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Obesity-related metabolic diseases are characterized by profound disturbances in glucose and lipid metabolism across multiple organs, yet the mediators that coordinate these tissue-specific alterations remain incompletely understood. Insulin-like growth factor-binding protein 2 (IGFBP2), a circulating and locally expressed regulatory protein, has emerged as a context-dependent modulator of metabolic homeostasis with potential relevance to obesity, insulin resistance, type 2 diabetes mellitus (T2DM), and metabolic dysfunction-associated steatotic liver disease (MASLD). In this review, we integrate evidence from in vitro studies, animal models, and human investigations to examine the tissue-specific roles of IGFBP2 in the liver, adipose tissue, pancreas, skeletal muscle, and cardiovascular system. We further discuss IGFBP2 within an autocrine, paracrine, and endocrine framework, with emphasis on its effects on glucose handling, lipid metabolism, insulin sensitivity, and metabolic adaptation in obesity-related disease states. In addition, we summarize current clinical evidence supporting circulating IGFBP2 as a candidate biomarker of metabolic dysfunction and discuss how nutritional factors and metabolic interventions may influence its expression and circulating levels. Collectively, available evidence suggests that IGFBP2 is a context-dependent regulator and potential translational indicator of metabolic dysregulation; however, important gaps remain regarding its tissue-specific sources and modes of action, receptor interactions, context-specific signaling mechanisms, and the strength of prospective human evidence.