Intermittent fasting reverses age- and obesity- associated adipose fibrosis through circadian reprogramming of adipose precursor cells.

Abstract Aging is a crucial factor for tissue fibrosis that is closely associated with the functional decline of various organs. Fibrosis of white adipose tissue (WAT) is a hallmark of dysfunctional WAT that is directly linked to age- and obesity-associated metabolic abnormalities. Recent studies have highlighted the role of dysfunctional adipose progenitor cells (APCs) in WAT fibrosis and impaired adaptive tissue plasticity, leading to systemic insulin resistance. However, therapeutic options for WAT fibrosis are limited. Intermittent fasting (IF) is an effective dietary regimen for weight control and metabolic improvement through various mechanisms. Here, we show that IF confers therapeutic benefits in aged and obese mice through the reduction of WAT fibrosis. Single-cell analyses revealed that IF significantly reduces fibrotic signatures within APCs along with the upregulation of circadian pathways. Importantly, mice lacking a core circadian gene exhibited increased fibrotic signatures in WAT and diminished beneficial response to IF, indicating the requirement of functional circadian rhythm in IF-induced WAT remodeling. Lastly, we observed that a dysregulated circadian rhythm in human APCs is associated with WAT fibrosis and insulin resistance. Collectively, our findings highlight the novel role of the APC circadian rhythm in the plasticity of WAT and the metabolic response to IF.