Abstract
Leptin regulates energy balance and body weight by activating its receptor LEPRb and multiple downstream signaling pathways, including the STAT3 and the IRS2/PI 3-kinase pathways, in the hypothalamus. Leptin stimulates activation of LEPRb-associated JAK2, which initiates cell signaling. Here we identified SH2-B, a JAK2-interacting protein, as a key regulator of leptin sensitivity, energy balance, and body weight. SH2-B homozygous null mice were severely hyperphagic and obese and developed a metabolic syndrome characterized by hyperleptinemia, hyperinsulinemia, hyperlipidemia, hepatic steatosis, and hyperglycemia. The expression of hypothalamic orexigenic NPY and AgRP was increased in SH2-B(-/-) mice. Leptin-stimulated activation of hypothalamic JAK2 and phosphorylation of hypothalamic STAT3 and IRS2 were significantly impaired in SH2-B(-/-) mice. Moreover, overexpression of SH2-B counteracted PTP1B-mediated inhibition of leptin signaling in cultured cells. Our data suggest that SH2-B is an endogenous enhancer of leptin sensitivity and required for maintaining normal energy metabolism and body weight in mice.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism*
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Animals
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Body Weight*
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Enzyme Activation
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Female
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Homeostasis*
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Hypothalamus
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Insulin Receptor Substrate Proteins
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Intracellular Signaling Peptides and Proteins
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Janus Kinase 2
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Leptin / metabolism*
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Male
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Metabolic Syndrome / genetics
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Metabolic Syndrome / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Obesity / genetics
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Obesity / metabolism
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Phosphoproteins / genetics
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Phosphoproteins / metabolism
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Protein-Tyrosine Kinases / genetics
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Protein-Tyrosine Kinases / metabolism
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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STAT3 Transcription Factor
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Signal Transduction / physiology
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Trans-Activators / genetics
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Trans-Activators / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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DNA-Binding Proteins
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Insulin Receptor Substrate Proteins
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Intracellular Signaling Peptides and Proteins
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Irs2 protein, mouse
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Leptin
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Phosphoproteins
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Proto-Oncogene Proteins
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STAT3 Transcription Factor
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Sh2bpsm1 protein, mouse
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Stat3 protein, mouse
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Trans-Activators
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Protein-Tyrosine Kinases
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Jak2 protein, mouse
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Janus Kinase 2