Advertisement

Time of Day and Nutrients in Feeding Govern Daily Expression Rhythms of the Gene for Sterol Regulatory Element-binding Protein (SREBP)-1 in the Mouse Liver*

Open AccessPublished:August 18, 2010DOI:https://doi.org/10.1074/jbc.M109.089391
      Sterol regulatory element-binding protein-1 (SREBP-1) plays a central role in transcriptional regulation of genes for hepatic lipid synthesis that utilizes diet-derived nutrients such as carbohydrates and amino acids, and expression of SREBP-1 exhibits daily rhythms with a peak in the nocturnal feeding period under standard housing conditions of mice. Here, we report that the Srebp-1 expression rhythm shows time cue-independent and Clock mutation-sensitive circadian nature, and is synchronized with varied photoperiods apparently through entrainment of locomotor activity and food intake. Fasting caused diminution of Srebp-1 expression, while diabetic db/db and ob/ob mice showed constantly high expression with loss of rhythmicity. Time-restricted feedings during mid-light and mid-dark periods exhibited differential effects, the latter causing more severe damping of the oscillation. Therefore, “when to eat in a day (the light/dark cycle),” rather than “whenever to eat in a day,” is a critical determinant to shape the daily rhythm of Srebp-1 expression. We further found that a high-carbohydrate diet and a high-protein diet, as well as a high-fat diet, cause phase shifts of the oscillation peak into the light period, underlining the importance of “what to eat.” Daily rhythms of SREBP-1 protein levels and Akt phosphorylation levels also exhibited nutrient-responsive changes. Taken together, these findings provide a model for mechanisms by which time of day and nutrients in feeding shape daily rhythms of the Srebp-1 expression and possibly a number of other physiological functions with interindividual and interdaily differences in human beings and wild animals subjected to day-by-day changes in dietary timing and nutrients.

      Introduction

      The circadian timekeeping system for physiology and behavior in mammals consists of a whole-body network of cell-intrinsic oscillators that rely on activation/repression-alternating feedback loops of clock gene expression (
      • Green C.B.
      • Takahashi J.S.
      • Bass J.
      ,
      • Reppert S.M.
      • Weaver D.R.
      ). Daily expression rhythms of clock genes as oscillation generators are synchronized (entrained) to the light/dark cycle in the central pacemaker localized to the suprachiasmatic nucleus (SCN)
      The abbreviations used are: SCN
      suprachiasmatic nucleus
      SREBP
      sterol regulatory element-binding protein
      LD
      light/dark
      ZT
      Zeitgeber time
      CT
      circadian time
      pAkt
      phospho-Ser473-Akt.
      of the hypothalamus, whereas they are predominantly entrained to the feeding/fasting cycle in other brain regions and peripheral organs (
      • Damiola F.
      • Le Minh N.
      • Preitner N.
      • Kornmann B.
      • Fleury-Olela F.
      • Schibler U.
      ,
      • Hara R.
      • Wan K.
      • Wakamatsu H.
      • Aida R.
      • Moriya T.
      • Akiyama M.
      • Shibata S.
      ,
      • Stokkan K.A.
      • Yamazaki S.
      • Tei H.
      • Sakaki Y.
      • Menaker M.
      ). On the other hand, it is poorly understood how daily rhythms of a large number of physiological functions as oscillation outputs are shaped and coordinated with each other.
      As a typical example of daily rhythms of liver functions exhibiting a wide spectrum of variety, we (
      • Ishihara A.
      • Matsumoto E.
      • Horikawa K.
      • Kudo T.
      • Sakao E.
      • Nemoto A.
      • Iwase K.
      • Sugiyama H.
      • Tamura Y.
      • Shibata S.
      • Takiguchi M.
      ,
      • Sakao E.
      • Ishihara A.
      • Horikawa K.
      • Akiyama M.
      • Arai M.
      • Kato M.
      • Seki N.
      • Fukunaga K.
