title: Short-term feeding at the wrong time is sufficient to desynchronize peripheral clocks and induce obesity with hyperphagia, physical inactivity and metabolic disorders in mice.
abstract: BACKGROUND
  The circadian clock regulates various physiological and behavioral rhythms such as feeding and locomotor activity. Feeding at unusual times of the day (inactive phase) is thought to be associated with obesity and metabolic disorders in experimental animals and in humans.
  
  
  OBJECTIVE
  The present study aimed to determine the underlying mechanisms through which time-of-day-dependent feeding influences metabolic homeostasis.
  
  
  METHODS
  We compared food consumption, wheel-running activity, core body temperature, hormonal and metabolic variables in blood, lipid accumulation in the liver, circadian expression of clock and metabolic genes in peripheral tissues, and body weight gain between mice fed only during the sleep phase (DF, daytime feeding) and those fed only during the active phase (NF, nighttime feeding). All mice were fed with the same high-fat high-sucrose diet throughout the experiment. To the best of our knowledge, this is the first study to examine the metabolic effects of time-imposed restricted feeding (RF) in mice with free access to a running wheel.
  
  
  RESULTS
  After one week of RF, DF mice gained more weight and developed hyperphagia, higher feed efficiency and more adiposity than NF mice. The daily amount of running on the wheel was rapidly and obviously reduced by DF, which might have been the result of time-of-day-dependent hypothermia. The amount of daily food consumption and hypothalamic mRNA expression of orexigenic neuropeptide Y and agouti-related protein were significantly higher in DF, than in NF mice, although levels of plasma leptin that fluctuate in an RF-dependent circadian manner, were significantly higher in DF mice. These findings suggested that the DF induced leptin resistance. The circadian phases of plasma insulin and ghrelin were synchronized to RF, although the corticosterone phase was unaffected. Peak levels of plasma insulin were remarkably higher in DF mice, although HOMA-IR was identical between the two groups. Significantly more free fatty acids, triglycerides and cholesterol accumulated in the livers of DF, than NF mice, which resulted from the increased expression of lipogenic genes such as Scd1, Acaca, and Fasn. Temporal expression of circadian clock genes became synchronized to RF in the liver but not in skeletal muscle, suggesting that uncoupling metabolic rhythms between the liver and skeletal muscle also contribute to DF-induced adiposity.
  
  
  CONCLUSIONS
  Feeding at an unusual time of day (inactive phase) desynchronizes peripheral clocks and causes obesity and metabolic disorders by inducing leptin resistance, hyperphagia, physical inactivity, hepatic fat accumulation and adiposity.
authors.affiliation: Biological Clock Research Group, Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki, Japan; Department of Applied Biological Science, Graduate School of Science and Technology, Tokyo University of Science, Noda, Chiba, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Yasumoto
authors.affiliation: Biological Clock Research Group, Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki, Japan; Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science, Noda, Chiba, Japan.
authors.forename: Chiaki
authors.initials: C
authors.lastname: Hashimoto
authors.affiliation: Biological Clock Research Group, Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki, Japan.
authors.forename: Reiko
authors.initials: R
authors.lastname: Nakao
authors.affiliation: Biological Clock Research Group, Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki, Japan; Department of Applied Molecular Chemistry, College of Industrial Technology, Nihon University, Narashino, Chiba, Japan.
authors.forename: Haruka
authors.initials: H
authors.lastname: Yamazaki
authors.affiliation: Biological Clock Research Group, Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki, Japan.
authors.forename: Hanako
authors.initials: H
authors.lastname: Hiroyama
authors.affiliation: Biological Clock Research Group, Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Nemoto
authors.affiliation: Biological Clock Research Group, Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki, Japan.
authors.forename: Saori
authors.initials: S
authors.lastname: Yamamoto
authors.affiliation: Food Function Division, National Food Research Institute, National Agriculture and Food Research Organization (NARO), Tsukuba, Ibaraki, Japan.
authors.forename: Mutsumi
authors.initials: M
authors.lastname: Sakurai
authors.affiliation: Biological Clock Research Group, Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki, Japan; Food Function Division, National Food Research Institute, National Agriculture and Food Research Organization (NARO), Tsukuba, Ibaraki, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Oike
authors.affiliation: Department of Applied Biological Science, Graduate School of Science and Technology, Tokyo University of Science, Noda, Chiba, Japan; Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science, Noda, Chiba, Japan.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Wada
authors.affiliation: Department of Applied Molecular Chemistry, College of Industrial Technology, Nihon University, Narashino, Chiba, Japan.
authors.forename: Chikako
authors.initials: C
authors.lastname: Yoshida-Noro
authors.affiliation: Biological Clock Research Group, Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki, Japan; Department of Applied Biological Science, Graduate School of Science and Technology, Tokyo University of Science, Noda, Chiba, Japan; Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, University of Tokyo, Kashiwa, Chiba, Japan. Electronic address: k-ooishi@aist.go.jp.
authors.forename: Katsutaka
authors.initials: K
authors.lastname: Oishi
mesh_terms: D052436:Adipose Tissue, White / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D050154:Adiposity; D000818:Animals; D001069:Appetite Regulation; D001522:Behavior, Animal; D001833:Body Temperature Regulation; D057906:Circadian Clocks; D002149:Energy Intake; D004734:Energy Metabolism; D005234:Fatty Liver / Q000209:etiology; D005248:Feeding Methods / Q000009:adverse effects*; D005786:Gene Expression Regulation; D006963:Hyperphagia / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D007031:Hypothalamus / Q000378:metabolism; D050356:Lipid Metabolism; D008099:Liver / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008297:Male; D008659:Metabolic Diseases / Q000209:etiology*; D008810:Mice, Inbred C57BL; D009043:Motor Activity; D018482:Muscle, Skeletal / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D009765:Obesity / Q000209:etiology*
keywords: Feeding rhythm; Leptin resistance; Lipogenesis; Peripheral clock