Natural Modulators of the PPARγ–Adiponectin Axis in Insulin Resistance: Structural Pharmacology, Receptor-State Selectivity, and Translational Readiness

Insulin resistance reflects maladaptive communication among adipose tissue, the liver, skeletal muscle, immune cells, and the vasculature. Peroxisome proliferator-activated receptor gamma (PPARγ) is a validated insulin-sensitizing target, but classical full agonism couples metabolic efficacy to weight gain, fluid retention, and skeletal liability. This critical narrative review evaluates plant-derived and dietary molecules through a receptor-state framework that distinguishes direct binding from reporter activation and separates full agonism, partial agonism, selective modulation, antagonism with retained metabolic function, and post-translational control of PPARγ. Adiponectin is considered a functional inter-organ circuit linking adipocyte PPARγ activity to AdipoR1/AdipoR2 signaling, AMPK, PPARα, ceramide metabolism, glucose disposal, and fatty-acid oxidation. Amorfrutins provide the most coherent target-led natural-product evidence, whereas chelerythrine offers a structurally defined selective-modulation benchmark; honokiol, diosmin, betulinic acid, valerenic acid, punicic acid, alkamides, and defined extracts show heterogeneous mechanistic and translational maturity. Human evidence linking natural PPARγ ligands to verified target engagement and improved insulin sensitivity remains limited. We therefore propose a seven-stage translational roadmap connecting chemical identity, orthogonal binding, receptor-state pharmacology, cellular function, tissue exposure, mechanism-matched safety, and randomized human proof.