Adipose-Specific GHR Knockout Confers Multidimensional Anti-Aging Advantages via Adipose Tissue Remodeling and Enhanced Metabolic Elasticity

The global growth hormone receptor knockout (GHR-/-) extends lifespan but causes adverse effects. Adipose tissue serves as a critical target organ for growth hormone (GH). Recent studies have suggested that GH signaling in adipose tissue influences aging progression, but the underlying regulatory mechanisms remain poorly understood. We generated adipose-specific GHR knockout mice (Ad-GHRKO; hereafter termed AKO) using 5-month-old and 20-month-old C57BL/6J males. The crucial function of adipose tissue GHR was examined by assessing age-related changes in mice during advanced aging. Adipose-specific GHR knockout extended healthspan through multifaceted geroprotection, manifested as significantly improved cognitive function, enhanced muscular/skeletal integrity, and a trend toward increased longevity. Mechanistically, adipose remodeling alleviated age-related lipid redistribution and restored glucose homeostasis, establishing a low-inflammation, high-plasticity depot that enhanced inter-tissue communication. Notably, we discovered that AKO mice exhibited significantly improved metabolic elasticity in adipose tissue. This enhancement is mechanistically linked to activation of the AMPK-SIRT1-Ac-PPARγ signaling axis. In vitro, pharmacological inhibition of AMPK abolished the beneficial effects of GHR ablation, confirming the central regulatory role of this pathway in maintaining adipose elasticity. These findings establish adipose GH signaling antagonism as a novel "metabolic elasticity switch" during aging, orchestrating adipose tissue to initiate reprogramming cascades that enhance metabolic elasticity and modulate healthspan through dynamic regulatory capacity rather than absolute activity levels, circumventing the adverse effects of systemic GH deficiency. These results resolve a critical knowledge gap in understanding how localized hormonal signaling in adipose tissue influences systemic aging trajectories. Our findings lay the foundation for developing targeted therapeutic strategies to mitigate age-related metabolic decline.