Adipose FGF21 signalling mediates the anti-senescence effects of protein restriction.

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. 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.