Sex-Specific transcriptomic changes in adipose tissue following adult-onset disruption of growth hormone receptor.

Abstract

Reduction in growth hormone (GH) signaling throughout life is known to extend lifespan and enhance healthspan in mice, and congenital GH receptor (GHR) mutations in both mice and humans confer protection against age-related diseases such as cancer, diabetes, and cognitive decline. To explore the health effects of disrupting GH action during adulthood, we previously generated adult-onset GHR knockout (6mGHRKO) mice by ablating GHR at 6 months of age. Both male and female 6mGHRKO mice exhibited reduced oxidative stress, with males showing improved insulin sensitivity and resistance to cancer, while females demonstrated extended lifespan. In the current study, we performed RNA sequencing on subcutaneous adipose tissue (Subq AT) from 6mGHRKO and control mice to investigate molecular mechanisms underlying these health benefits. Differential gene expression, gene ontology, pathway enrichment, and upstream regulator analyses revealed that GHR ablation predominantly downregulated gene expression, particularly in males. Sex-specific gene expression differences were more pronounced in control mice than in 6mGHRKO counterparts. Among the enriched processes, pathways related to extracellular matrix (ECM) organization emerged as differentially regulated between sexes and genotypes. These transcriptomic findings are exploratory and hypothesis-generating, highlighting ECM remodeling as a potential area for future mechanistic validation.