Novel Therapeutic Strategies to Combat Obesity-Associated Cardiometabolic Diseases Issue Date: 2021-04-28

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The handle https://hdl.handle.net/1887/3166010 holds various files of this Leiden University dissertation.

Author: Li, Z. Title: From gut to brain: novel therapeutic strategies to combat obesity-associated cardiometabolic diseases Issue Date: 2021-04-28

LIST OF PUBLICATIONS 1. Li Z, Zhou E, Liu C, Wicks H, Yildiz S, Razack F, Ying Z, Kooijman S, Koonen D, Heijink M, Giera M, Smits WK, Kuijper EJ, Groen AK, Willems van Dijk K, Rensen PCN, Wang Y. Dietary butyrate selectively promotesLachnospiraceae bacterium 28-4 to induce satiety, attenuate weight gain and ameliorate metabolic health. Submitted for publication. 2. Li Z, Zhou E, Razack F, Kooijman S, Willems van Dijk K, Rensen PCN, Wang Y. Dietary butyrate promotes intestinal GLP-1 release to reduce appetite and induce fat oxidation via central GLP-1 receptor signaling. Submitted for publication. 3. Zhou E, Nakashima H, Li R, van der Zande HJP, Liu C, Li Z, Müller C, Bracher F, Mohammed Y, de Boer JF, Kuipers F, Guigas B, Rensen PCN, Giera M, Wang Y. Inhibition of DHCR24 ameliorates hepatic steatosis and inflammation through LXRα without inducing hyperlipidemia in mice. Submitted for publication. 8 4. Zhou E, Li Z, Nakashima H, Choukoud A, Kooijman S, Berbée JFP, Rensen PCN, Wang Y. Beneficial effects of brown fat activation on top of PCSK9 inhibition on dyslipidemia and atherosclerosis development in APOE*3-Leiden.CETP mice. Pharmacol Res 2021; In press. 5. Liu C, Schönke M, Zhou E, Li Z, Kooijman S, Boon MR, Larsson M, Wallenius K, Dekker N, Barlind L, Peng X, Wang Y, Rensen PCN. Pharmacological treatment with FGF21 strongly improves plasma cholesterol metabolism to reduce atherosclerosis. Cardiovasc Res 2021; In press. 6. Zhou E, Li Z, Nakashima H, Liu C, Ying Z, Foks AC, Berbée, Willems van Dijk K, Rensen PCN, Wang Y. Hepatic SRB1 (Scavenger Receptor Class B Type 1) knockdown reduces atherosclerosis and enhances the antiatherosclerotic effect of brown fat activation in APOE*3-Leiden.CETP Mice. Arterioscler Thromb Vasc Biol 2021; In press. 7. Li Z, de Jonge WJ, Wang Y, Rensen PCN, Kooijman S. Electrical neurostimulation promotes brown adipose tissue thermogenesis. Front Endocrinol 2020; 11: 567545. 8. Zhou E, Hoeke G, Li Z, Eibergen AC, Schonk AW, Koehorst M, Boverhof R, Havinga R, Kuipers F, Coskun T, Boon MR, Groen AK, Rensen PCN, Berbée JFP, Wang Y. Colesevelam enhances the beneficial effects of brown fat activation on hyperlipidaemia and atherosclerosis development. Cardiovasc Res 2020; 116(10): 1710-1720. 9. Li Z, Yi C, Katiraei S, Kooijman S, Zhou E, Chung CK, Gao Y, van den Heuvel JK, Meijer OC, Berbée JFP, Heijink, Giera M, Willems van Dijk K, Groen AK, Rensen PCN, Wang Y. Butyrate reduces appetite and activates brown adipose tissue via the gut-brain neural circuit. Gut 2018; 67(7): 1269-1279.

199 10. van der Tuin SJL*, Li Z*, Berbée JFP, Verkouter I, Ringnalda LE, Neele AE, van Klinken JB, Rensen SS, Fu J, de Winther MPJ, Groen AK, Rensen PCN, Willems van Dijk K, Wang Y. Lipopolysaccharide lowers cholesteryl ester transfer protein by activating F4/80+ Clec4f+ Vsig4+ Ly6C- Kupffer cell subsets. J Am Heart Assoc 2018; 7(6): e008105. 11. Blauw LL, Li Z, Rensen SS, Greve JWM, Verhoeven A, Derks RJ, Giera M, Wang Y, Rensen PCN. Metabolic liver inflammation in obesity does not robustly decrease hepatic and circulating CETP. Atherosclerosis 2018; 275: 149-155. 12. Rozendaal YJW, Wang Y, Paalvast Y, Tambyrajah LL, Li Z, Willems van Dijk K, Rensen PCN, Kuivenhoven JA, Groen AK, Hilbers PAJ, van Riel NAW. In vivo and in silico dynamics of the development of metabolic syndrome. PLoS Comput Biol 2018; 14(6): e1006145. 13. Liu X, Pang D, Yuan T, Li Z, Li Z, Zhang M, Ren W, Ouyang H, Tang X. N-3 8 polyunsaturated fatty acids attenuates triglyceride and inflammatory factors level in hfat-1 transgenic pigs. Lipids Health Dis 2016; 15: 89. 14. Tang X, Wang G, Liu X, Han X, Li Z, Ran G, Li Z, Song Q, Ji Y, Wang H, Wang Y, Ouyang H, Pang D. Overexpression of porcine lipoprotein-associated phospholipase A2 in swine. Biochem Biophys Res Commun 2015; 465(3): 507- 11. 15. Ran G, Ren L, Han X, Liu X, Li Z, Pang D, Ouyang H, Tang X. Development of a rapid method for the visible detection of pork DNA in halal products by loop- mediated isothermal amplification. Food Anal Method 2015; 9: 565–570. 16. Li Z, Ren W, Han X, Liu X, Wang G, Zhang M, Pang D, Ouyang H, Tang X. ω3- polyunsaturated fatty acids suppress lipoprotein-associated phospholipase A2 expression in macrophages and animal models. Mol Nutr Food Res 2015; 59(9): 1771-9. 17. Han X, Wang T, Zhang J, Liu X, Li Z, Wang G, Song Q, Pang D, Ouyang H, Tang X. Apolipoprotein CIII regulates lipoprotein-associated phospholipase A2 expression via the MAPK and NFκB pathways. Biol Open 2015; 4(5): 661-5. 18. Wang H, Ouyang H, Tian Y, Li Z, Han X, Liu X, Ran G, Wang G, Pang D, Tang X. Nitro-oleic acid decreases transcription of the angiotensin II type I receptor gene in aortic smooth muscle cells. Biotechnol Bioproc E 2014; 19: 740–746. 19. Wang G, Ji Y, Li Z, Han X, Guo N, Song Q, Quan L, Wang T, Han W, Pang D, Ouyang H, Tang X. Nitro-oleic acid downregulates lipoprotein-associated phospholipase A2 expression via the p42/p44 MAPK and NFκB pathways. Sci Rep 2014; 4: 4905.

