title: Shp2 controls female body weight and energy balance by integrating leptin and estrogen signals.
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 (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.
authors.affiliation: Department of Pathology and Division of Biological Sciences, University of California, San Diego, La Jolla, California, USA.
authors.forename: Zhao
authors.initials: Z
authors.lastname: He
authors.forename: Sharon S
authors.initials: SS
authors.lastname: Zhang
authors.forename: Qingyuan
authors.initials: Q
authors.lastname: Meng
authors.forename: Shuangwei
authors.initials: S
authors.lastname: Li
authors.forename: Helen H
authors.initials: HH
authors.lastname: Zhu
authors.forename: Marie-Astrid
authors.initials: MA
authors.lastname: Raquil
authors.forename: Nazilla
authors.initials: N
authors.lastname: Alderson
authors.forename: Hai
authors.initials: H
authors.lastname: Zhang
authors.forename: Jiarui
authors.initials: J
authors.lastname: Wu
authors.forename: Liangyou
authors.initials: L
authors.lastname: Rui
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Cai
authors.forename: Gen-Sheng
authors.initials: GS
authors.lastname: Feng
mesh_terms: D000818:Animals; D001835:Body Weight / Q000235:genetics*; D059305:Diet, High-Fat; D004734:Energy Metabolism / Q000235:genetics*; D047628:Estrogen Receptor alpha / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D007031:Hypothalamus / Q000378:metabolism; D020738:Leptin / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D009765:Obesity / Q000235:genetics / Q000378:metabolism; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics* / Q000378:metabolism; D054411:Receptors, Leptin / Q000378:metabolism; D012737:Sex Factors; D015398:Signal Transduction
chemical_list: D047628:Estrogen Receptor alpha; D004967:Estrogens; D020738:Leptin; D054411:Receptors, Leptin; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11