單碳代謝為生物體內甲基的代謝過程，包含了葉酸循環、同半胱氨酸轉硫及轉甲基反應、甲硫胺酸及腺苷甲硫胺酸生合成、核苷酸合成等重要代謝路徑。 不同的研究暗示能量平衡可能與單碳代謝關係密切：先前研究發現肥胖者其血中甘胺酸的濃度較低。此外運動則會降低正常馬模型的血中甘胺酸和絲氨酸的濃度。有研究顯示限制卡路里在果蠅模型中會增加二磷酸腺苷和單磷酸腺苷的合成。在酵母菌模型中則會維持三磷酸腺苷的濃度。這些變化可能會造成體內單碳代謝的改變。本研究的目的在於探討長期餵食高脂飲食、長期有氧運動、長期阻力運動以及和長期限制卡路里對於體內單碳代謝之影響。 

Background and Objective. Obesity has become a worldwide epidemic disease and has a serious impact on the healthy development of the human body, which is a major hidden danger to public health. Ketogenic diet (KD) induces a unique metabolic state in mice including weight loss, low circulating glucose and triglycerides, high serum ketones and increased energy expenditure. It is unclear which alterations in one carbon metabolism result from protein/methionine restriction and/or from KD. The main objective of this study was to investigate the one carbon flow in ketogenic diet effect under sufficient protein and methionine. Study Design. GNMT expressing HepG2 cells that treated with physiological doses (1mM and 10mM) of ketone body β-hydroxybutyrate (BHB) were utilized as our in vitro model. Six-week old adult male C57BL/6JNarl mice (obtained from National Laboratory Animal Center) were utilized as our in vivo model. Mice were split into four groups at 8 weeks of age and housed under pathogen-free conditions on 12h day/night cycle and allowed ad labium access to food. Lard and medium-chain fatty acids (MCT) were used as the fat sources of the 2 ketogenic diets of the present study. Stable isotopic labeling experiments were performed in vivo to trace the one-carbon metabolic fluxes. Both KD diets resulted in elevated plasma BHB concentrations, proving both our in vivo ketogenic models were successful. Our data suggest that KD may re-direct the utilization and the partitioning of one carbon metabolic fluxes in humans.
肥胖已成為一種全球流行病，並且嚴重影響人體健康發展，生酮飲食在過去研究中表明可以減輕體重、增加能量消耗。生酮飲食是一種高脂肪、低碳水化合物的飲食，在生酮狀態下傾向於使用酮體和脂肪作為能量來源，一個葡萄糖和一個酮體皆能代謝形成兩個乙醯輔酶A，這些分子隨後進入檸檬酸循環並參與能量產生，然而酮體代謝的過程還原 NAD+ (菸鹼醯胺腺嘌呤二核苷酸)相對糖代謝少，因此生酮飲食會使腦中NAD+/NADH 比例改變。過去研究表示生酮飲食可以提高肌肉與肝臟中的AMPK (單磷酸腺苷活化蛋白質激酶)並抑制mTORC1 (雷帕黴素複合物1的哺乳動物靶標)來達到壽命延長的效果，且 AMPK可以提升NAD+。我們在體內以穩定同位素標定的方法探索給予豬油與中鏈脂肪作為主要能量來源的生酮飲食單碳代謝相關路徑的影響。過去研究尚未探討在無甲硫胺酸限制與膽鹼限制的生酮飲食且給予不同的脂肪來源進行單碳代謝之追蹤此為我們實驗的新穎性之一。

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單碳代謝為生物體內甲基的代謝過程，包含了葉酸循環、同半胱氨酸轉硫及轉甲基反應、甲硫胺酸及腺苷甲硫胺酸生合成、核苷酸合成等重要代謝路徑。 不同的研究暗示能量平衡可能與單碳代謝關係密切：先前研究發現肥胖者其血中甘胺酸的濃度較低。此外運動則會降低正常馬模型的血中甘胺酸和絲氨酸的濃度。有研究顯示限制卡路里在果蠅模型中會增加二磷酸腺苷和單磷酸腺苷的合成。在酵母菌模型中則會維持三磷酸腺苷的濃度。這些變化可能會造成體內單碳代謝的改變。本研究探討長期餵食高脂飲食、長期有氧運動、長期阻力運動以及和長期限制卡路里對於體內單碳代謝之影響。在動物模型中，不同類型的飲食和運動模式會影響單碳代謝產物和酵素表現，也會部份影響單碳代謝途徑在粒線體和胞內的變化。本研究提供多項證據顯示高脂飲食、有氧運動、阻力運動和限制卡路里對於單碳代謝的影響。

