Combined GIP receptor and GLP1 receptor agonism attenuates NAFLD in male APOE∗3-Leiden.CETP miceResearch in context
Zhixiong Ying,
Robin van Eenige,
Xiaoke Ge,
Christy van Marwijk,
Joost M. Lambooij,
Bruno Guigas,
Martin Giera,
Jan Freark de Boer,
Tamer Coskun,
Hongchang Qu,
Yanan Wang,
Mariëtte R. Boon,
Patrick C.N. Rensen,
Sander Kooijman
Affiliations
Zhixiong Ying
Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, the Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands
Robin van Eenige
Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, the Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands
Xiaoke Ge
Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, the Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands
Christy van Marwijk
Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, the Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands
Joost M. Lambooij
Department of Parasitology, Leiden University Medical Center, Leiden, the Netherlands; Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands
Bruno Guigas
Department of Parasitology, Leiden University Medical Center, Leiden, the Netherlands
Martin Giera
The Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, the Netherlands
Jan Freark de Boer
Departments of Pediatrics and Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
Tamer Coskun
Department of Diabetes/Endocrine, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN, United States
Hongchang Qu
Department of Diabetes/Endocrine, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN, United States
Yanan Wang
Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, the Netherlands; Med-X Institute, Center for Immunological and Metabolic Diseases and Department of Endocrinology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an Jiaotong University, Xi'an, China
Mariëtte R. Boon
Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, the Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands
Patrick C.N. Rensen
Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, the Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands
Sander Kooijman
Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, the Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands; Corresponding author. Albinusdreef 2, 2333ZA, Leiden, the Netherlands.
Summary: Background: Combined glucose-dependent insulinotropic polypeptide receptor (GIPR) and glucagon-like peptide-1 receptor (GLP1R) agonism is superior to single GLP1R agonism with respect to glycemic control and weight loss in obese patients with or without type 2 diabetes. As insulin resistance and obesity are strong risk factors for nonalcoholic fatty liver disease (NAFLD), in the current study we investigated the effects of combined GIPR/GLP1R agonism on NAFLD development. Methods: Male APOE∗3-Leiden.CETP mice, a humanized model for diabetic dyslipidemia and NAFLD when fed a high-fat high-cholesterol diet, received subcutaneous injections with either vehicle, a GIPR agonist, a GLP1R agonist, or both agonists combined every other day. Findings: GIPR and GLP1R agonism reduced body weight and additively lowered fasting plasma levels of glucose, triglycerides and total cholesterol. Strikingly, we report an additive reduction in hepatic steatosis as evidenced by lower hepatic lipid content and NAFLD scores. Underlying the lipid-lowering effects were a reduced food intake and intestinal lipid absorption and an increased uptake of glucose and triglyceride-derived fatty acids by energy-combusting brown adipose tissue. Combined GIPR/GLP1R agonism also attenuated hepatic inflammation as evidenced by a decreased number of monocyte-derived Kupffer cells and a reduced expression of inflammatory markers. Together, the reduced hepatic steatosis and inflammation coincided with lowered markers of liver injury. Interpretation: We interpretate that GIPR and GLP1R agonism additively attenuate hepatic steatosis, lower hepatic inflammation, ameliorate liver injury, together preventing NAFLD development in humanized APOE∗3-Leiden.CETP mice. We anticipate that combined GIPR/GLP1R agonism is a promising strategy to attenuate NAFLD progression in humans. Funding: This work was supported by a grant from the Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation, Dutch Federation of University Medical Centers, the Netherlands Organization for Health Research and Development, and the Royal Netherlands Academy of Sciences [CVON-GENIUS-II] to P.C.N.R., a Lilly Research Award Program [LRAP] Award to P.C.N.R. and S.K., a Dutch Heart Foundation [2017T016] grant to S.K., and an NWO-VENI grant [09150161910073] to M.R.B.; J.F.D.B. is supported by the Nutrition and Health initiative of the University of Groningen; Z.Y. is supported by a full-time PhD scholarship from the China Scholarship Council (201806850094 to Z.Y.).
