Metformin increases hepatic leptin receptor and decreases steatosis in mice.
In addition to the ascertained efficacy as antidiabetic drug, metformin is increasingly being used as weight-loss agent in obesity, and as insulin sensitizer in nonalcoholic fatty liver disease (NAFLD). However, the mechanisms underlying these effects are still incompletely understood. Emerging evidence suggest metformin as leptin sensitizer to mediate the weight-loss effect in the brain. In this study, we investigated effects of metformin on expression of leptin receptors in liver and kidney in mice. C57BL/6 mice were fed with chow diet (CD) or high-fat diet (HF) for 5months. Afterward, mice were treated with metformin (50mg/kg or 200mg/kg) for 15days. Metabolic parameters and hepatic gene expression were analyzed at the end of the treatment. We also tested the effects of metformin on plasma-soluble leptin receptor (sOB-R) levels in newly diagnosed type 2 diabetes mellitus (T2DM) patients, and assessed its effect on hepatosteatosis in mice. Results showed that metformin upregulates the expression of leptin receptors (OB-Ra, -Rb, -Rc, and -Rd) in liver but not kidney. The stimulation effect is dose-dependent in both chow and HF mice. Upregulation of OB-Rb, long signaling isoform, needs a relatively higher dose of metformin. This effect was paralleled by increased sOBR levels in mice and T2DM patients, and decreased hepatic triglyceride (TG) content and lipogenic gene expression, including sterol regulatory element-binding protein 1c (SREBP-1c), fatty acid synthase (FAS) and acetyl-CoA carboxylase-1 (ACC-1). Taken together, these data identify hepatic leptin receptor as target gene being upregulated by metformin which may enhance leptin sensitivity in liver to alleviate steatosis.
Department of Biochemistry and Molecular BiologyThird Military Medical University, Chongqing, China Department of Integrated MedicineXinqiao Hospital, Third Military Medical University, Chongqing, China.
Xuemei
X
Tang
Department of Biochemistry and Molecular BiologyThird Military Medical University, Chongqing, China Department of Integrated MedicineXinqiao Hospital, Third Military Medical University, Chongqing, China.
Jingwen
J
Li
Department of Biochemistry and Molecular BiologyThird Military Medical University, Chongqing, China.
Wei
W
Xiang
Department of Integrated MedicineXinqiao Hospital, Third Military Medical University, Chongqing, China.
Ye
Y
Cui
Department of Hepatobiliary SurgeryDaping Hospital & Institute of Surgery Research, Third Military Medical University, Chongqing, China.
Bin
B
Xie
Institute of PathologySouthwest Hospital, Third Military Medical University, Chongqing, China.
Xiaodong
X
Wang
Department of Integrated MedicineXinqiao Hospital, Third Military Medical University, Chongqing, China ganlixia@yahoo.com zihuixu@yeah.net.
Zihui
Z
Xu
Department of Biochemistry and Molecular BiologyThird Military Medical University, Chongqing, China ganlixia@yahoo.com zihuixu@yeah.net.
Lixia
L
Gan
D000072197:ADAM10 Protein / Q000378:metabolism; D000072198:ADAM17 Protein / Q000378:metabolism; D000368:Aged; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D005234:Fatty Liver / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008687:Metformin / Q000494:pharmacology / Q000627:therapeutic use*; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D011897:Random Allocation; D054411:Receptors, Leptin / Q000378:metabolism*; D014280:Triglycerides / Q000378:metabolism
D007004:Hypoglycemic Agents; D008565:Membrane Proteins; D054411:Receptors, Leptin; D014280:Triglycerides; D008687:Metformin; D053829:Amyloid Precursor Protein Secretases; D000072197:ADAM10 Protein; C491234:Adam10 protein, mouse; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse
leptin receptor; liver steatosis; metformin; soluble leptin receptor