Carbon monoxide-releasing molecule CORM-401 treatment elicits corticosterone-driven stress lipolysis and tissue-specific hypoxia-inducible factor activation

Metabolic syndrome is a global health concern characterized by obesity, insulin resistance, dyslipidemia, and hypertension - all of which increase risk of cardiovascular diseases and type 2 diabetes. CO-releasing molecules (CORMs) deliver low amounts of CO in vivo and have been reported to improve metabolic parameters in obese mice by inducing a transient mitochondrial uncoupling and improving insulin resistance. CO reduces oxygen-binding capacity of hemoglobin, which may cause tissue hypoxia and mediate metabolic alterations through the hypoxia-inducible factor (HIF) pathway. This study: 1) Analyzes whether the beneficial metabolic effects of CORMs are mediated by the HIF pathway, and 2) Evaluates the metabolic effects of long-term CORM-401 treatment in high-fat diet-fed mice. A 7-week-treatment of CORM-401 elicited a metabolic phenotype characterized by significantly reduced body weight and white adipose tissue (WAT) mass, increased energy expenditure and glucose tolerance, and higher LDL + VLDL cholesterol levels. CORM-treatment triggered lactatemia-induced metabolic acidosis which was compensated through increased respiration. No toxicity or organ damage was seen. HIF target mRNA levels were positively associated with carboxyhemoglobin levels in the CORM-401-treated tissues. CORM-401-treated mice exhibited elevated serum corticosterone levels, which showed associations with metabolic mRNAs in WAT and liver. These findings suggest a dual mechanism: glucocorticoid-driven stress activation as the primary mechanism accompanied by a low-grade, tissue specific HIF engagement underlying the observed metabolic effects of the CORM-401 treatment. Despite the mild beneficial effects on metabolism, the systemic hormonal effects of the long-term CORM-401 treatment warrant caution when evaluating its potential as a therapeutic for metabolic disorders.