Central and Peripheral Circadian Clocks Session 1: Circadian Rhythms and Digestive Disease: Where we Stand

Transcription

1 Central and Peripheral Circadian Clocks Session 1: Circadian Rhythms and Digestive Disease: Where we Stand Fred W. Turek, PhD Director, Center for Sleep and Circadian Biology Northwestern University Evanston, IL Circadian Rhythms in GI Health and Diseases Symposium Rush University Medical 1Center May 5, 2016

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3 Before Present 250,000 years Fire 5,000 years Candles 250 years Gas street lighting 120 years Electric lighting 3

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5 Rapid Evolution of Circadian Clock Field and its Role in Health and Disease Basic Research Descriptive Physiological basis and interaction with multiple systems Genetics Molecular basis and interactions with multiple molecular and cellular pathways Health Implications Shiftwork/jetlag Aging Obesity Diabetes CVD Cancer Mental disorders GI disorders Others 5

6 Obesity.a circadian/sleep disorder? 6

7 Circadian Dysregulation and A. National Institute of Mental Health: 2008 B. National Heart, Lung and Blood Institute: 2009 C. National Institute of Diabetes and Digestive and Kidney Diseases: 2010 D. National Institute on Aging: 2010 E. National Institute on Alcohol Abuse and Alcoholism RFA March 2011 Circadian Rhythms and Alcohol-Induced Tissue Damage F. National Institute of Arthritis and Musculoskeletal and Skin Diseases: 2013 G. National Institute of Environmental Health Sciences:

8 &ORFNV :LWKLQ 8V XJUI 'SFE 5VSFL 1SPGFTTPS %FQBSUNFOU PG /FVSPCJPMPHZ 8FJOCFSH $PMMFHF PG "SUT BOE 4DJFODFT BOE %JSFDUPS $FOUFS GPS 4MFFQ BOE $JSDBEJBO #JPMPHZ Internal clocks are not always in sync with external life. 3KRWR &RXUWHV\ RI 1$6$ (DUWK 2EVHUYDWRU\ c ± Ç wá 0w±ÑwÃáƍćąřƍćąĆċ ċřĉąƍżƍčřąąà 7KH PRGHUQ ZRUOG ZH OLYH LQ VHHPV WR EH LQFUHDVLQJO\ DOLJQHG DJDLQVW WKH SURSHU H[SUHVVLRQ DQG DOLJQPHQW RI RXU FLUFDGLDQ UK\WKPV DQG VOHHS ZDNH F\FOHV WKXV PDNLQJ LW LPSRUWDQW WR XQGHUVWDQG KRZ WKRVH F\FOHV ZRUN DQG KRZ WKH\ UHODWH WR RXU KHDOWK 8

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10 Sleep in Permanent & Rotating Shift Workers 8 Permanent Rotator Hours of Sleep Day Evening Night 10

11 Social Jet Lag Till Roenneberg 11

12 Circadian Dysregulation Genetic Models Environmental Models 12

13 Clock is a semidominant mutation 13

14 Domino Effect: Discovery of one gene leads to another CLOCK BMAL CRY PER TIM? 14

15 Obesity and Metabolic Syndrome in Circadian Clock Mutant Mice Turek FW, Joshu C, Kohsaka A, Lin E, Ivanova G, McDearmon E, Laposky A, Losee-Olson S, Easton A, Jensen DR, Eckel RH, Takahashi JS, and Bass J. Science 308, 13 May 2005, p

16 When the Clock stops ticking, metabolic syndrome explodes Circadian control depends on oscillating transcription factors, master switches synchronized by stimuli such as light and feeding. Recent studies show that altering circadian rhythmicity also results in pathophysiological changes resembling the metabolic syndrome. Staels, Nature Medicine

17 Nature Medicine Staels,

18 32 Scientific American, February

19 Clocks are everywhere in our bodies 19

20 Peripheral Clocks Maury et al., Circ Res

21 Reppert and Weaver (2002) Nature (418):

22 Circadian Dysregulation Genetic Models Environmental Models 22

23 Obesity,

24 Time of Feeding Protocol 9wk old B6 males L : D Measurements: Regular Control High Fat Control High Fat Dark Regular High Fat Regular High Fat High Fat N = 10 N = 10 N = 6 Continuous IR beam break activity Biweekly body weight Weekly food intake High Fat Light High Fat N = 6 Post-mortem body composition

25 Wrong timed feeding leads to increased weight gain Weekly Body Weights * * Weight (g) 30 * * * Ad Adlib HF Light-fed HF Dark-fed HF Adlib REG Ad lib REG Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6 * p < 0.05; post-hoc comparison from Repeated-Measures ANOVA Arbleet al., 2009 Obesity 25

26 Out-of-Phase Feeding Central vs. Peripheral Circadian Rhythm Dyssynchrony 26

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28 Daily Health Post 28

29 Importance of Sleep for Obesity, Diabetes and CVD Eve Van Cauter Group at University of Chicago

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31 IVGTT: Glucose Short Sleepers Normal Sleepers Van Cauter Time After Glucose Infusion (min.) 31

32 IVGTT: Insulin Short Sleepers Normal Sleepers Van Cauter Time After Glucose Infusion (min.) 32

33 STATUE RETURNS TO ITALY After a two-year visit to the United States, Michelangelo s David is returning to Italy.. 33

34 His Proud Sponsors in the U.S. were: 34

35 Circadian Disruption and Human Health Shiftwork / Jet lag Regulation of sleep-wake cycle Brain and Peripheral Tissue Specific Circadian Gene Dysregulation NEW FRONTIER Human Mental & Physical Health at Many Levels (Obesity, Diabetes, CVD, Depression) 35

36 da Vinci: Helicopter Blueprint years to build Circadian Clock Genes & Health: The Blueprint is there! 36

37 A Tipping Point Circadian Medicine Circadian Health 37

38 Sleep vs. Circadian Clinics in the U.S. 6,000 Sleep Clinics Circadian Clinics However 38

39 Circadian Clinic The Center for Circadian and Sleep Medicine Dr. Phyllis Zee Dr. Ravi Allada Dr. Fred Turek 39

40 Recent and Present Collaborators Collaborating Faculty: Ravi Allada Joseph Bass Ken Paller Ketema Paul Lawrence Pinto Kathy Reid Kazu Shimomura Joseph Takahashi Martha Vitaterna Phyllis Zee Collaborators from Rush University: Chris Forsyth Ali Keshavarzian Robin Voigt Fellows, Students and Staff: Samuel Bowers Adam Braeckman Helen Considine Vance Gao Susan Hall-Perdomo Peng Jiang Katie Lind Christopher Olker Eun Joo Song Keith Summa 40

41 Circadian desynchrony and metabolic dysfunction; did light pollution make us fat? Medical Hypotheses, 2011 C.A. Wyse a,,1, C. Selman a, M.M. Page a, A.N. Coogan b, D.G. Hazlerigg a a Circadian rhythmicity reigns across the spectrum of human life, from gene transcription in the cell nucleus, to organ function, behaviour and demography. How naïve of mankind to think that induction of chaos in this ancient and ubiquitous timing system could come without significant physiological consequence. 41

42 Circadian Medicine: The Next Frontier The Journey Continues 42