August 25, 2022

Inflammatory driver of obesity

Blocking the EGF receptor signaling pathway in immune system macrophages represents a new target for improving insulin resistance in people with obesity.

Insulin resistance can develop in those with obesity, with chronic inflammation being a key mediator. Macrophages (a type of immune cell) produce inflammatory signals that exacerbate dysfunction in adipose tissue, but their regulation in obesity is unknown. 

Ming-Zhi Zhang, MD, MSc, Raymond Harris, MD, and colleagues used mice given a high-fat diet to elucidate that epidermal growth factor receptor (EGFR) signaling induces insulin resistance.  

EGFR and its ligand, amphiregulin, were upregulated specifically in macrophages, leading to macrophage migration, proliferation, and accumulation in adipose tissue where they released pro-inflammatory factors.  

Deletion or pharmacological inhibition of EGFR in the macrophage lineage reduced insulin resistance in the presence of a high-fat diet, highlighting a potential therapeutic for obesity-induced insulin resistance. 

These findings, reported in Nature Communications, support that EGFR activation of adipose tissue macrophages contributes to the pathophysiology of obesity and identify a target for ameliorating insulin resistance.

These studies were supported by the National Institutes of Health (grants DK051265, DK095785, DK062794, DK114809, DK059637), Department of Veterans Affairs, Vanderbilt Center for Kidney Disease and National Natural Science Foundation of China.