      • Shimizu-Yabe A.
      • Iwase K.
      • Ohtsuka S.
      • Sato T.
      • Kohno Y.
      • Shibata S.
      • Takiguchi M.
      ) previously studied regulatory mechanisms for daily expression rhythms of the gene encoding Spot14 (
      • Cunningham B.A.
      • Moncur J.T.
      • Huntington J.T.
      • Kinlaw W.B.
      ,
      • LaFave L.T.
      • Augustin L.B.
      • Mariash C.N.
      ) a regulatory protein stimulating lipid biosynthesis that is one of the most closely feeding-related functions in the liver. Because the Spot14 promoter is under the control (
      • Mater M.K.
      • Thelen A.P.
      • Pan D.A.
      • Jump D.B.
      ) of sterol regulatory element-binding protein (SREBP)-1c (
      • Shimomura I.
      • Shimano H.
      • Horton J.D.
      • Goldstein J.L.
      • Brown M.S.
      ,
      • Yokoyama C.
      • Wang X.
      • Briggs M.R.
      • Admon A.
      • Wu J.
      • Hua X.
      • Goldstein J.L.
      • Brown M.S.
      ) a pivotal transcriptional regulator of genes for triglyceride synthesis, we here focused on Srebp-1 expression rhythms in the mouse liver.
      The SREBP family consists of three isoforms SREBP-1a, SREBP-1c/ADD1, and SREBP-2, which are basic helix-loop-helix-leucine zipper transcription factors (
      • Yokoyama C.
      • Wang X.
      • Briggs M.R.
      • Admon A.
      • Wu J.
      • Hua X.
      • Goldstein J.L.
      • Brown M.S.
      ,
      • Hua X.
      • Yokoyama C.
      • Wu J.
      • Briggs M.R.
      • Brown M.S.
      • Goldstein J.L.
      • Wang X.
      ,
      • Tontonoz P.
      • Kim J.B.
      • Graves R.A.
      • Spiegelman B.M.
      ). SREBP-1a and SREBP-1c are products of the Srebp-1 gene with alternative usage of different 5′ exons 1a and 1c, respectively, while SREBP-2 derives from a separate gene. These isoforms preferentially activate different sets of genes: SREBP-1c, genes for triglyceride synthesis; SREBP-2, genes for cholesterol synthesis; and SREBP-1a, genes both for triglyceride and cholesterol synthesis (
      • Horton J.D.
      • Goldstein J.L.
      • Brown M.S.
      ). Precursor forms of SREBPs located to the endoplasmic reticulum membrane are converted to nucleus-targeted transcription factors through vesicle transport into the Golgi apparatus and succeeding two-step proteolytic cleavage, in response to sterol depletion for SREBP-1a and SREBP-2 (
      • Goldstein J.L.
      • DeBose-Boyd R.A.
      • Brown M.S.
      ), and to insulin stimulation for SREBP-1c (
      • Yellaturu C.R.
      • Deng X.
      • Park E.A.
      • Raghow R.
      • Elam M.B.
      ).
      The activity of SREBP-1c is regulated also at the transcriptional level: expression of the Srebp-1c gene is up-regulated by carbohydrate feeding (
      • Horton J.D.
      • Bashmakov Y.
      • Shimomura I.
      • Shimano H.
      ), insulin (
      • Foretz M.
      • Pacot C.
      • Dugail I.
      • Lemarchand P.
      • Guichard C.
      • Le Lièpvre X.
      • Berthelier-Lubrano C.
      • Spiegelman B.
      • Kim J.B.
      • Ferré P.
      • Foufelle F.
      ,
      • Shimomura I.
      • Bashmakov Y.
      • Ikemoto S.
      • Horton J.D.
      • Brown M.S.
      • Goldstein J.L.
      ), and glucose (
      • Hasty A.H.
      • Shimano H.
      • Yahagi N.
      • Amemiya-Kudo M.
      • Perrey S.
      • Yoshikawa T.
