Related Experiment Video

Updated: Nov 7, 2025

Isolation, Characterization, and Purification of Macrophages from Tissues Affected by Obesity-related Inflammation
07:46

Isolation, Characterization, and Purification of Macrophages from Tissues Affected by Obesity-related Inflammation

Published on: April 3, 2017

25.6K

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

Romain Paccoud1, Céline Saint-Laurent1,2, Enzo Piccolo1,2

  • 1Institut des Maladies Métaboliques et Cardiovasculaires, INSERM UMR 1048, Université Paul Sabatier, Université de Toulouse, Toulouse F-31432, France.

Science Translational Medicine
|April 29, 2021
PubMed

Insights

Hyperactive SHP2 causes insulin resistance through inflammation, not fat issues. Inhibiting SHP2 improves insulin sensitivity by reducing inflammation and macrophage activation, offering a new therapeutic target.

Area of Science:

  • Endocrinology
  • Immunology
  • Metabolic Diseases

Background:

  • Insulin resistance is central to type 2 diabetes and obesity.
  • Mechanisms linking fat excess to insulin resistance, like lipotoxicity and metaflammation, are complex.
  • Noonan syndrome (NS) involves SHP2 hyperactivation, but its metabolic impact is unclear.

Purpose of the Study:

  • To investigate the role of SHP2 hyperactivation in insulin resistance.
  • To explore the mechanisms underlying SHP2-associated metabolic dysfunction.
  • To evaluate SHP2 inhibition as a therapeutic strategy for insulin resistance.

Main Methods:

  • Studied insulin resistance in Noonan syndrome patients and a mouse model with hyperactive SHP2.
  • Utilized bone marrow transplantation and macrophage depletion in mice.
  • Performed in vitro and in vivo analyses of macrophages (bone marrow-derived and liver).
  • Administered pharmaceutical SHP2 inhibitors to obese diabetic mice.

Main Results:

  • SHP2 hyperactivation caused insulin resistance independent of lipid abnormalities.
  • Insulin resistance in the NS mouse model correlated with tissue metaflammation.
  • Macrophage manipulation (transplantation, depletion) improved glucose homeostasis and reduced metaflammation.
  • Hyperactive SHP2 in macrophages promoted inflammation, altered macrophage homeostasis, and increased monocyte infiltration.
  • SHP2 inhibition in obese diabetic mice improved insulin sensitivity, reduced metaflammation, and decreased macrophage activation.

Conclusions:

  • SHP2 hyperactivation drives insulin resistance via inflammation, particularly involving macrophages.
  • SHP2 plays a critical role in metaflammation and metabolic impairment.
  • Targeting SHP2 with inhibitors presents a promising therapeutic approach for insulin resistance and related metabolic disorders.

More Related Videos

Investigation of Macrophage Polarization Using Bone Marrow Derived Macrophages10:07

Investigation of Macrophage Polarization Using Bone Marrow Derived Macrophages

Published on: June 23, 2013

67.5K
Live Images of GLUT4 Protein Trafficking in Mouse Primary Hypothalamic Neurons Using Deconvolution Microscopy08:47

Live Images of GLUT4 Protein Trafficking in Mouse Primary Hypothalamic Neurons Using Deconvolution Microscopy

Published on: December 7, 2017

10.0K

Related Concept Videos

Insulin: The Receptor and Signaling Pathways01:28

Insulin: The Receptor and Signaling Pathways

Insulin action is mediated through a receptor tyrosine kinase, akin to the IGF-1 receptor. The number of receptors per cell varies significantly, from 40 on erythrocytes to 300,000 on adipocytes and hepatocytes. The insulin receptor consists of linked α/β subunit dimers, forming a heterotetramer glycoprotein with two extracellular α subunits and two β subunits spanning the membrane. The α subunits inhibit the inherent tyrosine kinase activity of the β subunits, but...
1.9K
Inflammation01:38

Inflammation

Overview
57.1K
The JAK-STAT Signaling Pathway01:20

The JAK-STAT Signaling Pathway

Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as  SH2...
9.9K
Cell Specific Gene Expression01:58

Cell Specific Gene Expression

Multicellular organisms contain a variety of structurally and functionally distinct cell types, but the DNA in all the cells originated from the same parent cells. The differences in the cells can be attributed to the differential gene expression. Liver cells, whose functions include detoxification of blood, production of bile to metabolize fats, and synthesis of proteins essential for metabolism, must express a specific set of genes to perform their functions. Gene expression also varies with...
14.4K