A combination therapy for the treatment of obesity and obesity-related metabolic disorders
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AbstractINTRODUCTION: Obesity is becoming a global epidemic and increases the risk of various metabolic disorders including type 2 diabetes and non‐alcoholic fatty liver disease. Although there are several anti‐obesity medications approved by U.S. Food and Drug Administration, they have low efficacies in causing substantial weight loss to achieve health benefits and have various side effects. More effective pharmacotherapies are therefore in great need. Metformin is a first line medication for type 2 diabetes, and has been reported to have mild effects on inducing weight loss. Recent data from our laboratory show that recombinant human arginase (rhArg) has potent anti‐obesity and insulin sensitizing effects. This study aims to investigate the efficacy of combined treatment of rhArg and metformin on obesity and obesity‐associated metabolic disorders.
METHODS: A diet‐induced obesity (DIO) mouse model was used for the study. In brief, C57BL/6J male mice were fed a high‐fat diet (HFD) for 3 months. By that time, besides exhibiting an increase in bodyweight, the mice had developed hepatic steatosis, elevated blood glucose, impaired glucose tolerance and insulin resistance. The DIO mice were then stratified into 4 groups according to bodyweight, and received single treatment of either metformin or rhArg, or combined treatment of both drugs, or their vehicles. Age‐matched mice that were fed a chow diet and treated with vehicles served as the lean control. Glucose tolerance test and insulin tolerance test were conducted during the second month after commencement of the dosing regimen. At the end of 9 weeks of treatment, serum and tissues of various organs were collected for histological, biochemical and molecular analyses.
RESULTS: We found that combined treatment of rhArg and metformin had synergetic effects on inducing weight loss. Moreover, insulin sensitivity and glucose tolerance were significantly improved, and hepatic steatosis was markedly alleviated. We further found that the lipogenesis pathway was greatly inhibited, while lipolysis and lipid oxidation pathways were activated.
DISCUSSION & CONCLUSIONS: In summary, rhArg and metformin show good combination effects on reducing obesity and alleviating various obesity‐associated metabolic disorders. Metformin is clinically in use with few adverse effects, and arginine depletion using rhArg has shown to be well‐tolerated in clinical trials. Our present findings support that combined treatment of metformin and rhArg has good potential to be developed into a novel therapeutic strategy for obesity and its related metabolic disorders.
ACKNOWLEDGEMENTS: This study is supported by the Lo Ka Chung Charitable Foundation.
METHODS: A diet‐induced obesity (DIO) mouse model was used for the study. In brief, C57BL/6J male mice were fed a high‐fat diet (HFD) for 3 months. By that time, besides exhibiting an increase in bodyweight, the mice had developed hepatic steatosis, elevated blood glucose, impaired glucose tolerance and insulin resistance. The DIO mice were then stratified into 4 groups according to bodyweight, and received single treatment of either metformin or rhArg, or combined treatment of both drugs, or their vehicles. Age‐matched mice that were fed a chow diet and treated with vehicles served as the lean control. Glucose tolerance test and insulin tolerance test were conducted during the second month after commencement of the dosing regimen. At the end of 9 weeks of treatment, serum and tissues of various organs were collected for histological, biochemical and molecular analyses.
RESULTS: We found that combined treatment of rhArg and metformin had synergetic effects on inducing weight loss. Moreover, insulin sensitivity and glucose tolerance were significantly improved, and hepatic steatosis was markedly alleviated. We further found that the lipogenesis pathway was greatly inhibited, while lipolysis and lipid oxidation pathways were activated.
DISCUSSION & CONCLUSIONS: In summary, rhArg and metformin show good combination effects on reducing obesity and alleviating various obesity‐associated metabolic disorders. Metformin is clinically in use with few adverse effects, and arginine depletion using rhArg has shown to be well‐tolerated in clinical trials. Our present findings support that combined treatment of metformin and rhArg has good potential to be developed into a novel therapeutic strategy for obesity and its related metabolic disorders.
ACKNOWLEDGEMENTS: This study is supported by the Lo Ka Chung Charitable Foundation.
All Author(s) ListXiuhua Zheng, Leo Man Yuen Lee, Thomas Yun Chung Leung, Alisa Sau Wun Shum
Name of ConferenceTissue Engineering and Regenerative Medicine International Society (TERMIS) European Chapter Meeting 2023
Start Date of Conference28/03/2023
End Date of Conference31/03/2023
Place of ConferenceManchester
Country/Region of ConferenceGreat Britain
Proceedings TitleTissue Engineering Part A
Title of PublicationA combination therapy for the treatment of obesity and obesity-related metabolic disorders
Year2023
Month6
Day30
Volume Number29
Issue Number13-14
PublisherMary Ann Liebert, Inc.
Article numberPP‐241
ISSN1937-3341
eISSN1937-335X
LanguagesEnglish-United Kingdom
KeywordsDisease models
