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Loss of APJ mediated β-arrestin signalling improves high-fat diet induced metabolic dysfunction but does not alter
Na Li1, Xiaochuan Ma1, Ting Ban1
1Amgen Research, Amgen Biopharmaceutical R&D (Shanghai) Co., Ltd, Shanghai 201210, China.
Abstract:
Apelin receptor (APJ) is a G protein-coupled receptor that contributes to many physiological processes and is emerging as a therapeutic target to treat a variety of diseases. For most disease indications the role of G protein vs β-arrestin signalling in mitigating disease pathophysiology remains poorly understood. This hinders the development of G protein biased APJ agonists, which have been proposed to have several advantages over balanced APJ signalling agonists. To elucidate the contribution of APJ β-arrestin signalling, we generated a transgenic mouse harbouring a point mutation (APJ I107A) that maintains full G protein activity but fails to recruit β-arrestin following receptor activation. APJ I107A mutant mice did not alter cardiac function at rest, following exercise challenge or in response to pressure overload induced cardiac hypertrophy. Additionally, APJ I107A mice have comparable body weights, plasma glucose and lipid levels relative to WT mice when fed a chow diet. However, APJ I107A mice showed significantly lower body weight, blood insulin levels, improved glucose tolerance and greater insulin sensitivity when fed a high-fat diet. Furthermore, loss of APJ β-arrestin signalling also affected fat composition and the expression of lipid metabolism related genes in adipose tissue from high-fat fed mice. Taken together, our results suggest that G protein biased APJ activation may be more effective for certain disease indications given that loss of APJ mediated β-arrestin signalling appears to mitigate several aspects of diet induced metabolic dysfunction.
Insights
Targeting the apelin receptor (APJ) with G protein biased agonists may improve metabolic dysfunction. Loss of APJ β-arrestin signaling mitigated diet-induced metabolic issues in mice.
Area of Science:
- Pharmacology
- Cardiovascular Biology
- Metabolic Research
Background:
- The apelin receptor (APJ) is a G protein-coupled receptor involved in numerous physiological processes.
- Understanding the distinct roles of G protein and β-arrestin signaling pathways of APJ is crucial for developing targeted therapies.
- The therapeutic potential of G protein-biased APJ agonists remains largely unexplored due to incomplete knowledge of pathway-specific functions.
Purpose of the Study:
- To investigate the specific role of APJ β-arrestin signaling in physiological and pathophysiological conditions.
- To determine the effects of selectively disrupting APJ β-arrestin recruitment on metabolic and cardiac functions.
- To evaluate the potential of G protein-biased APJ agonism as a therapeutic strategy.
Main Methods:
- Generation of a transgenic mouse model (APJ I107A) with intact G protein activity but impaired β-arrestin recruitment.
- Assessment of cardiac function at rest, during exercise, and under pressure overload.
- Metabolic phenotyping, including body weight, glucose tolerance, insulin sensitivity, and plasma lipid profiles, under chow and high-fat diet conditions.
Main Results:
- APJ I107A mutant mice exhibited normal cardiac function under various physiological and stress conditions.
- While metabolic parameters were similar to wild-type mice on a chow diet, APJ I107A mice displayed reduced body weight, lower insulin levels, improved glucose tolerance, and enhanced insulin sensitivity on a high-fat diet.
- Disruption of APJ β-arrestin signaling altered adipose tissue composition and gene expression related to lipid metabolism in mice fed a high-fat diet.
Conclusions:
- Selective loss of APJ β-arrestin signaling mitigates diet-induced metabolic dysfunction without compromising cardiac function.
- G protein-biased activation of APJ may offer therapeutic advantages for specific disease indications, particularly metabolic disorders.
- These findings support the development of G protein-biased APJ agonists for treating metabolic diseases.
