Antibody-Mediated Targeting of the FGFR1c Isoform Increases Glucose Uptake in White and Brown Adipose Tissue in Male Mice
| Autor: | James D. Dunbar, Ricardo J. Samms, Francis J. P. Ebling, Dennis P. Smith, Jo E. Lewis, Paul J. Emmerson, Alan C. Perkins, Scott Cooper, Jeni Luckett, Andrew C. Adams, Kostas Tsintzas |
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| Rok vydání: | 2017 |
| Předmět: |
Blood Glucose
Male 0301 basic medicine medicine.medical_specialty Adipose Tissue White Adipose tissue macrophages Glucose uptake Population Adipose tissue 030209 endocrinology & metabolism White adipose tissue Biology Carbohydrate metabolism Special Section: Targeting and Regulation of Hormone Signaling Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Endocrinology Adipose Tissue Brown Energy Balance - Obesity - Metabolism Internal medicine Brown adipose tissue medicine Animals Insulin Protein Isoforms Obesity Receptor Fibroblast Growth Factor Type 1 Muscle Skeletal education Triglycerides education.field_of_study Triglyceride Antibodies Monoclonal Brain Lipase 3. Good health Enzyme Activation Mice Inbred C57BL Glucose 030104 developmental biology medicine.anatomical_structure Liver chemistry Rapid Communication Acetyl-CoA Carboxylase |
| Zdroj: | Endocrinology |
| ISSN: | 1945-7170 0013-7227 |
| Popis: | The increased prevalence of obesity and its cardiometabolic implications demonstrates the imperative to identify novel therapeutic targets able to effect meaningful metabolic changes in this population. Antibody-mediated targeting of fibroblast growth factor receptor 1c isoform (FGFR1c) has been shown to ameliorate hyperglycemia and protect from diet- and genetically-induced obesity in rodents and nonhuman primates. However, it is currently unknown which tissue(s) contribute to this glucose-lowering effect. Thus, to elucidate this effect, we treated euglycemic mice with H7, a monoclonal antibody that selectively targets FGFR1c, and used whole-body positron emission computed tomography with a glucose tracer (18F-fluorodeoxyglucose). Treatment with H7 increased basal glucose uptake in white adipose tissue (WAT), brown adipose tissue (BAT), the brain, and liver but reduced it in the quadriceps muscles. Consequentially, blood glucose was significantly reduced in response to treatment. Under insulin-stimulated conditions, the effects of H7 were maintained in WAT, BAT, liver, and muscle. Treatment with H7 decreased triglyceride (TG) content and increased adipose TG lipase content in white adipose tissue, while increasing activation of acetyl coenzyme A carboxylase, suggesting futile cycling of TGs, albeit favoring net hydrolysis. We demonstrated, in vitro, this is a direct effect of treatment in adipose tissue, as basal cellular respiration and glucose uptake were increased in response to treatment. Taken together, these data suggest that antibody-mediated targeting of FGFR1c exerts its powerful glucose-lowering efficacy primarily due to increased glucose uptake in adipose tissue. Targeting the FGFR1c isoform reduces blood glucose via increased uptake in adipose tissue. This is a direct effect of treatment and appears to lead to a futile (re)cycling of triglyceride content. |
| Databáze: | OpenAIRE |
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