Purpose of Perspective <p>This perspective aims to propose a mechanomedicine framework integrating the body’s intrinsic “mechanical intelligence” (MI) with artificial intelligence (AI), offering new potential approaches for diagnosis and treatment of weight rebound.</p> Recent Findings <p>Weight rebound after weight loss remains a significant challenge in obesity management. Traditional explanations focus on hormonal and metabolic adaptations, but emerging evidence underscores the importance of mechanical cues in adipose tissue. Persistent fibrosis and extracellular matrix (ECM) stiffness after weight loss may create a mechanical memory that favors weight rebound. We explore the biomechanics of adipose tissue during weight fluctuations, highlight the potential role of mechanobiology, and examine how AI help enhance mechanodiagnostics and mechanotherapy.</p> Summary <p>Both physiological and mechanical factors contribute to weight rebound after initial loss. The integration of MI (biomechanics and mechanobiology) in adipose tissue with AI-driven mechanodiagnostics and mechanotherapy may offer a novel perspective and promising future solutions to prevent weight rebound and transform obesity treatment.</p>