Sex-specific effects of GnIH on lipid metabolism in SD rats.

Gonadotropin-inhibitory hormone (GnIH) is a neuropeptide pivotal in reproduction, which has recently been implicated in appetite-driven obesity among mammals. Yet, its functions in metabolic homeostasis and sex-specific lipid regulation remain largely underexplored. In this study, we found that GnIH administration initially caused weight gain and increased food intake in both male and female rats within 2 weeks. However, at week 6, male rats receiving high-dose (10 μg/100 μL) GnIH gained weight, while female rats receiving low-dose (1 μg/100 μL) GnIH lost weight. In addition, high-dose GnIH increased organ weight and glucose levels in male rats, while reduced white adipose tissues (WAT) and raised triglycerides in females. Histologically, GnIH dose-dependently increased hepatic lipid vacuoles in male rats, while female rats exhibited nuclear swelling and cellular damage. Mechanistically, GnIH exhibited sex-specific effects on hepatic lipid metabolism. In male rats, it enhanced lipogenesis through the upregulation of microsomal triglyceride transfer protein (MTP) and CCAAT/enhancer binding protein (c/EBP), while inhibiting lipolysis via reduced peroxisome proliferator-activated receptor γ (PPARγ), Adiponectin (ADPN), and AMP-activated protein kinase α (AMPKα) phosphorylation. Conversely, female rats treated with GnIH displayed diminished MTP expression alongside elevated lipolysis. In WAT, GnIH promoted lipogenesis in male rats, evidenced by increased fatty acid synthase (FASN), stearoyl-CoA desaturase (SCD), and c/EBP levels. However, it suppressed this process in females even though lipolytic markers such as ADPN and PPARγ were elevated in both sexes. Overall, GnIH exerts distinct sex-specific effects on lipid metabolism, promoting anabolic pathways in males while triggering catabolic responses in females. These findings highlight the complex role of GnIH in energy homeostasis and underscore its potential as a target for sex-specific therapeutic interventions in metabolic disorders.