      • Osuga J.
      • Okazaki H.
      • Tamura Y.
      • Iizuka Y.
      • Shionoiri F.
      • Ohashi K.
      • Harada K.
      • Gotoda T.
      • Nagai R.
      • Ishibashi S.
      • Yamada N.
      ) in the liver and/or cultured hepatocytes. Concordantly, Srebp-1c mRNA (
      • Kohsaka A.
      • Laposky A.D.
      • Ramsey K.M.
      • Estrada C.
      • Joshu C.
      • Kobayashi Y.
      • Turek F.W.
      • Bass J.
      ,
      • Le Martelot G.
      • Claudel T.
      • Gatfield D.
      • Schaad O.
      • Kornmann B.
      • Sasso G.L.
      • Moschetta A.
      • Schibler U.
      ) and SREBP-1 protein (
      • Le Martelot G.
      • Claudel T.
      • Gatfield D.
      • Schaad O.
      • Kornmann B.
      • Sasso G.L.
      • Moschetta A.
      • Schibler U.
      ,
      • Brewer M.
      • Lange D.
      • Baler R.
      • Anzulovich A.
      ) levels exhibit daily rhythms with a peak during the feeding period, i.e. the dark period in the liver of nocturnal mice fed with standard chows. Here, we at first characterized general features of daily Srebp-1 expression rhythms, which exhibited time cue-independent and Clock mutation-sensitive circadian nature, entrainability to various photoperiods, and fasting- and diabetes-labile damping. We further showed that “when to eat in a day (the light/dark cycle)” under time-restricted feeding conditions and “what to eat” with chows varied in the composition of three major nutrients are principle determinants in shaping the Srebp-1 expression rhythm and possibly a number of other physiological rhythms.

      DISCUSSION

      Results of this work led us to hypothesize about mechanisms of daily regulation of Srebp-1 expression, as illustrated in Fig. 9. The schema for ad libitum feeding of the standard diet (Fig. 9A) was drawn from the observations that the Srebp-1 expression rhythm showed circadian nature (Fig. 2) susceptible to Clock mutation (Fig. 3), and that varied photoperiods entrained the Srebp-1 expression rhythm as well as daily rhythms of locomotor activity, food intake and the clock-related gene expression in the liver (Fig. 4). In Fig. 9A, the light-entrainable central clock, which is located in the SCN and adjusted everyday by light/dark cues conveyed from the eye (
      • Berson D.M.
      • Dunn F.A.
      • Takao M.
      ), synchronizes phases of a number of other clocks including the putative “feeding clock” responsible for feeding behavior and physiology (
      • Damiola F.
      • Le Minh N.
      • Preitner N.
      • Kornmann B.
      • Fleury-Olela F.
      • Schibler U.
      ,
      • Hara R.
      • Wan K.
      • Wakamatsu H.
      • Aida R.
      • Moriya T.
      • Akiyama M.
      • Shibata S.
      ,
      • Stokkan K.A.
      • Yamazaki S.
      • Tei H.
      • Sakaki Y.
      • Menaker M.
      ). Feeding-associated factors such as nutrients entrain the circadian clock of the liver, in phase with neuronal and hormonal factors under the control of the SCN and the “feeding clock.” All together, nutrients, the liver clock oscillator, and neuronal/hormonal factors in phase cooperate to bring about robustly rhythmic expression of the Srebp-1 gene.
