Department of Physiology, University of Melbourne, Parkville, 3010, VIC, Australia.
Laboratory of Exercise Sciences, School of Physiotherapy, Universidad Finis Terrae, Santiago, Chile.
Int J Obes (Lond). 2020 Feb;44(2):500-509. doi: 10.1038/s41366-019-0327-y. Epub 2019 Jan 31.
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.
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.
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; p < 0.005 fed vs fasted, and obese: 5.23 ± 3.38 to 5.019 ± 1.99 µg.mg; 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.
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.
肥胖与脂肪组织（AT）中胰岛素抵抗的发展有关。人类肥胖与脂肪细胞中糖原沉积增加有关。脂肪细胞在形成脂肪之前合成糖原。本研究检查了肥胖 Zucker 大鼠的脂肪组织糖原含量以及禁食对糖原代谢酶的影响。我们假设肥胖通过削弱糖原代谢酶的激活来对禁食产生迟钝的反应，从而抑制肥胖 Zucker 大鼠的糖原动员。
我们研究了 24 小时禁食对 12 周龄肥胖 Zucker 大鼠脂肪组织糖原代谢的影响。从自由喂养和禁食 24 小时的大鼠的附睾脂肪垫中收集脂肪组织。分析了糖原含量、糖原合酶和磷酸化酶酶活性以及蛋白激酶 A（PKA）活性，以及糖原代谢酶糖原合酶和磷酸化酶、葡萄糖转运蛋白 GLUT4 和 cAMP 反应元件结合蛋白的总蛋白和磷酸化蛋白含量。
12 周龄肥胖 Zucker 大鼠的脂肪组织糖原含量增加（脂肪组织糖原含量[平均值±标准差]，瘦鼠：3.95±2.78 至 0.75±0.69μg.mg；p<0.005 禁食与进食，肥胖鼠：5.23±3.38 至 5.019±1.99μg.mg；p=ns 禁食和进食，p<0.005 瘦鼠与肥胖鼠），并且在禁食 24 小时后，糖原动员受到损害。这些缺陷与功能失调的糖原代谢酶有关，其特征为：（1）糖原磷酸化酶磷酸化介导的激活受损和蛋白表达下调，（2）糖原合酶磷酸化介导的失活受损。此外，这些缺陷与禁食诱导的蛋白激酶 A（PKA）激活受损有关。
本研究提供了证据表明，脂肪组织中的糖原代谢存在缺陷，与禁食诱导的上游激酶蛋白激酶 A 的激活受损有关，这为肥胖相关的碳水化合物和脂肪代谢在 AT 中的原发性改变提供了一个收敛点。
