit feeding (18). In contrast to leptin, the effect of CCK on food intake occurs within 15 min after intraperitoneal administration of CCK-8, suggesting that CCK may act as a meal-related short term satiety signal (19,20).Both CCKARs and LRbs are widely distributed in nodose ganglia (NG) and the vagus nerve (21,22). There is evidence that a synergistic interaction between leptin and CCK leads to the reduction of short term food intake (23)(24)(25). In fact, the satiety action of CCK appears to depend on leptin signaling (26). Currently, the intracellular signaling mechanisms responsible for the synergistic interacti...

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Leptin Stimulates Both JAK2-dependent and JAK2-independent Signaling Pathways

Abstract: Leptin, an adipocyte-derived hormone, controls energy balance and body weight via its long form receptor LEPRb.

Cited by 78 publications

References 45 publications

Leptin stimulates the migration of colon carcinoma cells by multiple signaling pathways

Leptin stimulates the migration of colon carcinoma cells by multiple signaling pathways

Shp2 Controls Female Body Weight and Energy Balance by Integrating Leptin and Estrogen Signals

Synergistic Interaction between Leptin and Cholecystokinin in the Rat Nodose Ganglia Is Mediated by PI3K and STAT3 Signaling Pathways

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