Model Animal Research Center

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. 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 invitro assays. 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. 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.

The forecast skill of the Probability Matching Method (PMM) was evaluated based on ensemble precipitation forecasts over New Zealand, with a detailed analysis of the influence of New Zealand's topography. This study used New Zealand ensemble forecast data in 2023 and employed multiple objective verification methods to statistically analyze the difference in performance of PMM over mountainous and plain areas of New Zealand. Results indicate that topographic factors cause significant differences in the skill of the ensemble mean (EM) and PMM between mountainous and plain regions of New Zealand. In the mountainous areas of New Zealand, the performance of the EM is largely comparable to, or slightly better than, PMM. In contrast, PMM outperforms the EM over plain areas. The primary reason for this difference is that the most precipitation affecting New Zealand, moving from west to east, first encounters the western mountainous regions. The unified topography induces uplift motions in all ensemble members, resulting in high spatial consistency in precipitation patterns over the mountains. The smoothing effect caused by inter-member differences is thus weaker. Over plain areas, however, the lack of uniform topographic forcing makes precipitation more sensitive to differences in flow-over-mountain conditions and local thermal-dynamic conditions, leading to greater relative differences among members. Consequently, PMM exhibits higher forecast skill relative to the EM in plains. This also gives PMM a greater advantage over the North Island of New Zealand, as the topographic influence is more dominant in the South Island.

Pancreatic β cell homeostasis involving their proliferation, growth, and apoptosis is critical for postprandial insulin levels and glycaemic control. The regulatory mechanisms governing β cell homeostasis and insulin secretion are incompletely understood. This study aims to elucidate the role of Ral-GTPase activating protein (RalGAP) complexes in β cell homeostasis and insulin secretion. Pancreatic β cell-specific RalGAPβ knockout mice and RalGAPβ-knockdown INS-1 cells were constructed for studying the pancreatic function of RalGAP complexes. Metabolic phenotyping, immunoblotting, RT-QPCR, glucose-stimulated insulin secretion (GSIS), proliferation and apoptosis assays, RNA-sequencing and metabolomic profiling were performed. High-fat diet increased RalGAP complex and concomitantly decreased GTP-bound active RalA in pancreatic islets. Deletion of RalGAPβ, a common regulatory subunit of RalGAP complexes, destabilised RalGAPα1/α2 and elevated GTP-RalA in β cells. RalGAPβ deficiency promoted proliferation of β cells, increased their sizes, and inhibited streptozotocin-induced β cell apoptosis. Moreover, β cell-specific deletion of RalGAPβ enhanced KCl-stimulated insulin secretion in isolated islets as well as GSIS in vivo. Consequently, RalGAPβ deletion in β cells improved glucose tolerance in mice fed a chow or high-fat diet. At the molecular level, RalGAPβ deletion may reset the glucostat consisting of GLUT1 and GLUT2 to modulate glycemic set point. Furthermore, RalGAPβ deficiency elevated p70 S6-kinase in islets, whose inhibition abrogated RalGAPβ deficiency-induced β cell proliferation. RalGAP complexes function as a critical regulator of both β cell homeostasis and insulin secretion. Our results have implications for the discovery of drugs targeting RalGAP complexes to protect β cells in type 2 diabetes.

Mitochondria coordinate with lysosomes to maintain cellular homeomstasis. However, in mitochondrial defect condition, how they communicate is less clear. Here, utilizing dMterf4 RNAi fly model, we find that expression of lysosomal alpha-mannosidase VI (LManVI) is significantly downregulated. Mechanistically, we show that dMterf4 RNAi-triggered mitochondrial defect mediates downregulation of lysosomal LManVI through Med8/Tfb4-E(z)/pho axis, causing impairment of lysosomal function. Reciprocally, downregulation of lysosomal LManVI further decreases many mitochondrial genes expression through downregulation of transcriptional coactivator PGC-1, leading to aggravating the dMterf4 RNAi-mediated mitochondrial defect, suggesting that mitochondrial defect can crosstalk with lysosomes to make mitochondrial status worse in a positive feedback way. Finally, we demarcate that this interaction between mitochondria and lysosomes may be conserved in mammalian cells. Therefore, our findings unveil a communication mechanism between mitochondria and lysosomes in mitochondrial defect case, which provides insights about the treatments of related mitochondrial and lysosomal diseases through modulation of the mitochondria-lysosomes axis.

Mouse models serve as the most important laboratory resource for both biomedical research and preclinical study of drug development. National Resource Center of Mutant Mice (NRCMM) of China was initiated in 2001 and became one of the 31 members of National Science and Technology Resource Sharing Platform in 2019. Currently, NRCMM is co-managed by Model Animal Research Center of Nanjing University and Gempharmatech (GPT, a Shanghai Exchange enlisted public company). Dedicated to produce and collect genetic edited mouse models, NRCMM holds more than 22,000 mouse strains in 2024, compared with 18,500 strains reported in 2022. This review provides an update on our Knock-Out All Project (KOAP) and highlights resources available for immune system reconstitution models, disease models, and chromosome substitution strains at NRCMM.