      Figure thumbnail gr9
      FIGURE 9Schematically represented hypothesis for regulatory mechanisms of daily rhythms of Srebp-1 expression. A, coordination of multiple factors for the Srebp-1 expression under ad libitum feeding of the standard diet. Light/dark cues are conveyed from the eye to the SCN, and therein adjust the light-entrainable oscillator, which in turn synchronizes phases of a number of other clocks including the putative “feeding clock.” Feeding-derived nutrients entrain the circadian clock in the liver, in phase with neuronal and hormonal factors. Thus, all of these in-phase nutrients, liver clock oscillator, and neuronal/hormonal factors regulate the Srebp-1 expression in a coordinated manner. B, “when to eat in a day (the light/dark cycle)” as a major determinant of Srebp-1 expression rhythms under time-restricted feeding. Food intake, when separated from the SCN-governed feeding command, plays a predominant role in entraining the feeding clock as well as the liver clock. The Srebp-1 expression is regulated cooperatively by nutrients and the almost in-phase liver clock oscillator, but is also affected by out-of-phase neuronal and hormonal factors under the control of the light-entrained SCN. Therefore, timing for feeding in the light/dark cycle, namely, “when to eat in a day” is crucial for the Srebp-1 expression rhythm. C, “what to eat” as a substantial regulator of the Srebp-1 expression rhythm. Diets varied in compositions of three major nutrients, i.e. carbohydrate, fat, and protein, exhibit moderate effects on clock gene expression in the liver, and more profound effects on expression rhythms of metabolism-regulating genes such as Srebp-1. Effects of varied nutrients on the SCN clock and the feeding clock can be different from one another, but at any rate seem limited. Therefore, neuronal and hormonal factors under the control of these systemic clocks affect the Srebp-1 expression rhythm apparently in conflict with the nutrients.
      Under time-restricted feeding (Fig. 9B), food intake entrains clocks of most peripheral tissues and even of most brain regions besides the SCN more strongly than the light/dark cues do (
      • Damiola F.
      • Le Minh N.
      • Preitner N.
      • Kornmann B.
      • Fleury-Olela F.
      • Schibler U.
      ,
      • Hara R.
      • Wan K.
      • Wakamatsu H.
      • Aida R.
      • Moriya T.
      • Akiyama M.
      • Shibata S.
      ,
      • Stokkan K.A.
      • Yamazaki S.
      • Tei H.
      • Sakaki Y.
      • Menaker M.
      ). A typical example of the brain food-entrainable oscillator constituting at least a part of the “feeding clock” is located in the dorsomedial hypothalamic nucleus, which is responsible for food-anticipatory behavior under the restricted feeding (
      • Gooley J.J.
      • Schomer A.
      • Saper C.B.
      ,
      • Mieda M.
      • Williams S.C.
      • Richardson J.A.
      • Tanaka K.
      • Yanagisawa M.
      ) though controversial (
      • Landry G.J.
      • Simon M.M.
      • Webb I.C.
      • Mistlberger R.E.
      ). Food intake also entrains clocks of peripheral organs including the liver. These food-entrained clocks are desynchronized from the light-entrained clock of the SCN (
      • Damiola F.
      • Le Minh N.
      • Preitner N.
      • Kornmann B.
      • Fleury-Olela F.
      • Schibler U.
      ,
      • Hara R.
      • Wan K.
      • Wakamatsu H.
      • Aida R.
      • Moriya T.
      • Akiyama M.
      • Shibata S.
      ,
      • Stokkan K.A.
      • Yamazaki S.
      • Tei H.
      • Sakaki Y.
      • Menaker M.
      ). The food-entrained clock in the liver regulates Srebp-1 expression in cooperation with almost in-phase factors such as nutrients. On the other hand, SCN-governed relatively out-of-phase factors likely affect also the Srebp-1 expression, as typically remarked under 4-h restricted feeding in the dark period compared with that in the light period (Fig. 6B). Namely, daytime and nighttime feeding differentially affect food-entrainable rhythmicity of Srebp-1 expression. Thus, “when to eat in a day (the light/dark cycle),” rather than “whenever to eat in a day,” is an essential determinant of daily rhythms of Srebp-1 expression. Constantly high-level Srebp-1 expression lacking apparent rhythmicity in db/db and ob/ob mice (Fig. 5) may reflect attenuated feeding rhythmicity accompanied by arrhythmic locomotion (
      • Kudo T.
      • Akiyama M.
