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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:1571.)
© 2009 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Ketogenic Diet Disrupts the Circadian Clock and Increases Hypofibrinolytic Risk by Inducing Expression of Plasminogen Activator Inhibitor-1

Katsutaka Oishi; Daisuke Uchida; Naoki Ohkura; Ryosuke Doi; Norio Ishida; Koji Kadota; Shuichi Horie

From the Clock Cell Biology Research Group (K.O., D.U., R.D., N.I.), Institute for Biological Resources and Functions, National Institute of Advanced Industrial Science and Technology, Tsukuba, Ibaraki, Japan; the Graduate School of Life and Environmental Sciences (D.U., R.D., N.I.), University of Tsukuba, Ibaraki, Japan; the Department of Clinical Molecular Biology, Faculty of Pharmaceutical Sciences (N.O.), Teikyo University, Sagamihara, Kanagawa, Japan; the Agricultural Bioinformatics Research Unit (K.K.), Graduate School of Agricultural and Life Sciences, The University of Tokyo, Japan; and the Department of Clinical Biochemistry (S.H.), Kagawa Nutrition University, Sakado, Saitama, Japan.

Correspondence to Katsutaka OISHI, PhD, Clock Cell Biology Research Group, National Institute of Advanced Industrial Science and Technology, Central 6, 1-1-1 Higashi, Tsukuba, Ibaraki 305-8566. E-mail k-ooishi{at}aist.go.jp

Objectives— Metabolic disorders such as diabetes and obesity are considered risk factors for cardiovascular diseases by increasing levels of blood plasminogen activator inhibitor-1 (PAI-1). Ketogenic diets (KDs) have been used as an approach to weight loss in both obese and nonobese individuals. We examined circadian changes in plasma PAI-1 and its mRNA expression levels in tissues from mice fed with a KD (KD mice), to evaluate its effects on fibrinolytic functions.

Methods and Results— Two weeks on the kDa increased plasma levels of free fatty acids and ketones accompanied by hypoglycemia in mice. Plasma PAI-1 concentrations were extremely elevated in accordance with mRNA expression levels in the heart and liver, but not in the kidneys of KD mice. Circadian expression of PAI-1 mRNA was phase-advanced for 4.7, 7.9, and 7.8 hours in the heart, kidney, and adipose tissues, respectively, as well as that of circadian genes mPer2 and DBP in KD mice, suggesting that peripheral clocks were phase-advanced by ketosis despite feeding ad libitum under a periodic light-dark cycle. The circadian clock that regulates behavioral activity rhythms was also phase-advanced, and its free-running period was significantly shortened in KD mice.

Conclusions— Our findings suggest that ketogenic status increases hypofibrinolytic risk by inducing abnormal circadian expression of PAI-1.

We discovered that the circadian clock that regulates behavioral activity rhythms was phase-advanced, and its free-running period was significantly shortened in mice fed with a ketogenic diet (kDa). Here, we demonstrated that a kDa increases hypofibrinolytic risk by inducing the abnormal circadian expression of PAI-1.

Key Words: clock gene • ketosis • metabolic disorders • weight loss • obesity • hypofibrinolysis