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

• Published in: International Journal of Obesity Vol. 44; no. 2; pp. 500 - 509
• Main Authors: Flores-Opazo, Marcelo, Trieu, Jennifer, Naim, Timur, Valladares-Ide, Denisse, Zbinden-Foncea, Hermann, Stapleton, David
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.02.2020; Nature Publishing Group
• Subjects: 631/443/319/1642/393; 631/443/319/2723; 82; 82/1; 82/29; 82/80; Activation; Adipocytes; Adipose tissue; Adipose Tissue - enzymology; Adipose Tissue - metabolism; Adipose tissues; Animals; Blood Glucose - metabolism; Body fat; Carbohydrate metabolism; Carbohydrates; Cyclic adenylic acid; Cyclic AMP-Dependent Protein Kinases - metabolism; Deactivation; Defects; Dextrose; Enzymatic activity; Enzyme activity; Enzymes; Epidemiology; Ethylenediaminetetraacetic acid; Fasting; Fasting - physiology; Female; Glucose; Glucose metabolism; Glucose transporter; Glycogen; Glycogen - metabolism; Glycogen phosphorylase; Glycogen synthase; Glycogens; Health Promotion and Disease Prevention; Inactivation; Insulin; Insulin - metabolism; Insulin resistance; Internal Medicine; Kinases; Laboratory testing; Lipid metabolism; Lipids; Male; Medicine; Medicine & Public Health; Metabolic Diseases; Metabolism; Obesity; Obesity - metabolism; Phosphorylase; Phosphorylases; Phosphorylation; Physiological aspects; Protein binding; Protein kinase A; Protein kinases; Proteins; Public Health; Rats; Rats, Zucker; Rodents; Synthesis; United States
• ISSN: 0307-0565; 1476-5497
• DOI: 10.1038/s41366-019-0327-y

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.