Early-life sex hormone deficiency promotes beneficial remodeling in white adipose tissue and whole-body metabolism

Abstract

Aims: This study investigates the impact of female sex hormone deficiency (FSHD) on white adipose tissue (WAT) development, focusing on two distinct depots: retroperitoneal adipose tissue (RPAT) and inguinal adipose tissue (IAT).Materials and methods: Prepubertal ovariectomy was performed, and animals were pair-fed (FSHD-PF) to account for hyperphagia.Key findings: FSHD-PF animals exhibited reduced plasma triglyceride and insulin levels, with improved glucose handling. A redistribution of adipose tissue was observed, with increased IAT mass and decreased RPAT mass, accompanied by a reduction in adipocyte size in RPAT. Expression markers of inflammation, such as ob and tnf-α, were significantly decreased in RPAT of FSHD-PF, suggesting a potential reduction in the inflammatory state. Likewise, we found that prepubertal ovariectomy also modulated adipocyte precursor cells (APCs), leading to increased cd34 expression in both depots, indicative of greater competency. However, RPAT showed elevatedpparγ-2 levels, while IAT exhibited increased wnt10b, suggesting a depot-specific regulation. Notably, IATderived APCs from FSHD-PF animals display enhanced differentiation capacity in vitro. Cold exposure further modulated WAT browning, with a notable increase in UCP-1 protein expression although observed in IAT from FSHD-PF rats only.Significance: This study is the first to examine FSHD in the context of WAT development, identifying early-life ovarian hormone loss as a critical and previously underexplored determinant of metabolic regulation. Accordingly, the consequences of early FSHD, together with its association with non-shivering thermogenesis, emerge as promising areas for further investigation with potential therapeutic relevance.