200 CURRICULUM VITAE

Zhuang Li was born on 26 October 1988 in Changchun, Jilin Province, China. After graduating from the Jilin Provincial Experimental High School in Changchun, he was enrolled in Jilin University in 2008, with a major in Animal Biotechnology. In 2012, after obtaining his BSc degree, he continued his master study ‘Biochemistry and Molecular Biology’ at the same university. He worked on a 3-year research program entitled ω‘ 3-polyunsaturated fatty acids suppress lipoprotein-associated phospholipase A2 expression in macrophages and animal models’ under the supervision of Prof. dr. Xiaochun Tang and Prof. dr. Ouyang Hongsheng, and received his MSc degree in 2015.

Sponsored by a prestigious personal fellowship by the Chinese Scholarship Council, he started his PhD project in October 2015 under the supervision of Prof. dr. Patrick C.N. Rensen and Prof. dr. Yanan Wang, at the Division of Endocrinology of the Department of Medicine, at Leiden University Medical Center, Leiden, The 8 Netherlands. His research mainly focused on identifying novel gut-based therapeutic strategies to combat obesity and associated cardiometabolic disorders, as well as on elucidating underlying mechanisms. In particular, he demonstrated that dietary butyrate, via acting on the gut-brain neural circuit, reduces appetite and activates brown adipose tissue, hence improving energy metabolism (Li, Gut 2018, highly cited paper according to Web of Science). For this work he was awarded the Best Publication Award for best Dutch original research paper on obesity at the Netherlands Association for the Study of Obesity (NASO) Spring Meeting in 2018, as well as a Rexinchang Scholarship for best gut-related research at the China 1st GUT Festival in 2019.

From October 2019 till present, he continues to work in the same research group as a postdoctoral researcher, exploring the role of the gut microbiome in the beneficial effects of dietary butyrate on host metabolic health. He is currently supported by a personal international fellowship for Endocrinology research by the IBSA Foundation obtained in 2019 and by a Prof. dr. J. Terpstra Award for best diabetes research proposal by the Dutch Association for Diabetes Research (NVDO) in 2019.

201 ACKNOWLEDGMENTS

Without the support and understanding of many, I could not have overcome the language barrier and cope with cultural misunderstandings at the beginning of my PhD training abroad, and finally go through five years of research life that culminated in this thesis. Therefore, I wish to express my appreciation to everyone who stood behind me.

Throughout my PhD studies, the most irreplaceable persons were my promotors and supervisors, Prof. dr. Patrick Rensen and Prof. dr. Yanan Wang, who introduced me to this unknown but wonderful scientific world. You not only guided me how to become an independent scientist but also inspired me how to enjoy a colorful life. What I learnt from you is the most precious gift of my PhD training.

In addition, thanks to my fantastic and warmhearted colleagues from the big family 8 of ENDO and HG for extending their compassion and providing flexibility when needed. Ko, Onno, Jimmy, Mariëtte, Sander, Lisanne, Milena, Borja, Jan, Andrea, Eline, Laura, Maaike Schilperoort, Maaike Straat, Robin, Wietse, Rob, Chris, Trea, Hetty, Amanda, Isabel, and others, with your unlimited support and help I never felt alone when I met difficult scientific questions. I am happy and lucky to still work as a team member with all of you.

Besides, I would like to show my gratitude to the collaborators who helped me completing this thesis. Many thanks Chunxia and Yuanqing for guiding me to investigate the gut-brain neural axis; Wiep Klaas and Ingrid for their great assistance in isolating and amplifying gut microbiota; and Martin and Marieke for their great expertise in measuring short-chain fatty acids.

Furthermore, I am incredibly grateful to my Chinese colleagues Enchen, Cong, Zhixiong, Xiaoke, Jinlan, who are also true friends. I very much enjoyed, and still enjoy, the relaxing Chinese lunchtimes with you, which allow to refresh myself in between full days of hard work. To all my Chinese friends in the Netherlands, thank you for enriching my life. I enjoyed the time we were playing and laughing together, which colored my life a lot.

Last but not least, there are no words that can express my thanks to my beloved family. My parents, thank you for constantly supporting me, forgiving me, loving me, and making me. My wife Jiaxin and my son Aiden, you are the light of my life, brightening my world with the warmth of your love.

Zhuang April 2021

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