      • Kuriyama K.
      • Sudo M.
      • Moriya T.
      • Shibata S.
      ), though this view remains to be verified.
      As for diets with varied nutritional compositions (Fig. 9C), their effects on the systemic daily rhythms such for locomotor activity and feeding may be different from one another, but in any way seem limited (Refs.
      • Kohsaka A.
      • Laposky A.D.
      • Ramsey K.M.
      • Estrada C.
      • Joshu C.
      • Kobayashi Y.
      • Turek F.W.
      • Bass J.
      ,
      • Yanagihara H.
      • Ando H.
      • Hayashi Y.
      • Obi Y.
      • Fujimura A.
      for a high-fat diet).
      E. Matsumoto, A. Ishihara, S. Tamai, A. Nemoto, K. Iwase, T. Hiwasa, S. Shibata, and M. Takiguchi, unpublished data.
      In accordance, their effects on daily expression rhythms of clock-related genes in the liver are marginal (Fig. 7, second and third panels from the top, and Refs.
      • Kohsaka A.
      • Laposky A.D.
      • Ramsey K.M.
      • Estrada C.
      • Joshu C.
      • Kobayashi Y.
      • Turek F.W.
      • Bass J.
      ,
      • Yanagihara H.
      • Ando H.
      • Hayashi Y.
      • Obi Y.
      • Fujimura A.
      ), but those on the Srebp-1 expression rhythm were dramatic (Fig. 7, top panels). Concordant with the previous report (
      • Kohsaka A.
      • Laposky A.D.
      • Ramsey K.M.
      • Estrada C.
      • Joshu C.
      • Kobayashi Y.
      • Turek F.W.
      • Bass J.
      ), the high-fat diet caused phase advance of the Srebp-1 mRNA rhythm. Furthermore, we found that the high-carbohydrate and high-protein diets also caused phase advance of the Srebp-1 mRNA rhythm with a shifted peak in the light period. Aberrations in daily rhythms of SREBP-1 protein levels were also observed (Fig. 7, bottom panels). Therefore, “what to eat” affects the daily rhythm of Srebp-1 expression profoundly, while its effect on clock-related gene expression is modest. Plausible explanation for these differential effects of varied nutrients is as follows: daily oscillation of clock gene expression in the liver is relatively resistant to nutrient changes, in order to keep time for feeding behavior-associated liver functions that must be entrained to the feeding period; on the other hand, the daily expression rhythm of Srebp-1, one of the most pivotal genes in metabolic regulation, likely requires to be modulated sensitively in response to nutrient variations. Taken together, views in Fig. 9, B and C, provide a model for mechanisms by which time of day and nutrients in feeding shape daily rhythms of a number of physiological functions with interindividual and interdaily differences in human beings and wild animals subjected to day-by-day changes in dietary timing and nutrients.
      Interestingly, all three nonstandard diets used in this study caused phase shift of the Srebp-1 expression rhythm. Because SREBP-1 is an activator of genes involved in fatty acid biosynthesis utilizing diet-derived nutrients such as carbohydrates and carbon skeletons of amino acids, the Srebp-1 expression profile with rapid increase in the early dark (feeding) period on the standard diet appears reasonable or “normal,” compared with “abnormal” profiles on the varied diets. We can rationalize that the “standard” diet has been empirically selected referring to animal health conditions such as growth rate, fertility, and longevity. It is tempting to speculate that “standard” diet-driven “normal” daily expression rhythms of metabolism-regulating genes such as Srebp-1 are prerequisite for animal health. On the other hand, further investigation into formation mechanisms and biological meanings of the varied diet-driven “abnormal” profiles will give insights into mechanisms for adaptation of lipogenesis to nutritional changes.

      Acknowledgments

      We thank H. Sugiyama and Y. Tamura for advice in statistical analysis, A. Oohira for help in sequence analysis, and members of our laboratories for suggestions, help, and discussions.

      REFERENCES

        • Green C.B.
