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

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.

Targeting protein phosphatases for the treatment of inflammation-related diseases: From signaling to therapy

“…By contrast, depletion of macrophages or pharmacological inhibition of SHP2 improved insulin sensitivity and reduced metaflammation. 84 Choi et al similarly showed that insulin stimulation triggered a negative feedback pathway involving SHP2-MAPK that phosphorylated the insulin receptor substrate 1/2 and then promoted endocytosis, which inhibited the insulin receptor-mediated activation of PI3K-AKT signaling. 85 SHP099, an allosteric inhibitor of SHP2, blocked this feedback regulation, prolonged insulin action on metabolism, and improved insulin sensitivity in a high-fat-diet-induced mouse model of diabetes.…”

SHP2/SPI1axis promotes glycolysis and the inflammatory response of macrophages in Helicobacter pylori‐induced pediatric gastritis

“…SHP2 is closely associated with the immune response, cancer development, cellular metabolism, and cell growth 33,34 . Additionally, SHP2 has been shown to promote a proinflammatory phenotype of macrophages, modify resident macrophage homeostasis, and trigger monocyte infiltration 35 . Thus, higher expression of SHP2 might regulate the function of macrophages in H. pylori ‐associated gastritis tissue.…”

Nonresolving inflammation redux

“…Enzyme targets include cGAS ( Ablasser and Chen, 2019 ); the kinases JAK1/2 ( Hoang et al., 2021 ), ephrin-B3 ( Clark et al., 2021 ), and Fgr ( Crainiciuc et al., 2022 ); the tyrosine phosphatase SHP2 ( Paccoud et al., 2021 ); the proteases proprotein convertase subtilisin/Kexin 9 (PCSK 9) ( Patriki et al., 2022 ) and the immunoproteasome ( Ah Kioon et al., 2021 ; Kirk et al., 2021 ); the 8-oxoguanine DNA glycosylase OGG-1 ( Visnes et al., 2018 ); and the histone 3 Lys27 trimethyltransferase Ezh2 ( Zhang et al., 2018 ). Adaptor protein targets include STING ( Ablasser and Chen, 2019 ) and NRLP3 ( Wang et al., 2022 ).…”