Research ArticleMetabolism

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

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Science Translational Medicine  28 Apr 2021:
Vol. 13, Issue 591, eabe2587
DOI: 10.1126/scitranslmed.abe2587

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Inflaming insulin resistance

Patients with the developmental disorder Noonan syndrome (NS) may be prone to insulin resistance. Studying the hyperactivation of tyrosine phosphatase SHP2 associated with this disease, Paccoud et al. now pinpoint an inflammatory origin of insulin resistance. Hyperactivation of SHP2 associated with glucose intolerance and insulin resistance in patients with NS. In a hyperactive SHP2 mouse model, bone marrow–derived and liver-resident macrophages shifted toward a proinflammatory profile, leading to altered systemic glucose homeostasis. Small-molecule targeting of SHP2 in wild-type diet-induced obese mice reduced inflammation in metabolic tissues and improved insulin sensitivity, hinting at the potential of targeting SHP2 for metabolic syndrome.

Abstract

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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