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GIP Receptor Antagonist, SKL-14959 Indicated Alteration of the Lipids Metabolism to Catabolism by the Inhibition of Plasma LPL Activity, Resulting in the Suppression of Weight Gain on Diets-Induced Obesity Mice

Authors Nakamura T, Tanimoto H, Okamoto M, Takeuchi M, Tsubamoto Y, Noda H

Received 22 December 2020

Accepted for publication 16 February 2021

Published 9 March 2021 Volume 2021:14 Pages 1095—1105

DOI https://doi.org/10.2147/DMSO.S297353

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 3

Editor who approved publication: Prof. Dr. Juei-Tang Cheng


Takashi Nakamura, Hitomi Tanimoto, Masayuki Okamoto, Mitsuaki Takeuchi, Yoshiharu Tsubamoto, Hitoshi Noda

Biological Research Group Drug Discovery Laboratories, Sanwa Kagaku Kenkyusho, Mie, Japan

Correspondence: Takashi Nakamura
Sanwa Kagaku Kenkyusho, Biological Research Group Drug Discovery Laboratories, 363 Shiosaki, Hokusei-Cho, Inabe-City, Mie, 511-0406, Japan
Tel +81-594-72-6221
Fax +81-594-72-0071
Email [email protected]

Introduction: Glucose-dependent insulinotropic polypeptide (GIP) plays a crucial role in the regulation of lipid metabolism via lipoprotein lipase (LPL). GIP receptor antagonist, SKL-14959, suppressed the weight gain in the diet-induced obesity model. However, the mechanism is not unclear. Therefore, we aimed to give insight into the reason.
Methods: Mice were divided into three groups of the low-fat diet, high-fat diets mixture with or without SKL-14959 for 151 days, and were monitored body weight and food consumption through the test. Oral glucose tolerance test (OGTT) and insulin tolerance test (ITT) were also performed. After that, blood, liver, muscle and adipose tissue were collected. Blood samples were measured glycosylated hemoglobin A1c (HbA1c), glucose, insulin, GIP level and plasma LPL activity. Triacylglycerol (TG) contents of liver and muscles were also measured. Moreover, a simple correlation analysis was performed.
Results: SKL-14959 suppressed the body weight gain, decreased body mass index (BMI), HbA1c, and fasting glucose level, and trended to decline adipose tissues weight and TG contents compared with the vehicle, and inhibited plasma LPL activity. OGTT and ITT in the SKL-14959 group were not significantly changed relative to the vehicle. Additionally, upon treatment with SKL-14959 treatment, weight gain had weak correlation with lipase activity. Furthermore, lipase activity was associated with the fat mass and not white but red muscle TG contents and liver TG contents were not associated with lipase activity but HbA1c.
In Conclusion: SKL-14959 might direct lipids metabolism to catabolism by inhibition of plasma LPL activity, resulting in the suppression of weight gain on diets-induced obesity mice.

Keywords: GIP, GIP receptor antagonist, anti-obesity, lipase activity, lipid metabolism

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