Obesity and mitochondrial uncoupling – an opportunity for the carbon monoxide-based pharmacology of metabolic diseases

Obesity, a chronic and progressive disease with a complex etiology, remains a significant global health challenge. Despite advancements in lifestyle interventions, pharmacological therapies, and bariatric surgery, substantial barriers to effective and sustained obesity management persist. Resistance to weight loss and gradual weight regain are commonly reported, limiting the long-term success of both non-pharmacological and pharmacological strategies. A possible contributor is metabolic adaptation, a phenomenon characterized by reduced metabolic rate and energy expenditure following weight loss, which hinders therapeutic efficacy. To address these challenges, increasing attention has been directed toward strategies that counteract maladaptive mechanisms by modulating metabolic rate and enhancing energy expenditure. One promising approach involves mitochondrial uncoupling, where electron transport and oxygen consumption are disconnected from ATP synthesis, promoting energy dissipation. Preclinical studies have demonstrated the potential of various chemical compounds with uncoupling activity as anti-obesity agents. Additionally, carbon monoxide (CO) has emerged as a significant gaseous signaling molecule in human physiology, with anti-inflammatory, antioxidative, and cytoprotective properties. Advances in CO-based pharmacology have led to the development of controlled-release CO donors, enabling precise therapeutic application. Experimental studies suggest that CO modulates mitochondrial bioenergetics, induces mild mitochondrial uncoupling, and regulates mitochondrial biogenesis. By integrating these findings, this review uniquely connects scientific threads, offering a comprehensive synthesis of current knowledge while proposing innovative directions in mitochondrial, metabolic and CO-based pharmacological research. It highlights the potential of CO-based pharmacology to regulate metabolic rate, support weight loss, and address obesity-related dysfunctions, thus suggesting novel pathways for advancing obesity treatment.