        • Takahashi J.S.
        • Bass J.
        Cell. 2008; 134: 728-742
        • Reppert S.M.
        • Weaver D.R.
        Nature. 2002; 418: 935-941
        • Damiola F.
        • Le Minh N.
        • Preitner N.
        • Kornmann B.
        • Fleury-Olela F.
        • Schibler U.
        Genes Dev. 2000; 14: 2950-2961
        • Hara R.
        • Wan K.
        • Wakamatsu H.
        • Aida R.
        • Moriya T.
        • Akiyama M.
        • Shibata S.
        Genes Cells. 2001; 6: 269-278
        • Stokkan K.A.
        • Yamazaki S.
        • Tei H.
        • Sakaki Y.
        • Menaker M.
        Science. 2001; 291: 490-493
        • Ishihara A.
        • Matsumoto E.
        • Horikawa K.
        • Kudo T.
        • Sakao E.
        • Nemoto A.
        • Iwase K.
        • Sugiyama H.
        • Tamura Y.
        • Shibata S.
        • Takiguchi M.
        J. Biol. Rhythms. 2007; 22: 324-334
        • Sakao E.
        • Ishihara A.
        • Horikawa K.
        • Akiyama M.
        • Arai M.
        • Kato M.
        • Seki N.
        • Fukunaga K.
        • Shimizu-Yabe A.
        • Iwase K.
        • Ohtsuka S.
        • Sato T.
        • Kohno Y.
        • Shibata S.
        • Takiguchi M.
        J. Biol. Chem. 2003; 278: 30450-30457
        • Cunningham B.A.
        • Moncur J.T.
        • Huntington J.T.
        • Kinlaw W.B.
        Thyroid. 1998; 8: 815-825
        • LaFave L.T.
        • Augustin L.B.
        • Mariash C.N.
        Endocrinology. 2006; 147: 4044-4047
        • Mater M.K.
        • Thelen A.P.
        • Pan D.A.
        • Jump D.B.
        J. Biol. Chem. 1999; 274: 32725-32732
        • Shimomura I.
        • Shimano H.
        • Horton J.D.
        • Goldstein J.L.
        • Brown M.S.
        J. Clin. Invest. 1997; 99: 838-845
        • Yokoyama C.
        • Wang X.
        • Briggs M.R.
        • Admon A.
        • Wu J.
        • Hua X.
        • Goldstein J.L.
        • Brown M.S.
        Cell. 1993; 75: 187-197
        • Hua X.
        • Yokoyama C.
        • Wu J.
        • Briggs M.R.
        • Brown M.S.
        • Goldstein J.L.
        • Wang X.
        Proc. Natl. Acad. Sci. U.S.A. 1993; 90: 11603-11607
        • Tontonoz P.
        • Kim J.B.
        • Graves R.A.
        • Spiegelman B.M.
        Mol. Cell. Biol. 1993; 13: 4753-4759
        • Horton J.D.
        • Goldstein J.L.
        • Brown M.S.
        J. Clin. Invest. 2002; 109: 1125-1131
        • Goldstein J.L.
        • DeBose-Boyd R.A.
        • Brown M.S.
        Cell. 2006; 124: 35-46
        • Yellaturu C.R.
        • Deng X.
        • Park E.A.
        • Raghow R.
        • Elam M.B.
        J. Biol. Chem. 2009; 284: 31726-31734
        • Horton J.D.
        • Bashmakov Y.
        • Shimomura I.
        • Shimano H.
        Proc. Natl. Acad. Sci. U.S.A. 1998; 95: 5987-5992
        • Foretz M.
        • Pacot C.
        • Dugail I.
        • Lemarchand P.
        • Guichard C.
        • Le Lièpvre X.
        • Berthelier-Lubrano C.
        • Spiegelman B.
        • Kim J.B.
        • Ferré P.
        • Foufelle F.
        Mol. Cell. Biol. 1999; 19: 3760-3768
        • Shimomura I.
