title: Intramuscular injection of exogenous leptin induces adiposity, glucose intolerance and fatty liver by repressing the JAK2-STAT3/PI3K pathway in a rat model.
abstract: Obesity, diabetes and fatty liver disease are extremely common in leptin-resistant patients. Dysfunction of leptin or its receptor is associated with obesity. The present study aimed to assess the effects of intramuscular injection of exogenous leptin or its receptor on fat deposition and leptin-insulin feedback regulation. Forty-five 40-day old female Sprague Dawley (SD) rats were injected thrice with leptin or its receptor intramuscularly. Adiposity and fat deposition were assessed by assessing the Lee's index, body weight, food intake, and total cholesterol, high density lipoprotein, low density lipoprotein, and triglyceride levels, as well as histological properties (liver and adipose tissue). Serum glucose, leptin, and insulin amounts were evaluated, and glucose tolerance assessed to monitor glucose metabolism in SD rats; pancreas specimens were analyzed immunohistochemically. Hypothalamic phosphorylated Janus kinase 2 (p-JAK2), phosphorylated signal transducer and activator of transcription 3 (p-STAT3), and phosphatidylinositol-3-kinase (PI3K) signaling, and hepatic sterol regulatory element binding protein-1 (SREBP-1) were qualified by Western blotting. Leptin receptor immunogen reduced fat deposition, increased appetite, and lowered serum leptin levels, enhancing STAT3 signaling in hypothalamus and down-regulating hepatic SREBP-1. In contrast, SD rats administered leptin immunogen displayed significantly increased body weight and fat deposition, with up-regulated SREBP-1, indicating adiposity occurrence. SD rats administered leptin immunogen also showed glucose intolerance, β- cell reduction in the pancreas, and deregulation of JAK2-STAT3/PI3K signaling, indicating that Lep rats were at risk of diabetes. In conclusion, intramuscular injection of exogenous leptin or its receptor, a novel rat model approach, can be used in obesity pathogenesis and therapeutic studies.
authors.affiliation: Key Laboratory of Oral Medicine, Guangzhou Institure of Oral Disease, Stomatology Hospital of Guangzhou Medical University, Guangzhou 510140, China; Center of Emphasis in Infectious Diseases, Department of Biomedical Sciences, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA.
authors.forename: Lihong
authors.initials: L
authors.lastname: Wu
authors.affiliation: First Department of Orthopedics, The Affiliated Nanhai Hospital of Southern Medical University, Foshan 528200, China.
authors.forename: Guoxiong
authors.initials: G
authors.lastname: Chen
authors.affiliation: Department of Laboratory Animal Center, Southern Medical University, Guangzhou 510515, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Liu
authors.affiliation: Key Laboratory of Oral Medicine, Guangzhou Institure of Oral Disease, Stomatology Hospital of Guangzhou Medical University, Guangzhou 510140, China.
authors.forename: Xuechao
authors.initials: X
authors.lastname: Yang
authors.affiliation: Key Laboratory of Oral Medicine, Guangzhou Institure of Oral Disease, Stomatology Hospital of Guangzhou Medical University, Guangzhou 510140, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Gao
authors.affiliation: Key Laboratory of Oral Medicine, Guangzhou Institure of Oral Disease, Stomatology Hospital of Guangzhou Medical University, Guangzhou 510140, China.
authors.forename: Liwen
authors.initials: L
authors.lastname: Huang
authors.affiliation: Key Laboratory of Oral Medicine, Guangzhou Institure of Oral Disease, Stomatology Hospital of Guangzhou Medical University, Guangzhou 510140, China.
authors.forename: Hongbing
authors.initials: H
authors.lastname: Guan
authors.affiliation: Key Laboratory of Oral Medicine, Guangzhou Institure of Oral Disease, Stomatology Hospital of Guangzhou Medical University, Guangzhou 510140, China.
authors.forename: Zhengmao
authors.initials: Z
authors.lastname: Li
authors.affiliation: Key Laboratory of Oral Medicine, Guangzhou Institure of Oral Disease, Stomatology Hospital of Guangzhou Medical University, Guangzhou 510140, China.
authors.forename: Zhichao
authors.initials: Z
authors.lastname: Zheng
authors.affiliation: Key Laboratory of Oral Medicine, Guangzhou Institure of Oral Disease, Stomatology Hospital of Guangzhou Medical University, Guangzhou 510140, China.
authors.forename: Meiling
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Laboratory Animal Center, Southern Medical University, Guangzhou 510515, China; Department of Laboratory Animal Science, Songshan Lake Pearl Laboratory Animal Sci. & Tech. Co., Ltd., Dongguan 523808, China. Electronic address: doctorguweiwang@163.com.
authors.forename: Weiwang
authors.initials: W
authors.lastname: Gu
authors.affiliation: Key Laboratory of Oral Medicine, Guangzhou Institure of Oral Disease, Stomatology Hospital of Guangzhou Medical University, Guangzhou 510140, China. Electronic address: gelinhu@yeah.net.
authors.forename: Linhu
authors.initials: L
authors.lastname: Ge
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D050154:Adiposity / Q000187:drug effects*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004195:Disease Models, Animal; D004435:Eating / Q000187:drug effects; D005234:Fatty Liver / Q000378:metabolism*; D005260:Female; D018149:Glucose Intolerance / Q000097:blood / Q000378:metabolism*; D006943:Hyperglycemia / Q000097:blood / Q000150:complications / Q000378:metabolism; D007109:Immunity / Q000187:drug effects; D007273:Injections, Intramuscular; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism; D053614:Janus Kinase 2 / Q000378:metabolism*; D020738:Leptin / Q000008:administration & dosage* / Q000009:adverse effects* / Q000097:blood; D008055:Lipids / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D017207:Rats, Sprague-Dawley; D054411:Receptors, Leptin / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism
chemical_list: D007328:Insulin; D020738:Leptin; D008055:Lipids; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor; D051780:Sterol Regulatory Element Binding Protein 1; D058539:Phosphatidylinositol 3-Kinase; D053614:Janus Kinase 2
keywords: Fatty liver; Glucose intolerance; JAK2-STAT3; Leptin; Obesity; PI3K