Metformin-induced increases in GDF15 are important for suppressing appetite and promoting weight loss
| Autor: | Gregory R. Steinberg, Natalia McInnes, Brennan K. Smith, Rachel Lu, Sibylle Hess, Emily A. Day, Pedrum Mohammadi-Shemirani, Andrew G. McArthur, Marisa R Morrow, Robert M Gutgesell, Amogelang R. Raphenya, Mostafa Kabiri, Guillaume Paré, Rebecca J. Ford, Hertzel C. Gerstein |
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| Rok vydání: | 2019 |
| Předmět: |
medicine.medical_specialty
endocrine system diseases Endocrinology Diabetes and Metabolism medicine.medical_treatment media_common.quotation_subject 030209 endocrinology & metabolism Type 2 diabetes 03 medical and health sciences 0302 clinical medicine Weight loss Oral administration Physiology (medical) Internal medicine Diabetes mellitus Internal Medicine medicine 030304 developmental biology media_common 2. Zero hunger 0303 health sciences business.industry Insulin nutritional and metabolic diseases Appetite Cell Biology medicine.disease 3. Good health Metformin Endocrinology GDF15 medicine.symptom business medicine.drug |
| Zdroj: | Nature Metabolism. 1:1202-1208 |
| ISSN: | 2522-5812 |
| Popis: | 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 understood1-3. 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 system4. 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: | OpenAIRE |
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