Adipose FGF21 signalling mediates the anti‐senescence effects of protein restriction

Abstract Dietary protein restriction (PR) is a well‐recognized nutritional intervention that enhances metabolic health and extends lifespan. However, the mechanisms behind this phenomenon are not well understood. Here, using genetic loss‐of‐function models for fibroblast growth factor 21 ( Fgf21) and its obligate co‐receptor β‐Klotho ( Klb ), we demonstrate that FGF21–KLB signalling in adipocytes is indispensable for the anti‐senescence effects of PR. Specifically, adipocyte FGF21 signalling preserves mitochondrial integrity, maintains an anti‐inflammatory milieu and sustains nicotinamide adenine dinucleotide (NAD + ) homeostasis under PR. Mechanistically, FGF21 enhances adipocyte NAD + abundance through activation of AMP‐activated protein kinase to maintain mitochondrial integrity. Additionally, high‐protein feeding induces adipocyte senescence and metabolic dysfunction could be mitigated by exogenous FGF21 supplementation. Together, these findings establish adipose FGF21 signalling as a pivotal endocrine axis that couples dietary protein availability to adipocyte NAD + metabolism and identify it as a promising target for the prevention and treatment of age‐related metabolic disorders. image Key points Dietary protein restriction improves metabolic health and extends lifespan, but the mechanisms responsible for these benefits are not fully understood. Fibroblast growth factor 21 (FGF21) is a hormone strongly induced by low‐protein diets and has emerged as an important regulator of metabolic adaptation. We show that FGF21 signalling specifically in adipose tissue is essential for the anti‐senescence effects of dietary protein restriction. FGF21 preserves mitochondrial integrity by maintaining nicotinamide adenine dinucleotide metabolism through AMP‐activated protein kinase activation. Targeting the FGF21–adipose tissue pathway may provide new strategies to prevent or treat age‐related metabolic dysfunction.