Abstract
Leptin, an adipocyte-derived hormone, plays a crucial role in regulating food intake and energy homeostasis. However, individuals with obesity exhibit hyperleptinemia and impaired leptin responsiveness, which contribute to greater food intake, reduced energy expenditure, and metabolic dysregulation, exacerbating weight gain and obesity-related complications. Leptin resistance remains a major challenge in obesity treatment, limiting the efficacy of leptin-based therapies. G-protein coupled receptors (GPCRs) are a large family of seven-transmembrane (7TM) receptors that respond to a variety of ligands, including neuropeptides, gastrointestinal hormones, and metabolites. GPCRs are central regulators of glucose metabolism and energy balance, which have emerged as key drug targets for diabetes and obesity. Combining leptin with GPCR-targeting therapies, such as gut peptides, shows promise in overcoming leptin resistance and improving metabolic outcomes. Understanding the molecular crosstalk between leptin and GPCRs provides valuable insights for expanding leptin's therapeutic potential and developing effective anti-obesity treatments. In this review, we highlight the therapeutic potential of combining molecules targeting GPCR signaling with leptin for obesity treatment.