Loss of Adipose Growth Hormone Receptor in Mice Enhances Local Fatty Acid Trapping and Impairs Brown Adipose Tissue Thermogenesis

Liyuan Ran; Xiaoshuang Wang; Ai Mi; Yanshuang Liu; Jin Wu; Haoan Wang; Meihua Guo; Jie Sun; Bo Liu; Youwei Li; Dan Wang; Rujiao Jiang; Ning Wang; Wenting Gao; Li Zeng; Lin Huang; Xiaoli Chen; Derek LeRoith; Bin Liang; Xin Li; Yingjie Wu

doi:10.1016/j.isci.2019.05.020

Loss of Adipose Growth Hormone Receptor in Mice Enhances Local Fatty Acid Trapping and Impairs Brown Adipose Tissue Thermogenesis

iScience. 2019 Jun 28:16:106-121. doi: 10.1016/j.isci.2019.05.020. Epub 2019 May 16.

Authors

Liyuan Ran¹, Xiaoshuang Wang¹, Ai Mi¹, Yanshuang Liu², Jin Wu¹, Haoan Wang¹, Meihua Guo¹, Jie Sun³, Bo Liu¹, Youwei Li¹, Dan Wang¹, Rujiao Jiang¹, Ning Wang¹, Wenting Gao¹, Li Zeng², Lin Huang⁴, Xiaoli Chen⁵, Derek LeRoith⁶, Bin Liang⁷, Xin Li⁸, Yingjie Wu⁹

Affiliations

¹ Institute for Genome Engineered Animal Models of Human Diseases, Dalian Medical University, Dalian 116044, China; National Center of Genetically Engineered Animal Models for International Research, Dalian Medical University, Dalian 116044, China; Liaoning Provence Key Lab of Genome Engineered Animal Models, Dalian Medical University, Dalian 116044, China.
² Institute for Genome Engineered Animal Models of Human Diseases, Dalian Medical University, Dalian 116044, China; National Center of Genetically Engineered Animal Models for International Research, Dalian Medical University, Dalian 116044, China.
³ Institute for Genome Engineered Animal Models of Human Diseases, Dalian Medical University, Dalian 116044, China; National Center of Genetically Engineered Animal Models for International Research, Dalian Medical University, Dalian 116044, China; Liaoning Provence Key Lab of Genome Engineered Animal Models, Dalian Medical University, Dalian 116044, China; College of Integrative Medicine, Dalian Medical University, Dalian 116044, China.
⁴ Department of Pathophysiology, Dalian Medical University, Dalian 116044, China.
⁵ Department of Food Science and Nutrition, University of Minnesota, Twin Cities, MN, USA.
⁶ Division of Endocrinology, Diabetes and Bone Disease, Department of Medicine, Icahn Mount Sinai School of Medicine, New York 10029, USA.
⁷ Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming 650223, China. Electronic address: liangb@mail.kiz.ac.cn.
⁸ Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York 10010, USA; Department of Urology, New York University Langone Medical Center, New York 10016, USA; Perlmutter Cancer Institute, New York University Langone Medical Center, New York 10016, USA. Electronic address: xl15@nyu.edu.
⁹ Institute for Genome Engineered Animal Models of Human Diseases, Dalian Medical University, Dalian 116044, China; National Center of Genetically Engineered Animal Models for International Research, Dalian Medical University, Dalian 116044, China; Liaoning Provence Key Lab of Genome Engineered Animal Models, Dalian Medical University, Dalian 116044, China; College of Integrative Medicine, Dalian Medical University, Dalian 116044, China; Division of Endocrinology, Diabetes and Bone Disease, Department of Medicine, Icahn Mount Sinai School of Medicine, New York 10029, USA; Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York 10010, USA. Electronic address: yingjiewu@dmu.edu.cn.

Abstract

Growth hormone (GH) binds to its receptor (growth hormone receptor [GHR]) to exert its pleiotropic effects on growth and metabolism. Disrupted GH/GHR actions not only fail growth but also are involved in many metabolic disorders, as shown in murine models with global or tissue-specific Ghr deficiency and clinical observations. Here we constructed an adipose-specific Ghr knockout mouse model Ad-GHRKO and studied the metabolic adaptability of the mice when stressed by high-fat diet (HFD) or cold. We found that disruption of adipose Ghr accelerated dietary obesity but protected the liver from ectopic adiposity through free fatty acid trapping. The heat-producing brown adipose tissue burning and white adipose tissue browning induced by cold were slowed in the absence of adipose Ghr but were recovered after prolonged cold acclimation. We conclude that at the expense of excessive subcutaneous fat accumulation and lower emergent cold tolerance, down-tuning adipose GHR signaling emulates a healthy obesity situation which has metabolic advantages against HFD.

Keywords: Cellular Physiology; Diabetology; Endocrinology; Physiology.