Clomiphene Citrate Ameliorates Hyperglycemic Phenotype Induced by Catch-Up Growth in Stunting-Like Drosophila

Abstract

Catch-up growth following early life undernutrition is a major risk factor for metabolic dysfunction, including insulin resistance and type 2 diabetes mellitus. Here, we developed a Drosophila melanogaster model of catch-up-growth-associated metabolic dysregulation and used clomiphene citrate (CC) as a pharmacological probe to explore conserved metabolic regulatory pathways. Larvae were maintained on a low-calorie diet until the early third instar and subsequently returned to a standard diet to induce compensatory growth. Metabolic phenotyping included glucose levels, reactive oxygen species (ROS), triglycerides, locomotor performance, and transcriptional analysis of insulin- and hormone-related regulators (dilp2, dInR, dPHM, and dHNF4). Catch-up growth flies exhibited sustained hyperglycemia, elevated ROS, and increased triglyceride levels, indicating dysregulated glucose and lipid homeostasis, while locomotor function remained relatively preserved at the early adult stages. CC supplementation was associated with attenuation of hyperglycemia and oxidative stress, together with modulation of insulin- and hormone-related transcriptional markers. Molecular docking and molecular dynamics simulations provided hypothesis-generating structural insights into potential interactions of CC with metabolic regulators. Collectively, these findings establish Drosophila as a tractable model for investigating early-stage metabolic consequences of catch-up growth and support the use of CC as a tool compound for mechanistic exploration, while highlighting the need for further validation in mammalian systems.