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Physiology

Defective fasting-induced PKA activation impairs adipose tissue glycogen degradation in obese Zucker rats

International Journal of Obesity volume 44, pages 500–509 (2020)Cite this article

Subjects

Abstract

Background

Obesity is associated with development of insulin resistance in adipose tissue (AT). Human obesity has been associated with increased glycogen deposition in adipocytes. Adipocytes synthesise glycogen prior to the formation of lipids. The present study examined adipose glycogen content in obese Zucker rats and the effect of fasting on glycogen-metabolising enzymes. We hypothesised that obesity imposes a blunted response to fasting through impaired activation of glycogen-metabolizing enzymes, which dampens glycogen mobilization in obese Zucker rats.

Methods

We investigated the effect of 24h fasting on AT glycogen metabolism in 12-week old obese Zucker rats. Epididymal fat pads were collected from rats fed ad-libitum and fasted for 24h. Glycogen content, glycogen synthase and phosphorylase enzyme activity, and PKA activity were analysed as well as total and phosphorylated protein content for glycogen-metabolizing enzymes glycogen synthase and phosphorylase, glucose transporter GLUT4, and cAMP-dependent response element binding protein levels.

Results

Twelve-week old obese Zucker rats showed increased AT glycogen content (adipose glycogen content [mean ± SD], lean: 3.95 ± 2.78 to 0.75 + 0.69 µg.mg−1; p < 0.005 fed vs fasted, and obese: 5.23 ± 3.38 to 5.019 ± 1.99 µg.mg−1; p = ns fed and fasted and p < 0.005 lean vs obese), and impaired fasting-induced glycogen mobilization following a 24h fast. These defects were associated with dysfunctional glycogen-metabolizing enzymes, characterized by: (1) blunted phosphorylation-mediated activation and downregulated protein expression of glycogen phosphorylase, and (2) an impaired phosphorylation-mediated inactivation of glycogen synthase. Furthermore, these defects were related to impaired fasting-induced protein kinase A (PKA) activation.

Conclusion

This study provides evidence of a defective glycogen metabolism in the adipose associated with impaired fasting-induced activation of the upstream kinase protein kinase A, which render a converging point to obesity-related primary alterations in carbohydrate and lipid metabolism in the AT.

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Data availability

Information and data supporting the results of this investigation are included within the article and are available from the corresponding author on reasonable request.

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Acknowledgements

The authors gratefully acknowledge professor Dr. Mark Hargreaves from the department of Physiology, faculty of Medicine, University of Melbourne, for his support and assistance throughout the project, and the review and comments provided during the preparation of this manuscript.

Funding

MFO was granted by the Becas Chile scholarship program of CONYCIT.

Author contributions

DS and MFO designed the study. MFO acquired data, analyzed/interpreted data, wrote and revised the manuscript. JT and TN conducted animal dissections. DS, DVI and HZF analyzed/interpreted data and reviewed the manuscript. All authors are fully responsible for all content and editorial decisions and were involved at all stages of manuscript development, and have approved the final version of the manuscript to be published.

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Authors and Affiliations

  1. Department of Physiology, University of Melbourne, Parkville, 3010, VIC, Australia

    Marcelo Flores-Opazo, Jennifer Trieu, Timur Naim & David Stapleton

  2. Laboratory of Exercise Sciences, School of Physiotherapy, Universidad Finis Terrae, Santiago, Chile

    Marcelo Flores-Opazo, Denisse Valladares-Ide & Hermann Zbinden-Foncea

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Correspondence to Marcelo Flores-Opazo.

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Flores-Opazo, M., Trieu, J., Naim, T. et al. Defective fasting-induced PKA activation impairs adipose tissue glycogen degradation in obese Zucker rats. Int J Obes 44, 500–509 (2020). https://doi.org/10.1038/s41366-019-0327-y

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