The novel SPPARM YR3-16 ameliorates metabolic disorders in vivo and attenuates adipocyte inflammation in vitro via PPARγ-dependent ERK suppression.

Obesity-related metabolic disorders and adipocyte inflammation are key drivers of type 2 diabetes, but conventional therapies remain suboptimal in addressing these core pathologies. This study aimed to characterize YR3-16 as a novel selective peroxisome proliferator-activated receptor γ modulator (SPPARM) with efficacy in improving metabolic homeostasis and reducing adipocyte inflammation. YR3-16 is a novel tetrahydroisoquinoline derivative that selectively activates PPARγ and exhibits a binding mode distinct from that of pioglitazone. In spontaneous obese and type 2 diabetic KKAy mice, oral administration of YR3-16 (three doses, 25/50/75 mg/kg) for 30 days dose-dependently ameliorated metabolic disorders: it improved insulin sensitivity (insulin tolerance test), and reduced plasma triglycerides, free fatty acids and total cholesterol. Consistent results were also observed in diet-induced obese (DIO) mice. In 3 T3-L1 adipocytes, YR3-16 (10 μM) reprogrammed lipid metabolism at the gene transcriptional level, and suppressed pro-inflammatory cytokine secretion (tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β)), associated with the inhibition of extracellular signal-regulated kinase (ERK) signaling pathway, which was abolished by the peroxisome proliferator-activated receptor γ antagonist GW9662. YR3-16, as a novel SPPARM, concurrently improves metabolic disorders in vivo and attenuates adipocyte inflammation via peroxisome proliferator-activated receptor γ activation, highlighting its potential for treating obesity-related diseases.