SUN-652 Redefining Metabolic Regulation in Pathological Cachexia: Beyond UCP1-Dependent Thermogenesis

Abstract Disclosure: Z. Zhao: None. C. Auger: None. M. Li: None. J. Yook: None. M. Emont: None. T. Yamamuro: None. Y. Higuchi: None. M. Formato: None. H. Nishida: None. S. Kajimura: None. Cachexia of chronic disease is a complex and multifactorial syndrome characterized by disrupted energy homeostasis, a shift towards a catabolic state, and profound endocrine dysregulation. The underlying etiologies are both severe and chronic, such as cancer, heart failure, and burn injury. Cachexia affects an estimated nine million individuals in industrialized nations alone and has been correlated with increased morbidity and mortality. Despite its prevalence and gravity, we still lack a mechanistic understanding and an effective targeted therapy for cachexia. This highlights the critical need for a robust animal model to investigate the human pathophysiology of cachexia. Severe burn injury, involving more than 20% of total body surface area (TBSA), can trigger a characteristic and persistent hypermetabolic state. Thus, burn injury could serve as a robust system to study hypermetabolism in the context of cachexia. Previous studies highlight that severe burns promote the “browning” of subcutaneous white adipose tissue (sWAT) and activate brown adipose tissue (BAT). While both sWAT and BAT were implicated in burn-induced hypermetabolism, my results challenged the paradigm by demonstrating that UCP1, the canonical thermogenic protein, was not required for this response, as UCP1KO animals exhibited similar hypermetabolic phenotypes. Physiological and multi-omic studies (transcriptomic and proteomic) indicated that interorgan lipid mobilization increased after burn. Accordingly, my proposal aims to gain a deeper, mechanistic understanding of burn-induced hypermetabolism with a focus on UCP1-independent thermogenesis in adipose tissues. Key objectives include understanding the molecular and cellular changes in adipose depots post-burn, assessing the role of beige and brown adipocytes in metabolic homeostasis, and determining the bioenergetic contributions of UCP1-independent pathways to systemic hypermetabolism. Specifically, this project explores lipid futile cycling as an adaptive or maladaptive response to energy imbalance. Findings will inform whether lipid cycling represents a viable therapeutic strategy to ameliorate hypermetabolism in cachectic patients. Presentation: Sunday, July 13, 2025