Version 2 2020-12-18, 00:31Version 2 2020-12-18, 00:31
Version 1 2020-11-19, 16:10Version 1 2020-11-19, 16:10
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posted on 2020-12-18, 00:31authored byJessica L. Cote, Lawrence S. Argetsinger, Anabel Flores, Alan C. Rupp, Joel M. Cline, Lauren C. DeSantis, Alexander H. Bedard, Devika P. Bagchi, Paul B. Vander, Abrielle M. Cacciaglia, Erik S. Clutter, Gowri Chandrashekar, Ormond A. MacDougald, Martin G. Myers, Jr, Christin Carter-Su
Mice lacking SH2B1 and humans with inactivating
mutations of SH2B1 display severe obesity and insulin resistance. SH2B1 is an adapter protein
that is recruited to the receptors of multiple hormones and neurotrophic
factors. Of the four known
alternatively-spliced SH2B1isoforms, SH2B1b and SH2B1g exhibit
ubiquitous expression, whereas SH2B1a and SH2B1d are
essentially restricted to the brain. To understand the roles for SH2B1a and SH2B1d in energy
balance and glucose metabolism, we generated mice lacking these brain-specific isoforms
(adKO
mice). adKO mice exhibit decreased food intake, protection from
weight gain on standard and high fat diets, and an adiposity-dependent
improvement in glucose homeostasis. SH2B1 has been suggested to impact energy
balance via the modulation of leptin action. However, adKO mice exhibit leptin sensitivity that
is similar to that of wild-type mice by multiple measures. Thus, decreasing the
abundance of SH2B1a and/or SH2B1d relative to the other SH2B1 isoforms
likely shifts energy balance towards a lean phenotype via a primarily leptin-independent
mechanism. Our findings
suggest that the different alternatively-spliced isoforms of SH2B1 perform
different functions invivo.
Funding
This research was supported by National Institutes of Health grants R01-DK-054222 and R01-DK-107730 (to C.C.-S.), R01-DK-056731 (to M.G.M.), and R01-DK-062876 and R01-DK-092759 (to O.A.M.).