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

  • Diabetes Obes Metab. 2026 Jun;28(6):4741-4758. doi: 10.1111/dom.70655.
Rui Ma  1  2 ,  Liyuan Ran  2  3 ,  Jinyang Geng  1  2 ,  Yue Zhang  4 ,  Jie Liu  1 ,  Zichao Yu  5 ,  Bin Liang  6 ,  Li Qiang  7 ,  Yingjie Wu  1  2
Affiliations
  • 1. Institute for Genome Engineered Animal Models of Human Diseases, National Center of Genetically Engineered Animal Models for International Research, Liaoning Province Key Lab of Genetically Engineered Animal Models, Dalian Medical University, Dalian, China.
  • 2. Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Institute of Laboratory Animal Models, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China.
  • 3. Metabolism and Disease Research Center, Central Hospital Affiliated to Shandong First Medical University, Jinan, China.
  • 4. Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology & Visual Science Key Laboratory, Beijing, China.
  • 5. School of Laboratory Animal & Shandong Laboratory Animal Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China.
  • 6. Center for Life Sciences, School of Life Sciences, Yunnan University, Kunming, Yunnan, China.
  • 7. Department of Physiology‌, Peking University‌, Beijing, China.
PMID: 41847844 DOI: 10.1111/dom.70655
Abstract

Objective: Global growth hormone receptor knockout (GHR-/-) extends lifespan but also causes adverse effects. As a key target of growth hormone (GH), adipose tissue may mediate aging, though the underlying mechanisms remain unclear. We investigated how adipose-specific GHR ablation influences multisystem aging, with a focus on metabolic health and cognitive function.

Methods: We generated adipose-specific GHR knockout (Ad-GHRKO) mice and assessed healthspan parameters including cognitive function, musculoskeletal integrity and metabolic profiles. Adipose tissue remodelling and inflammation were examined by histology and protein analysis. Subcutaneous white adipose transcriptomics identified gene expression changes. The role of the AMPK-SIRT1-Ac-PPARγ pathway in metabolic elasticity and aging was elucidated by Western blot and in vitro assays.

Results: Ad-GHRKO mice exhibited extended healthspan, with enhanced cognitive performance, improved muscle strength and bone mass and a lifespan increase trend. Mechanistically, GHR ablation remodelled adipose tissue, reducing age-related lipid redistribution, restoring glucose homeostasis and creating a low-inflammation, high-plasticity depot. This reprogramming boosted systemic metabolic elasticity primarily via AMPK-SIRT1-Ac-PPARγ activation. AMPK inhibition abolished benefits, confirming its pivotal role.

Conclusion: Our findings identify adipose-specific GH signalling antagonism as a regulatory switch that recalibrates the local balance between GH and IGF-1 actions, thereby reprogramming adipose tissue to promote coordinated systemin metabolic resilience during aging. This tissue-targeted strategy circumvents the developmental and endocrine limitations associated with global GH/IGF-1 suppression. Rather than merely extending lifespan, adipose-specific GHR ablation supports healthier aging by preserving metabolic homeostasis, maintaining multisystem functional integrity and reducing age-associated inflammatory and fibrotic remodelling. Collectively, these results highlight a potentially translatable approach for mitigating age-related metabolic and cognitive decline.

Keywords
adipose tissue; adipose tissue remodelling; aging; growth hormone receptor; metabolic elasticity.
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