Critical role of the Src homology 2 (SH2) domain of neuronal SH2B1 in the regulation of body weight and glucose homeostasis in mice

David L. Morris, Kae Won Cho, Liangyou Rui

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

SH2B1 is an SH2 domain-containing adaptor protein that plays a key role in the regulation of energy and glucose metabolism in both rodents and humans. Genetic deletion of SH2B1 in mice results in obesity and type 2 diabetes. Single-nucleotide polymorphisms in the SH2B1 loci and chromosomal deletions of the SH2B1 loci associate with obesity and insulin resistance in humans. In cultured cells, SH2B1 promotes leptin and insulin signaling by binding via its SH2 domain to phosphorylated tyrosines in Janus kinase 2 and the insulin receptor, respectively. Here we generated three lines of micetoanalyze the role of the SH2 domain of SH2B1 in the central nervous system. Transgenic mice expressing wildtype, SH2 domain-defective (R555E), or SH2 domain-alone (ΔN503) forms of SH2B1 specifically in neurons were crossed with SH2B1 knockout mice to generate KO/SH2B1, KO/R555E, or KO/ΔN503 compound mutant mice. R555E had a replacement of Arg555 with Glu within the SH2 domain. ΔN503 contained an intact SH2 domain but lacked amino acids 1-503. Neuron-specific expression of recombinant SH2B1, but not R555E or ΔN503, corrected hyperphagia, obesity, glucose intolerance, and insulin resistance in SH2B1 null mice. Neuron-specific expression of R555E in wild-type mice promoted obesity and insulin resistance. These results indicate that in addition to the SH2 domain, N-terminal regions of neuronal SH2B1 are also required for the maintenance of normal body weight and glucose metabolism. Additionally, mutations in the SH2 domain of SH2B1 may increase the susceptibility to obesity and type 2 diabetes in a dominant-negative manner.

Original languageEnglish (US)
Pages (from-to)3643-3651
Number of pages9
JournalEndocrinology
Volume151
Issue number8
DOIs
StatePublished - Aug 2010
Externally publishedYes

Fingerprint

src Homology Domains
Homeostasis
Body Weight
Glucose
Obesity
Insulin Resistance
Neurons
Type 2 Diabetes Mellitus
Janus Kinase 2
Ideal Body Weight
Hyperphagia
Glucose Intolerance
Insulin Receptor
Leptin
Knockout Mice
Energy Metabolism
Transgenic Mice
Single Nucleotide Polymorphism
Tyrosine
Cultured Cells

ASJC Scopus subject areas

  • Endocrinology

Cite this

Critical role of the Src homology 2 (SH2) domain of neuronal SH2B1 in the regulation of body weight and glucose homeostasis in mice. / Morris, David L.; Cho, Kae Won; Rui, Liangyou.

In: Endocrinology, Vol. 151, No. 8, 08.2010, p. 3643-3651.

Research output: Contribution to journalArticle

Morris, David L. ; Cho, Kae Won ; Rui, Liangyou. / Critical role of the Src homology 2 (SH2) domain of neuronal SH2B1 in the regulation of body weight and glucose homeostasis in mice. In: Endocrinology. 2010 ; Vol. 151, No. 8. pp. 3643-3651.
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