Hepatic adaptations to maintain metabolic homeostasis in response to fasting and refeeding in mice.
Hepatic adaptations to maintain metabolic homeostasis in response to fasting and refeeding in mice.
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DOI：
10.1186/s12986-016-0122-x
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发表时间：
2016
影响因子：
4.5
通讯作者：
Renquist BJ
中科院分区：
文献类型：
--
作者：
Geisler CE;Hepler C;Higgins MR;Renquist BJ
肥胖和相关代谢性疾病发病率的增加推动了从遗传或药物上缓解代谢功能障碍的研究。这些研究采用了一系列的禁食-再喂养模式，包括4-24小时禁食、“过夜”禁食或进餐。尽管如此，我们仍然缺乏文献来描述禁食和重新进食持续时间的变化所带来的生理上的适应。由于肝脏是全身代谢动态平衡的中心，我们研究了快速诱导的糖原分解、糖异生和酮类生成的时间，以及膳食诱导的糖原生成和远离酮类生成的转换。12~14周龄雄性C57BL/6J小鼠禁食0、4、8、12、16小时，点灯后处死4小时。在另一项旨在了解进食反应的研究中，我们让禁食的小鼠在牺牲前喂养1到2个小时。采用混合模型方差分析方法对数据进行分析。禁食引发了强烈的代谢变化，表现为血糖、非酯化脂肪酸(NEFA)、三酰甘油和β-OH丁酸盐以及肝脏三酰甘油、非酯化脂肪酸和糖原含量的变化。糖原分解是在禁食的前8小时内维持血糖的主要来源，而从头开始的糖异生是此后的主要来源。血清β-OH丁酸的增加是由于β氧化和乙酰辅酶A分流到酮体合成(分别增加了CPT1(肉毒碱棕榈酰转移酶1)和HMGCS2(3-羟基-3-甲基戊二酰辅酶A合成酶2)的表达)增加了酶对脂肪酸流动的能力。与对禁食的相对缓慢的代谢适应相反，进食一餐会导致快速的代谢变化，包括在一小时内完全抑制血清β-OH丁酸和NEFAs。在这里，我们提供了代谢适应时间的详细描述，以响应禁食和再喂养，为代谢稳态实验的研究设计提供信息。由于禁食和肥胖都以脂肪组织脂解升高、肝脏脂肪堆积、酮体生成和糖异生为特征，了解从禁食状态到摄食状态代谢转变背后的驱动因素可能为限制肥胖症中异常的糖异生和酮体生成提供靶点。
The increased incidence of obesity and associated metabolic diseases has driven research focused on genetically or pharmacologically alleviating metabolic dysfunction. These studies employ a range of fasting-refeeding models including 4–24 h fasts, “overnight” fasts, or meal feeding. Still, we lack literature that describes the physiologically relevant adaptations that accompany changes in the duration of fasting and re-feeding. Since the liver is central to whole body metabolic homeostasis, we investigated the timing of the fast-induced shift toward glycogenolysis, gluconeogenesis, and ketogenesis and the meal-induced switch toward glycogenesis and away from ketogenesis. Twelve to fourteen week old male C57BL/6J mice were fasted for 0, 4, 8, 12, or 16 h and sacrificed 4 h after lights on. In a second study, designed to understand the response to a meal, we gave fasted mice access to feed for 1 or 2 h before sacrifice. We analyzed the data using mixed model analysis of variance. Fasting initiated robust metabolic shifts, evidenced by changes in serum glucose, non-esterified fatty acids (NEFAs), triacylglycerol, and β-OH butyrate, as well as, liver triacylglycerol, non-esterified fatty acid, and glycogen content. Glycogenolysis is the primary source to maintain serum glucose during the first 8 h of fasting, while de novo gluconeogenesis is the primary source thereafter. The increase in serum β-OH butyrate results from increased enzymatic capacity for fatty acid flux through β-oxidation and shunting of acetyl-CoA toward ketone body synthesis (increased CPT1 (Carnitine Palmitoyltransferase 1) and HMGCS2 (3-Hydroxy-3-Methylglutaryl-CoA Synthase 2) expression, respectively). In opposition to the relatively slow metabolic adaptation to fasting, feeding of a meal results in rapid metabolic changes including full depression of serum β-OH butyrate and NEFAs within an hour. Herein, we provide a detailed description of timing of the metabolic adaptations in response to fasting and re-feeding to inform study design in experiments of metabolic homeostasis. Since fasting and obesity are both characterized by elevated adipose tissue lipolysis, hepatic lipid accumulation, ketogenesis, and gluconeogenesis, understanding the drivers behind the metabolic shift from the fasted to the fed state may provide targets to limit aberrant gluconeogenesis and ketogenesis in obesity.
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影响因子：
4
作者：
Caton, Paul W.;Nayuni, Nanda K.;Corder, Roger
通讯作者：
Corder, Roger
影响因子：
4.1
作者：
HOLNESS, MJ;MACLENNAN, PA;SUGDEN, MC
通讯作者：
SUGDEN, MC
DOI：
10.1152/ajpendo.90617.2008
发表时间：
2008-12-01
影响因子：
5.1
作者：
Andrikopoulos, Sofianos;Blair, Amy R.;Proietto, Joseph
通讯作者：
Proietto, Joseph
影响因子：
24
作者：
Beltran-Sanchez, Hiram;Harhay, Michael O.;Harhay, Meera M.;McElligott, Sean
通讯作者：
McElligott, Sean
DOI：
10.1016/s0006-291x(03)01409-8
发表时间：
2003-08-29
影响因子：
3.1
作者：
Cheng, G;Polito, CC;Chavin, KD
通讯作者：
Chavin, KD