Neuronal SH2B1 is essential for controlling energy and glucose homeostasis

Decheng Ren, Yingjiang Zhou, David Morris, Minghua Li, Zhiqin Li, Liangyou Rui

Research output: Contribution to journalArticle

136 Citations (Scopus)

Abstract

SH2B1 (previously named SH2-B), a cytoplasmic adaptor protein, binds via its Src homology 2 (SH2) domain to a variety of protein tyrosine kinases, including JAK2 and the insulin receptor. SH2B1-deficient mice are obese and diabetic. Here we demonstrated that multiple isoforms of SH2B1 (α, β, γ, and/or δ) were expressed in numerous tissues, including the brain, hypothalamus, liver, muscle, adipose tissue, heart, and pancreas. Rat SH2B1β was specifically expressed in neural tissue in SH2B1-transgenic (SH2B1Tg) mice. SH2B1Tg mice were crossed with SH2B1-knockout (SH2B1KO) mice to generate SH2B1TgKO mice expressing SH2B1 only in neural tissue but not in other tissues. Systemic deletion of the SH2B1 gene resulted in metabolic disorders in SH2B1KO mice, including hyperlipidemia, leptin resistance, hyperphagia, obesity, hyperglycemia, insulin resistance, and glucose intolerance. Neuron-specific restoration of SH2B1β not only corrected the metabolic disorders in SH2B1TgKO mice, but also improved JAK2-mediated leptin signaling and leptin regulation of orexigenic neuropeptide expression in the hypothalamus. Moreover, neuron-specific overexpression of SH2B1 dose-dependently protected against high-fat diet-induced leptin resistance and obesity. These observations suggest that neuronal SH2B1 regulates energy balance, body weight, peripheral insulin sensitivity, and glucose homeostasis at least in part by enhancing hypothalamic leptin sensitivity.

Original languageEnglish (US)
Pages (from-to)397-406
Number of pages10
JournalJournal of Clinical Investigation
Volume117
Issue number2
DOIs
StatePublished - Feb 1 2007
Externally publishedYes

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Leptin
Homeostasis
Glucose
Knockout Mice
Transgenic Mice
Hypothalamus
Insulin Resistance
Obesity
Janus Kinase 2
Neurons
Obese Mice
Hyperphagia
Glucose Intolerance
src Homology Domains
Insulin Receptor
Gene Deletion
High Fat Diet
Hyperlipidemias
Neuropeptides
Hyperglycemia

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Neuronal SH2B1 is essential for controlling energy and glucose homeostasis. / Ren, Decheng; Zhou, Yingjiang; Morris, David; Li, Minghua; Li, Zhiqin; Rui, Liangyou.

In: Journal of Clinical Investigation, Vol. 117, No. 2, 01.02.2007, p. 397-406.

Research output: Contribution to journalArticle

Ren, Decheng ; Zhou, Yingjiang ; Morris, David ; Li, Minghua ; Li, Zhiqin ; Rui, Liangyou. / Neuronal SH2B1 is essential for controlling energy and glucose homeostasis. In: Journal of Clinical Investigation. 2007 ; Vol. 117, No. 2. pp. 397-406.
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