Peroxisome proliferator-activated receptor γ (PPARγ) isoforms heterodimerize with retinoic X receptors to modulate gene expression related to adipocyte differentiation, fatty acid uptake and storage, and glucose metabolis. Natural agonists of PPARγ include fatty acids (e.g., linoleic acid and 15-deoxy-Δ-prostaglandin J), while thiazolidinediones (e.g., rosiglitazone and pioglitazone) are potent synthetic agonists. FMOC-L-leucine is a partial agonist of PPARγ. It activates PPARγ with a lower potency (K = 15 versus 0.035 µM) but a similar maximal efficacy compared to rosiglitazone. FMOC-L-leucine improves insulin resistance in normal, diet-induced glucose-intolerant and in diabetic db/db mice, yet has reduced adipogenic activity. As a result, it is classified as a selective PPARγ modulator (SPPARM), capable of producing insulin-sensitizing effects while minimizing side effects associated with full agonists.