Study of the mechanism of action of LT175, a dual PPAR ligand that ameliorates the metabolic profile and insulin sensitivity in a mouse model of insulin resistance

Peroxisome proliferator-activated receptors (PPARs) are ligand-dependent transcription factors that play a key role in the regulation of energy metabolism. Recent works at developing dual PPAR \u3b1/\u3b3 agonists devoid of the side effects of the antidiabetic agents thiazolidinediones and glitazars. We studied the molecular mechanism of action of a new compound, LT175, and the regulation of glucose and lipid metabolism in cell and animal models. In cell-based assays LT175 activates both PPAR\u3b1 and PPAR\u3b3. The study of coregulator recruitment by FRET revealed that LT175 is a full PPAR\u3b1 and a partial PPAR\u3b3 agonist. We tested the biological activity of Lt175 in mouse adipocytes, showing lower lipid accumulation than rosiglitazone, related to the lower expression of CD36 (fatty acid uptake), PEPCK and GYK (glycerol 3-phosphate formation). Using PPRE-LUC reporter mice we showed that LT175 switches on the PPAR-dependent transcription program in typical target tissues. Administration of LT175 to Diet Induced Obese mice decreases plasma glucose, insulin, Non-Esterified Fatty Acids, triglycerides and cholesterol, ameliorates the metabolic profile and insulin sensitivity. LT175 decreases body weight, lowering visceral fat as assessed by Magnetic Resonance Imaging. RT-qPCR shows that LT175 enhances the expression of PPAR target genes in the liver and adipose tissue. LT175, opposite to rosiglitazone, does not increase the expression of renal sodium transporter ENaC\u3b3, which is involved in fluid retention. In conclusion, LT175 has favourable effects on glucose and lipid metabolism with a reduction of some of the major side-effects induced by PPAR\u3b3 agonists and could represent a new PPAR ligand with a better profile than glitazones. Supported by a grant from Fondazione Cariplo 2009.2727, FP6 SOUTH LSHM-CT2006-037498 and Giovanni Armenise\u2013Harvard Foundation