Interplay between obesity-associated insulin resistance and immune system through the lens of evolutionary medicine

Insulin resistance (IR), commonly associated with obesity, is linked to a range of metabolic and immune-related disorders in the contemporary human population. Nevertheless, it is evolutionary well-conserved, suggesting its potential survival advantages to our ancestors. This review aims to explore the intricate interplay between IR and the immune system as well as its implications for the development of immune-metabolic and allergic diseases in the modern era. From an evolutionary medicine perspective, the longevity of ancient humans relied on energy storage to endure food shortages and effectively activate the immune system against various diseases. Under normal conditions, insulin induces glycogen and triglyceride synthesis in the liver and adipose tissues. However, IR directs more glucose to insulin-independent tissues, such as the immune system, which are critical for survival in adverse conditions. The persistent IR in our current lifestyle promotes low-grade inflammation, accompanied by various metabolic and allergic disorders. Critically, this evolutionary mismatch not only explains disease susceptibility but also informs therapeutic design to target immune-metabolic crosstalk. Moreover, our evolutionary analysis demonstrates that the genomic regions near the PTEN, IL27, and NUPR1 genes could play an important role in this interaction across diverse populations.