        • Bashmakov Y.
        • Ikemoto S.
        • Horton J.D.
        • Brown M.S.
        • Goldstein J.L.
        Proc. Natl. Acad. Sci. U.S.A. 1999; 96: 13656-13661
        • Hasty A.H.
        • Shimano H.
        • Yahagi N.
        • Amemiya-Kudo M.
        • Perrey S.
        • Yoshikawa T.
        • Osuga J.
        • Okazaki H.
        • Tamura Y.
        • Iizuka Y.
        • Shionoiri F.
        • Ohashi K.
        • Harada K.
        • Gotoda T.
        • Nagai R.
        • Ishibashi S.
        • Yamada N.
        J. Biol. Chem. 2000; 275: 31069-31077
        • Kohsaka A.
        • Laposky A.D.
        • Ramsey K.M.
        • Estrada C.
        • Joshu C.
        • Kobayashi Y.
        • Turek F.W.
        • Bass J.
        Cell Metab. 2007; 6: 414-421
        • Le Martelot G.
        • Claudel T.
        • Gatfield D.
        • Schaad O.
        • Kornmann B.
        • Sasso G.L.
        • Moschetta A.
        • Schibler U.
        PLoS Biology. 2009; 7: e1000181
        • Brewer M.
        • Lange D.
        • Baler R.
        • Anzulovich A.
        J. Biol. Rhythms. 2005; 20: 195-205
        • Chomczynski P.
        • Sacchi N.
        Anal. Biochem. 1987; 162: 156-159
        • Preitner N.
        • Damiola F.
        • Lopez-Molina L.
        • Zakany J.
        • Duboule D.
        • Albrecht U.
        • Schibler U.
        Cell. 2002; 110: 251-260
        • Ripperger J.A.
        • Shearman L.P.
        • Reppert S.M.
        • Schibler U.
        Genes Dev. 2000; 14: 679-689
        • Hirao A.
        • Tahara Y.
        • Kimura I.
        • Shibata S.
        PLoS ONE. 2009; 4: e6909
        • King D.P.
        • Zhao Y.
        • Sangoram A.M.
        • Wilsbacher L.D.
        • Tanaka M.
        • Antoch M.P.
        • Steeves T.D.
        • Vitaterna M.H.
        • Kornhauser J.M.
        • Lowrey P.L.
        • Turek F.W.
        • Takahashi J.S.
        Cell. 1997; 89: 641-653
        • Shimba S.
        • Ishii N.
        • Ohta Y.
        • Ohno T.
        • Watabe Y.
        • Hayashi M.
        • Wada T.
        • Aoyagi T.
        • Tezuka M.
        Proc. Natl. Acad. Sci. U.S.A. 2005; 102: 12071-12076
        • Zhang Y.
        • Proenca R.
        • Maffei M.
        • Barone M.
        • Leopold L.
        • Friedman J.M.
        Nature. 1994; 372: 425-432
        • Chen H.
        • Charlat O.
        • Tartaglia L.A.
        • Woolf E.A.
        • Weng X.
        • Ellis S.J.
        • Lakey N.D.
        • Culpepper J.
        • Moore K.J.
        • Breitbart R.E.
        • Duyk G.M.
        • Tepper R.I.
        • Morgenstern J.P.
        Cell. 1996; 84: 491-495
        • Lee G.H.
        • Proenca R.
        • Montez J.M.
        • Carroll K.M.
        • Darvishzadeh J.G.
        • Lee J.I.
        • Friedman J.M.
        Nature. 1996; 379: 632-635
        • Duez H.
        • van der Veen J.N.
        • Duhem C.
        • Pourcet B.
        • Touvier T.
        • Fontaine C.
        • Derudas B.
        • Baugé E.
        • Havinga R.
        • Bloks V.W.
        • Wolters H.
        • van der Sluijs F.H.
        • Vennström B.
        • Kuipers F.
        • Staels B.
