Hypoxia-inducible factor 1αa regulates lipid metabolism to coordinate adipocyte hypertrophy and hyperplasia in grass carp.

Obesity significantly burdens global health. Conversely, some animals efficiently store substantial fat during food abundance while maintaining metabolic health, offering unique insights into the mechanisms of healthy adipose expansion. Understanding these short-term physiological adaptations is therefore crucial. Here, using the grass carp (Ctenopharyngodon idellus) as a model, which exhibits remarkable fat storage capacity, we found that adipose tissue responded to energy overload first and expanded through adipocyte hypertrophy and hyperplasia. Mechanistically, hypoxia inducible factor 1αa (HIF1αa) was activated in mature adipocytes after short-term high-energy intake, thereby bidirectionally regulating adipose triglyceride lipase (ATGL) to drive healthy expansion of adipose tissue in grass carp: (1) HIF1αa downregulates ATGL protein levels via the ubiquitin-proteasome pathway, promoting adipocyte hypertrophy; (2) HIF1αa upregulates ATGL transcription to sustain basal lipolysis, releasing free fatty acids that activate peroxisome proliferator-activated receptor γ in preadipocytes to promote adipocyte hyperplasia. Crucially, unlike obese mice requiring 7 weeks, grass carp exhibited rapid adipocyte hyperplasia. This not only increases the energy storage limit but also prevents excessive hypertrophy of adipocytes. Taken together, our study reveals how grass carp utilizes hypoxia signal (a signal often associated with metabolic disorders in mammals) to coordinate the pattern of adipose tissue expansion, achieving rapid and healthy lipid storage. Our findings redefine hypoxia's role as a metabolic orchestrator rather than a stress indicator, providing a theoretical basis for addressing obesity-related diseases in humans caused by excessive energy intake.