The transition through menopause brings metabolic shifts that can destabilize weight regulation for decades, yet the hormonal mechanisms governing these changes remain poorly mapped. Understanding which biomarkers predict favorable weight trajectories could transform preventive care for the 1.1 billion postmenopausal women worldwide. This analysis of 4,020 participants from the landmark Women's Health Initiative reveals that asprosin—a relatively recently discovered adipokine released during fasting states—may serve as a protective factor against weight gain, but only in specific populations. Among non-obese postmenopausal women (BMI under 30), those with the highest baseline asprosin levels gained 1.61 kg less over three years compared to women with the lowest levels. This protective effect disappeared entirely in obese participants, suggesting asprosin's metabolic influence becomes dysregulated at higher body weights. The study tracked participants for three years using rigorous body composition measurements, including DXA scans in a subset, making it the largest prospective investigation of asprosin's role in postmenopausal weight regulation. Asprosin operates through multiple pathways—stimulating hepatic glucose production while influencing appetite centers in the hypothalamus. This dual action theoretically positions it as both a metabolic signal and appetite regulator, though previous research has focused mainly on its role in diabetes rather than weight stability. The finding that asprosin's protective effects are BMI-dependent suggests the hormone may function differently across metabolic states, potentially becoming less effective as insulin resistance develops. For clinical practice, this research introduces asprosin as a candidate biomarker for identifying postmenopausal women at lower risk for weight gain, though the mechanism remains correlative rather than causal.