Dendrimer-tesaglitazar therapy ameliorates obesity and atherosclerosis in both male and female apoE knockout mice
Diego Almodiel, Wathsala Liyanage, Javier Allende Labasita, Travis Brady, Saanvi Sudhir, Alfredo Hernandez, Mahin Gadkari, Marta Martinez Yus, Rangaramanujam M. Kannan, Sujatha Kannan, Lakshmi Santhanam · Physiology · 2025
Background: Obesity and atherosclerosis have been identified as chronic inflammatory diseases driven by macrophages in the white adipose tissue (WAT) and arterial plaque deposits. There are currently no therapeutic options that treat both atherosclerosis and obesity. Peroxisome proliferator activated receptors (PPARs) located in macrophages present a promising therapeutic target as PPAR-α and PPAR-γ agonists have been shown to improve lipid metabolism and inhibit macrophage foam cell formation. Additionally, PPAR agonists have been reported to cause browning of adipose tissue, a phenotypic change of WAT into a more metabolically active state, with the added benefit of reducing adipocyte size. Our goal is to determine if targeting macrophages in the WAT and plaque can confer benefits of decreased weight and plaque burden to alleviate obesity and atherosclerosis. We target macrophages using D-Tesa, a dendrimer conjugate of a dual PPAR-α/γ agonist, Tesaglitazar. Methods: 22-25-week-old, male and female apolipoprotein E knockout (ApoE -/- ) mice were fed high fat diet (HFD) for 16 weeks to induce atherosclerosis. After 16 weeks on HFD, mice were randomized into four groups, with groups 2-4 continuing on HFD: 1) Baseline: sacrificed immediately after 16 weeks of HFD to determine physiological parameters before treatment, 2) D-Tesa group: D-Tesa for 6 weeks (20µg/kg twice weekly, P.O.) 3) Free Tesaglitazar: free Tesaglitazar for 6 weeks (20µg/kg twice weekly, P.O, and 4) Vehicle: received PBS for 6 weeks. Cy5 labeled D-Tesa, D-Tesa-Cy5, was administered to a separate ApoE -/- mouse on HFD to determine uptake in plaque and WAT using confocal microscopy. Body weight measurements were taken throughout the experiment. After the third week of treatment, mice were subject to indirect calorimetry in a CLAMS system. Upon sacrifice, aortas were harvested to quantify plaque burden, and WAT was collected for histological analysis and to determine protein expression. Results: D-Tesa-Cy5 localization studies reveal that conjugate is up taken by macrophages in the WAT and aorta. Both male and female mice treated with D-Tesa had a significant reduction in weight, despite continued consumption of HFD. This weight loss was not due to appetite suppression, but instead the browning of WAT. Adipocytes in free Tesaglitazar and D-Tesa treated mice had a reduced size compared to vehicle treated mice due to browning, indicated by an increase in UCP-1 protein expression. D-Tesa treated mice exhibited decreased fat mass, increased lean (muscle) mass, and increased energy expenditure that was not observed in free Tesaglitazar or vehicle treated mice. Plaque burden was significantly decreased in both male and female mice treated with D-Tesa versus vehicle treated mice. Conclusion: Cy5 labeled D-Tesa localized in macrophages within atherosclerotic plaque as well WAT, showing delivery of payload to diseased cells. D-Tesa is able to slow the progression of atherosclerosis and cause weight loss in both male and female ApoE -/- mice. This benefit of weight loss resulted from browning of adipose tissue, leading to physiological improvement in energy expenditure. This work was supported by an AHA Predoctoral Fellowship (D.A.), a NHLBI grant R01HL148112 01 (L.S.) and the Traystman Endowment (S.K.). This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.