Adaptations of glucagon-like peptide-1 receptor agonist-induced weight loss, drivers of weight regain and future directions of therapeutics.

Obesity, characterized by excess gain in body fat, alters energy balance and metabolic health. Weight loss is an effective strategy to favourably restore metabolic parameters in obese condition, and this can be achieved through caloric restriction, exercise, bariatric surgery and pharmacotherapy. Recently, glucagon-like peptide-1 receptor agonists (GLP-1RAs) and associated combination therapies have proven to be effective weight loss inducers that also contribute to improvements in glycaemia and lipidaemia. However, side effects and socioeconomic barriers often lead to treatment discontinuation, which raises concerns about the effects of cessation on metabolic health. Regardless of the weight loss method, weight regain is common, although its underlying mechanisms remain unclear. Recent research has explored factors such as metabolic adaptation, shifts in appetite-related hormones and changes in the adipose tissue to better understand these consequences. This review summarizes current knowledge on the metabolic and physiological responses to GLP-1RA-induced weight loss and provides insight into potential mechanisms of weight regain after GLP-1RA withdrawal. It also explores how emerging GLP-1RA-based combination therapies might help mitigate this challenge.