脂肪酸的組成在生物體細胞膜結構以及能量代謝與儲存中扮演重要角色。魚油補充在人類跟小鼠中可以透過降低血漿中三酸甘油脂進而減少心血管疾病的風險。同半胱氨酸則是獨立的心血管疾病的危險因子。先前文獻中關於魚油對同半胱氨酸含量的影響並無一致結論。研究還顯示在高糖高氧化壓力下補充魚油會降低小鼠肝臟中硫腺苷基甲硫氨酸，但在正常情況下卻會造成甲硫氨酸腺苷基轉移酶活性上升。本研究探討不同脂肪酸以及膳食中的魚油補充對硫腺苷基甲硫氨酸代謝的影響，並希望對之前的不一致的文獻結果做進一步探討其可能原因。 我們在細胞實驗中使用特定穩定性同位素標定探討脂肪酸對轉甲基路徑的分流的變化。動物模式中探討老鼠短期或是跨代補充魚油對不同組織的脂肪酸組成及s-腺苷基甲硫氨酸代謝的影響。在動物模型中還發現代謝疾病會影響小鼠肝臟中脂肪酸比例。長期和短期補充魚油會影響老鼠的肝臟單碳代謝。

Background. The epidemic occurrence of obesity in the general population has caused an increase in the incidence of obesity-associated diseases. Endurance exercise significantly attenuated high-fat diet-induced obesity. Caloric restriction dramatically prevented high-fat diet-induced metabolic abnormalities. The objective of this study was to investigate the effects of long-term high fat consumption, physical activity and caloric restriction on one-carbon metabolism. Design and Methods. Forty-two male C57BL/6JNarl mice aged 5-week-old, were randomly assigned to three treatment groups: control diet group, caloric restriction diet group and high-fat diet group. After 12 weeks of dietary intervention, CTL group were further subdivided into control and control diet with exercise; high-fat diet-fed mice were further subdivided into high-fat diet, high-fat diet with exercise, control diet with 30% caloric restriction, and control diet with 30% caloric restriction combined exercise groups. Metabolic kinetic studies were conducted after the 15-week intervention period by stable isotopic tracers and GC/MS.

Results and conclusions. Long-term high-fat consumption, caloric restriction, or physical activity significantly altered body weight and body fat. They also significantly altered hepatic adenosylmethionine formation and utilization. Long-term high-fat consumption and caloric restriction significantly altered hepatic transmethylation gene expression profile whereas global genomic DNA methylation remained unchanged in the liver. Some of the alterations induced by high fat consumption were reversed by caloric restriction and/or physical activity. Further studies are needed to determine the underlying mechanism(s) by which maternal high-fat exposure during may result in alterations in 1-carbon metabolism.
肥胖在全世界的盛行率有逐年上升的趨勢，與肥胖相關的疾病也隨之增加。先前研究指出體能活動可以明顯減低高脂肪飲食所引起的肥胖。此外，也有文獻指出給予熱量限制的飲食可以有效地防止高脂肪飲食所引起的代謝異常。單碳代謝參與人體許多重要的生理調控路徑，並且影響生物體內的甲基化變化，而單碳代謝的失調在人體疾病過程也扮演重要角色。本研究的目的為探討給予不同的飲食介入與體能活動對於單碳代謝的影響。給予小鼠不同飲食介入及體能活動，分析其單碳代謝路徑中相關代謝產物、酵素活性、基因表現並以穩定同位素追蹤單碳路徑動態平衡變化。在動物模式中，高脂肪飲食介入會導致小鼠的肥胖，並且影響單碳代謝相關酵素的活性；而給予不同飲食介入及體能活動後，也會部分影響單碳代謝途徑的變化。高脂肪飲食誘發肥胖所造成的體內單碳代謝改變，可以部分的被不同飲食介入或體能活動扭轉回復。