Andres-Hernando Ana, Jensen Thomas J, Kuwabara Masanari, Orlicky David J, Cicerchi Christina, Li Nanxing, Roncal-Jimenez Carlos A, Garcia Gabriela E, Ishimoto Takuji, Maclean Paul S, Bjornstad Petter, Sanchez-Lozada Laura Gabriela, Kanbay Mehmet, Nakagawa Takahiko, Johnson Richard J, Lanaspa Miguel A
Division of Renal Diseases and Hypertension and.
Division of Endocrine, Diabetes, and Metabolism, University of Colorado Denver, Aurora, Colorado, USA.
JCI Insight. 2021 Jan 11;6(1):140848. doi: 10.1172/jci.insight.140848.
Subjects with obesity frequently have elevated serum vasopressin levels, noted by measuring the stable analog, copeptin. Vasopressin acts primarily to reabsorb water via urinary concentration. However, fat is also a source of metabolic water, raising the possibility that vasopressin might have a role in fat accumulation. Fructose has also been reported to stimulate vasopressin. Here, we tested the hypothesis that fructose-induced metabolic syndrome is mediated by vasopressin. Orally administered fructose, glucose, or high-fructose corn syrup increased vasopressin (copeptin) concentrations and was mediated by fructokinase, an enzyme specific for fructose metabolism. Suppressing vasopressin with hydration both prevented and ameliorated fructose-induced metabolic syndrome. The vasopressin effects were mediated by the vasopressin 1b receptor (V1bR), as V1bR-KO mice were completely protected, whereas V1a-KO mice paradoxically showed worse metabolic syndrome. The mechanism is likely mediated in part by de novo expression of V1bR in the liver that amplifies fructokinase expression in response to fructose. Thus, our studies document a role for vasopressin in water conservation via the accumulation of fat as a source of metabolic water. Clinically, they also suggest that increased water intake may be a beneficial way to both prevent or treat metabolic syndrome.
肥胖受试者的血清血管加压素水平通常会升高，这可通过测量其稳定类似物—— copeptin来发现。血管加压素主要通过尿液浓缩作用来重吸收水分。然而，脂肪也是代谢水的一个来源，这增加了血管加压素可能在脂肪积累中发挥作用的可能性。据报道，果糖也能刺激血管加压素。在此，我们检验了果糖诱导的代谢综合征由血管加压素介导这一假说。口服给予果糖、葡萄糖或高果糖玉米糖浆会增加血管加压素（copeptin）的浓度，且这一过程由果糖激酶介导，果糖激酶是一种对果糖代谢具有特异性的酶。通过补充水分来抑制血管加压素，既能预防也能改善果糖诱导的代谢综合征。血管加压素的作用是由血管加压素1b受体（V1bR）介导的，因为V1bR基因敲除小鼠得到了完全保护，而V1a基因敲除小鼠却反常地表现出更严重的代谢综合征。其机制可能部分是由肝脏中V1bR的从头表达介导的，这种表达会在果糖的刺激下增强果糖激酶的表达。因此，我们的研究证明了血管加压素通过脂肪积累作为代谢水来源在保水方面的作用。临床上，这些研究还表明增加水的摄入量可能是预防或治疗代谢综合征的一种有益方法。
