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

He, Zhao; Zhang, Sharon S.; Meng, Qing‐Yuan; Li, Shuangwei; Zhu, Helen He; Raquil, Marie Astrid; Alderson, Nazilla; Zhang, Hai; Wu, Jiarui; Rui, Liangyou; Cai, Dongsheng; Feng, Gen Sheng

doi:10.1128/mcb.06712-11

Cited by 57 publications

(48 citation statements)

References 43 publications

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“…These results indicate a positive role of Shp2 in amplification of leptin signal in the hypothalamic control of body weight and energy balance. Consistently, selective expression of a dominant active mutant of Shp2 in forebrain neurons enhanced leptin sensitivity in rodents (20).…”

mentioning

confidence: 68%

Nonreceptor tyrosine phosphatase Shp2 promotes adipogenesis through inhibition of p38 MAP kinase

Zhu

Bauler

et al. 2012

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

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The molecular mechanism underlying adipogenesis and the physiological functions of adipose tissue are not fully understood. We describe here a unique mouse model of severe lipodystrophy. Ablation of Ptpn11/Shp2 in adipocytes, mediated by aP2-Cre, led to premature death, lack of white fat, low blood pressure, compensatory erythrocytosis, and hepatic steatosis in Shp2 fat−/− mice. Fat transplantation partially rescued the lifespan and blood pressure in Shp2 fat−/− mice, and administration of leptin also restored partially the blood pressure of mutant animals with endogenous leptin deficiency. Consistently, homozygous deletion of Shp2 inhibited adipocyte differentiation from embryonic stem (ES) cells. Biochemical analyses suggest a Shp2-TAO2-p38-p300-PPARγ pathway in adipogenesis, in which Shp2 suppresses p38 activation, leading to stabilization of p300 and enhanced PPARγ expression. Inhibition of p38 restored adipocyte differentiation from Shp2 −/− ES cells, and p38signaling is also suppressed in obese patients and obese animals. These results illustrate an essential role of adipose tissue in mammalian survival and physiology and also suggest a common signaling mechanism involved in adipogenesis and obesity development.transduction | preadipocyte | dephosphorylation | substrate trapping

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mentioning

confidence: 68%

Nonreceptor tyrosine phosphatase Shp2 promotes adipogenesis through inhibition of p38 MAP kinase

Zhu

Bauler

et al. 2012

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

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“…Furthermore, deletion of Shp2 from POMC neurons results in mild obesity and increased susceptibility to DIO (Banno, et al 2010). Similarly, female mice expressing a dominant active SHP2 mutant in the brain are resistant to DIO (He, et al 2012). Thus, these data are consistent with the notion that LepRb→SHP2 signaling is important for leptin action and the control of energy homeostasis, rather than SHP2 mediating feedback inhibition on LepRb.…”

Section: Leprb Signaling and Physiologymentioning

confidence: 99%

20 YEARS OF LEPTIN: Connecting leptin signaling to biological function

Allison

Myers

2014

Journal of Endocrinology

197

165

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Hypothalamic leptin action promotes negative energy balance and modulates glucose homeostasis, as well as serving as a permissive signal to the neuroendocrine axes that control growth and reproduction. Since the initial discovery of leptin 20 years ago, we have learned a great deal about the molecular mechanisms of leptin action. An important aspect of this has been the dissection of the cellular mechanisms of leptin signaling, and how specific leptin signals influence physiology. Leptin acts via the long form of the leptin receptor, LepRb. LepRb activation and subsequent tyrosine phosphorylation recruits and activates multiple signaling pathways, including STAT transcription factors, SHP2 and ERK signaling, the IRS-protein/PI3Kinase pathway, and SH2B1. Each of these pathways controls specific aspects of leptin action and physiology. Important inhibitory pathways mediated by suppressor of cytokine signaling (SOCS) proteins and protein tyrosine phosphatases (PTPases) also limit physiologic leptin action. This review summarizes the signaling pathways engaged by LepRb and their effects on energy balance, glucose homeostasis, and reproduction. Particular emphasis is given to the multiple mouse models which have been used to elucidate these functions in vivo.

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“…Although this observation requires to be confirmed in larger groups of patients, it is not totally unexpected when considering certain reports which addressed the function of Shp2 (the PTPN11 gene product) in the mouse metabolism. For example, expression of a dominant active mutant of Shp2 (which is biochemically comparable to a mutant causing NS) in the mouse brain leads to resistance to high fat diet-induced obesity and to improved insulin sensitivity [47]. Consequently it is possible to speculate that NS patients could be somewhat protected from metabolic disorders, which could minimize the possible adverse effects of GH therapy on carbohydrate and lipid metabolism.…”

Section: Potential Adverses Effects Of Gh Therapymentioning

confidence: 99%

Growth hormone and noonan syndrome: update in dysfunctional signaling aspects and in therapy for short stature

Raynal¹

2014

Horm Stud

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Short stature is a frequent feature of Noonan syndrome (NS), a disease caused by mutations of genes encoding components of the Ras/mitogen-activated protein kinases (MAPK) signalling pathway. To date numerous patients have been treated with growth hormone (GH) in various countries. However this treatment is still controversial, as its efficacy is a matter of debate. The final height gain of GH therapy represents 5 to 10 cm, at best, which is disappointing considering the length and burden of the treatment. The reasons explaining this lack of efficiency are poorly understood and they seemed to involve a waning effect after the first year of GH treatment or acceleration of bone maturation in patients on GH. Moreover, GH therapy raises questions about its safety, especially in subjects with NS who are at risk for cardiac defects and malignancies. Cases of severe adverse effects were described, yet too sporadically to conclude that they were certainly caused by GH therapy. Novels insights in understanding the dysfunction of GH-dependent processes in NS were recently reported and this manuscript aims at reviewing the latest advances. Clinical data suggested that growth retardation could be caused by a partial postreceptor resistance to GH, an impaired sensitivity to GH which could also explain the modest efficiency of GH therapy in NS patients. Similar observations were also obtained in a NS mouse model harboring a mutation in the gene encoding the tyrosine phosphatase Shp2. In the mouse, the mechanism of GH resistance is thought to involve upregulation by mutated Shp2 of GH-induced Ras/MAPK, a signaling pathway which seemed to play a negative regulatory role in the production of GH mediators involved in bone growth. Despite these recent finding, the underlying mechanisms of growth retardation and GH therapy in NS remain to be further explored in order to improve treatment for short stature.

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

Cited by 57 publications

References 43 publications

Nonreceptor tyrosine phosphatase Shp2 promotes adipogenesis through inhibition of p38 MAP kinase

Nonreceptor tyrosine phosphatase Shp2 promotes adipogenesis through inhibition of p38 MAP kinase

20 YEARS OF LEPTIN: Connecting leptin signaling to biological function

Growth hormone and noonan syndrome: update in dysfunctional signaling aspects and in therapy for short stature

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