Brain insulin receptor gene network shapes risk for metabolic disease after early-life stress in women

Stress happening during critical periods of development shapes individual physiology and increases the risk for obesity, inflammatory, and metabolic disturbances throughout life. However, there are individual differences and not everyone exposed to stress or adversity early during development develops chronic adult disease. Insulin regulates peripheral glucose metabolism, acts as a neuromodulator in the brain, and is possibly implicated in individual differences in response to early adversity. Expression-based polygenic scores (ePRS) reflect variations in the expression of a tissue-specific gene co-expression network. We have previously shown that brain-based insulin receptor ePRS (ePRS-IR) can identify risk for metabolic and frailty outcomes in older adults. Here, we show that the mesocorticolimbic ePRS-IR moderates the association between early adversity and increased visceral adipose tissue as well as metabolic syndrome in a large sample of adult women (UK Biobank). These findings suggest that variations in the function of the brain insulin receptor network influence the susceptibility to the long-term effects of adversity, highlighting a target system for prevention and novel treatments.