Effects of long-term leptin administration on homocysteine transmethylation and transsulfuration

Abstract

Our previous study demonstrated novel finding of a direct promoting effect of high cellular insulin or glucose exposure on homocysteine remethylation, adoMet synthase activity, and adoMet synthesis. We have also provided new evidence indicating that when hepatic tissue is exposed to elevated insulin or glucose, the cellular methylation balance is altered. Hyperleptinemia is commonly seen in humans suffering from metabolic syndrome or type II diabetes; and leptin concentration has been suggested as an independent predictor of type II diabetes in men. However, the impact of path physiological elevations in leptin on homocysteine metabolism is not fully illustrated. The objective of the study was to investigate the impact of elevated leptin on homocysteine metabolism and methyl group kinetics in vivo. Effects of long-term leptin administration on homocysteine transmethylation and transsulfuration metabolic fluxes were investigated in mouse models using stable isotopic tracers and gas chromatography/mass spectrometry. Homocysteine remethylation and transsulfuration metabolic fluxes were investigated using stable isotopic tracers and gas chromatography/mass spectrometry. The methylation status was determined. Our preliminary in vivo study indicated that long-term leptin administration altered homocysteine metabolism in a tissue specific manner.

本研究室近期在體外研究發現胰島素對於細胞內同半胱胺酸代謝影響顯著。另外也發現當細胞暴露在高糖情況時其同半胱氨酸轉硫反應會受到抑制而其再甲基化代謝路徑會促進而提腺甘甲硫氨酸合成。除血糖及胰島素異常，人類的第二型糖尿病常伴隨高瘦體素血症。瘦體素是一種脂肪細胞生成的細胞激素。有研究顯示瘦體素在代謝症候群的發展過程中可能扮演獨立的角色，然而瘦體素如何影響同半胱胺酸代謝以及甲基動態平衡目前尚未闡明。本研究以動物模式長期介入生理劑量的瘦體素探討其對於同半胱胺酸代謝影響，並以同位素及氣相層析質譜儀分析體內實驗中瘦體素如何影響同半胱胺酸轉硫及轉甲基代謝分流，並對於體內長期暴露在瘦體素狀況時甲基族動態平衡做全面性探討。同半胱胺酸代謝異常是心血管疾病獨立危險因子之一。細胞內的同半胱胺酸可透過再甲基化作用合成甲硫胺酸或是經轉硫作用降解。本研究對於釐清糖尿病或代謝症候群或其他高瘦體素血症狀況對於體內同半胱胺酸轉甲基與轉硫代謝機轉之影響有所貢獻。