        Gastroenterology. 2008; 135: 689-698
        • Osborne T.F.
        • Espenshade P.J.
        Genes Dev. 2009; 23: 2578-2591
        • Hirano Y.
        • Yoshida M.
        • Shimizu M.
        • Sato R.
        J. Biol. Chem. 2001; 276: 36431-36437
        • Sundqvist A.
        • Bengoechea-Alonso M.T.
        • Ye X.
        • Lukiyanchuk V.
        • Jin J.
        • Harper J.W.
        • Ericsson J.
        Cell Metab. 2005; 1: 379-391
        • Walker A.K.
        • Yang F.
        • Jiang K.
        • Ji J.Y.
        • Watts J.L.
        • Purushotham A.
        • Boss O.
        • Hirsch M.L.
        • Ribich S.
        • Smith J.J.
        • Israelian K.
        • Westphal C.H.
        • Rodgers J.T.
        • Shioda T.
        • Elson S.L.
        • Mulligan P.
        • Najafi-Shoushtari H.
        • Black J.C.
        • Thakur J.K.
        • Kadyk L.C.
        • Whetstine J.R.
        • Mostoslavsky R.
        • Puigserver P.
        • Li X.
        • Dyson N.J.
        • Hart A.C.
        • Näär A.M.
        Genes Dev. 2010; 24: 1403-1417
        • Amemiya-Kudo M.
        • Shimano H.
        • Yoshikawa T.
        • Yahagi N.
        • Hasty A.H.
        • Okazaki H.
        • Tamura Y.
        • Shionoiri F.
        • Iizuka Y.
        • Ohashi K.
        • Osuga J.
        • Harada K.
        • Gotoda T.
        • Sato R.
        • Kimura S.
        • Ishibashi S.
        • Yamada N.
        J. Biol. Chem. 2000; 275: 31078-31085
        • Deng X.
        • Yellaturu C.
        • Cagen L.
        • Wilcox H.G.
        • Park E.A.
        • Raghow R.
        • Elam M.B.
        J. Biol. Chem. 2007; 282: 17517-17529
        • Fleischmann M.
        • Iynedjian P.B.
        Biochem. J. 2000; 349: 13-17
        • Li S.
        • Brown M.S.
        • Goldstein J.L.
        Proc. Natl. Acad. Sci. U.S.A. 2010; 107: 3441-3446
        • Porstmann T.
        • Griffiths B.
        • Chung Y.L.
        • Delpuech O.
        • Griffiths J.R.
        • Downward J.
        • Schulze A.
        Oncogene. 2005; 24: 6465-6481
        • Yellaturu C.R.
        • Deng X.
        • Cagen L.M.
        • Wilcox H.G.
        • Mansbach 2nd, C.M.
        • Siddiqi S.A.
        • Park E.A.
        • Raghow R.
        • Elam M.B.
        J. Biol. Chem. 2009; 284: 7518-7532
        • Berson D.M.
        • Dunn F.A.
        • Takao M.
        Science. 2002; 295: 1070-1073
        • Gooley J.J.
        • Schomer A.
        • Saper C.B.
        Nat. Neurosci. 2006; 9: 398-407
        • Mieda M.
        • Williams S.C.
        • Richardson J.A.
        • Tanaka K.
        • Yanagisawa M.
        Proc. Natl. Acad. Sci. U.S.A. 2006; 103: 12150-12155
        • Landry G.J.
        • Simon M.M.
        • Webb I.C.
        • Mistlberger R.E.
        Am. J. Physiol. 2006; 290: R1527-R1534
        • Kudo T.
        • Akiyama M.
        • Kuriyama K.
        • Sudo M.
        • Moriya T.
        • Shibata S.
        Diabetologia. 2004; 47: 1425-1436
        • Yanagihara H.
        • Ando H.
        • Hayashi Y.
        • Obi Y.
        • Fujimura A.
        Chronobiol. Int. 2006; 23: 905-914