Shp2 controls female body weight and energy balance by integrating leptin and estrogen signals

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

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31 Scopus citations

Abstract

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 (Shp2D61A) 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, Shp2D61A female mice showed dramatically enhanced leptin sensitivity. Microinjection of Shp2D61A-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.

Original languageEnglish (US)
Pages (from-to)1867-1878
Number of pages12
JournalMolecular and cellular biology
Volume32
Issue number10
DOIs
StatePublished - May 1 2012

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ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

He, Z., Zhang, S. S., Meng, Q., Li, S., Zhu, H. H., Raquil, M. A., Alderson, N., Zhang, H., Wu, J., Rui, L., Cai, D., & Feng, G. S. (2012). Shp2 controls female body weight and energy balance by integrating leptin and estrogen signals. Molecular and cellular biology, 32(10), 1867-1878. https://doi.org/10.1128/MCB.06712-11