Proteomic changes in the hypothalamus after treatment with GLP-1RA, Tesaglitazar, or GLP-1RA/Tesaglitazar (GLP-1RA mediated Tesaglitazar delivery)

The peroxisome proliferator-activated receptors alpha and gamma (PPAR𝛼/𝛾) play important roles in the regulation of energy, lipid and glucose metabolism. Drugs targeting these proteins such as Fibrates and TZDs have both shown beneficial cardiovascular effects in clinical trials, which together with their complementary action on glucose and lipid metabolism spurred the development of PPAR𝛼/𝛾 dual-agonists (Glitazars) for the treatment of type-2 diabetes (T2D) and dyslipidemia. While effectively improving glucose and lipid metabolism in clinical trials, the development of many Glitazars was terminated due to unfavorable effects on the cardiovascular and/or renal system. Here we evaluate a single molecule conjugate of the PPAR𝛼/𝛾 dual-agonist Tesaglitazar covalently attached to the incretin hormone glucagon-like peptide-1 receptor agonist (GLP-1RA). We hypothesized that GLP-1-mediated delivery of Tesaglitazar as well as synergism between the two agents would lead to overal beneficial effects and decrease the TZD risk profile.