Lifestyle factors, including social relationships and diet, influence mood homeostasis, a mechanism often dysregulated in high-incidence mental illnesses like depression and Alzheimer’s dementia (AD). Given that insulin-like growth factor 1 (IGF-1) modulates mood and its blood levels are altered in both AD and affective disorders, we investigated whether IGF-1 activity in the brain was affected in mice subjected to social isolation or a high-fat diet (HFD). We found that both lifestyle conditions increased anxiety and depression-like behavior in C57BL/6 mice of both sexes, as determined by the elevated zero maze/open field tests and the forced swim test, respectively. These lifestyle conditions were associated with loss of neuronal responses to systemic IGF-1. Enhanced neuronal activity in the prefrontal cortex—measured via Ca⁺⁺ fiber photometry following intraperitoneal IGF-1 administration—was absent in both socially isolated and HFD-fed mice. However, only the HFD-fed group exhibited elevated serum IGF-1 levels. These findings suggest that loss of brain IGF-1 input may contribute to the observed mood disturbances, providing potential new targets to explore the heightened risk of depression and AD associated with loneliness and unhealthy diets in humans. Importantly, because reduced IGF-1 activity in the brain is not consistently reflected in serum levels, serum measurements are an unreliable indicator of brain IGF-1 activity.