Spotlight on the Mechanism of Action of Semaglutide

Initially intended to control blood glucose levels in patients with type 2 diabetes, semaglutide, a potent glucagon-like peptide 1 analogue, has been established as an effective weight loss treatment by controlling appetite. Integrating the latest clinical trials, semaglutide in patients with or without diabetes presents significant therapeutic efficacy in ameliorating cardiometabolic risk factors and physical functioning, independent of body weight reduction. Semaglutide may modulate adipose tissue browning, which enhances human metabolism and exhibits possible benefits in skeletal muscle degeneration, accelerated by obesity and ageing. This may be attributed to anti-inflammatory, mitochondrial biogenesis, antioxidant and autophagy-regulating effects. However, most of the supporting evidence on the mechanistic actions of semaglutide is preclinical, demonstrated in rodents and not actually confirmed in humans, therefore warranting caution in the interpretation. This article aims to explore potential innovative molecular mechanisms of semaglutide action in restoring the balance of several interlinking aspects of metabolism, pointing to distinct functions in inflammation and oxidative stress in insulin-sensitive musculoskeletal and adipose tissues. Moreover, possible applications in protection from infections and anti-aging properties are discussed. Semaglutide enhancement of the core molecular mechanisms involved in the progress of obesity and diabetes, although mostly preclinical, may provide a framework for future research applications in human diseases overall.