Metformin-induced increases in GDF15 are important for suppressing appetite and promoting weight loss.

Autor: Day EA; Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada.; Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, Ontario, Canada., Ford RJ; Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada.; Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, Ontario, Canada., Smith BK; Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada.; Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, Ontario, Canada., Mohammadi-Shemirani P; Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, Ontario, Canada.; Department of Pathology, McMaster University, Hamilton, Ontario, Canada., Morrow MR; Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada.; Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, Ontario, Canada., Gutgesell RM; Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada.; Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, Ontario, Canada., Lu R; Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada.; Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, Ontario, Canada., Raphenya AR; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada., Kabiri M; Sanofi Aventis Deutschland, Translational in vivo Models, Sanofi Research and Development, Frankfurt, Germany., McArthur AG; Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada.; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada., McInnes N; Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada.; Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.; Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, Ontario, Canada., Hess S; Sanofi Aventis Deutschland GmbH, Research and Development Division, Translational Medicine and Early Development, Biomarkers and Clinical Bioanalyses, Frankfurt, Germany., Paré G; Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada.; Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.; Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, Ontario, Canada.; Department of Pathology, McMaster University, Hamilton, Ontario, Canada.; Thrombosis and Atherosclerosis Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, Ontario, Canada., Gerstein HC; Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada.; Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.; Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, Ontario, Canada., Steinberg GR; Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada. gsteinberg@mcmaster.ca.; Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, Ontario, Canada. gsteinberg@mcmaster.ca.; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada. gsteinberg@mcmaster.ca.
Jazyk: angličtina
Zdroj: Nature metabolism [Nat Metab] 2019 Dec; Vol. 1 (12), pp. 1202-1208. Date of Electronic Publication: 2019 Dec 09.
DOI: 10.1038/s42255-019-0146-4
Abstrakt: Metformin is the most commonly prescribed medication for type 2 diabetes, owing to its glucose-lowering effects, which are mediated through the suppression of hepatic glucose production (reviewed in refs. 1-3 ). However, in addition to its effects on the liver, metformin reduces appetite and in preclinical models exerts beneficial effects on ageing and a number of diverse diseases (for example, cognitive disorders, cancer, cardiovascular disease) through mechanisms that are not fully understood 1-3 . Given the high concentration of metformin in the liver and its many beneficial effects beyond glycemic control, we reasoned that metformin may increase the secretion of a hepatocyte-derived endocrine factor that communicates with the central nervous system 4 . Here we show, using unbiased transcriptomics of mouse hepatocytes and analysis of proteins in human serum, that metformin induces expression and secretion of growth differentiating factor 15 (GDF15). In primary mouse hepatocytes, metformin stimulates the secretion of GDF15 by increasing the expression of activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP; also known as DDIT3). In wild-type mice fed a high-fat diet, oral administration of metformin increases serum GDF15 and reduces food intake, body mass, fasting insulin and glucose intolerance; these effects are eliminated in GDF15 null mice. An increase in serum GDF15 is also associated with weight loss in patients with type 2 diabetes who take metformin. Although further studies will be required to determine the tissue source(s) of GDF15 produced in response to metformin in vivo, our data indicate that the therapeutic benefits of metformin on appetite, body mass and serum insulin depend on GDF15.
Databáze: MEDLINE
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