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SHP2 drives inflammation-triggered insulin resistance by reshaping tissue macrophage populations.

Romain PaccoudCéline Saint-LaurentEnzo PiccoloMylène TajanAlizée DortignacOphélie PereiraSophie Le GonidecInès BabaAdélaïde GélineauHaoussa AskiaMaxime BranchereauJulie CharpentierJean PersonnazSophie BrankaJohanna AuriauSimon DeleruyelleMickaël CanouilNicolas BetonJean Pierre SallesMaïthé TauberJacques WeillPhilippe FroguelBenjamin G NeelToshiyuki ArakiChristophe HeymesRémy BurcelinIsabelle Castan-LaurellPhilippe ValetCédric DrayEmmanuel L GautierThomas EdouardJean-Philippe PradèreArmelle Yart
Published in: Science translational medicine (2021)
Insulin resistance is a key event in type 2 diabetes onset and a major comorbidity of obesity. It results from a combination of fat excess-triggered defects, including lipotoxicity and metaflammation, but the causal mechanisms remain difficult to identify. Here, we report that hyperactivation of the tyrosine phosphatase SHP2 found in Noonan syndrome (NS) led to an unsuspected insulin resistance profile uncoupled from altered lipid management (for example, obesity or ectopic lipid deposits) in both patients and mice. Functional exploration of an NS mouse model revealed this insulin resistance phenotype correlated with constitutive inflammation of tissues involved in the regulation of glucose metabolism. Bone marrow transplantation and macrophage depletion improved glucose homeostasis and decreased metaflammation in the mice, highlighting a key role of macrophages. In-depth analysis of bone marrow-derived macrophages in vitro and liver macrophages showed that hyperactive SHP2 promoted a proinflammatory phenotype, modified resident macrophage homeostasis, and triggered monocyte infiltration. Consistent with a role of SHP2 in promoting inflammation-driven insulin resistance, pharmaceutical SHP2 inhibition in obese diabetic mice improved insulin sensitivity even better than conventional antidiabetic molecules by specifically reducing metaflammation and alleviating macrophage activation. Together, these results reveal that SHP2 hyperactivation leads to inflammation-triggered metabolic impairments and highlight the therapeutical potential of SHP2 inhibition to ameliorate insulin resistance.
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