The Role of Sleep and Arousal in the Development of Obesity"

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1 The Role of Sleep and Arousal in the Development of Obesity" Dr. Fred W. Turek Center for Sleep & Circadian Biology Northwestern University Treatment and Prevention of Obesity: Approaches and Needs Copenhagen September 12, 2007

2 SLEEP CIRCADIAN RHYTHMS FUEL METABOLISM FROM THE BEGINNING

4 Suprachiasmatic nucleus (SCN) Master Circadian Pacemaker Lesioning the SCN abolishes most biological rhythms AELS3071 Percentiles: /10/01 07/19/01 07/29/01 08/08/01 08/18/01 08/28/01 09/07/01

5 Circadian regulation of sleep Two-Process model: The circadian pacemaker modulates the time of sleep and wake onset (Daan and Borbely, 1984) C and S are independent processes, that interact to optimize the quantity an quality of sleep.

10 Average sleep duration of the normal working population has decreased from about 9 hours per night in 1910 to about 7.5 hours currently, a trend that is inverse to that of obesity.

11 Importance of Sleep for Obesity, Diabetes and CVD Eve Van Cauter Group at University of Chicago 1999

12 From Van Cauter

13 IVGTT: Glucose 300 PLASMA GLUCOSE (mg/dl) Short Sleepers Normal Sleepers Time After Glucose Infusion (min.) From Van Cauter

14 IVGTT: Insulin 700 PLASMA INSULIN ( (pmol pmol/l) Short Sleepers Normal Sleepers Time After Glucose Infusion (min.) From Van Cauter

15 From Van Cauter

16 Royal Road to Obesity

17 Neuroscience of Drug Reward: Relevance to Food Reward F.J. Vaccarino, PhD Professor and Chair, Department of Psychology Professor, Department of Psychiatry University of Toronto Principal Editor, Neuroscience of Psychoactive Substance Use and Dependence Published by World Health Organization, 2004

18 Links between food reward and drug reward: individual differences Effects of sleep deprivation on food reward and drug award Effects of Stress on food reward and drug reward Reward signals, food choices and different macronutrients Beyond Dopamine From Vaccarino

19 Natural Factors Associated with Enhanced DAergic Transmission Intrinsic: Extrinsic: hunger sex curiosity/exploration sweet food attractive sexual stimuli enriched environment From Vaccarino

20 Sleep deprivation produces behavioral supersensitivity to DA agonists, amphetamine and cannabis in rats Tufik et al., 1978 Ferguson et al., 1969 Carlini et al., 1977

21 Sweets - 33% Salty foods - 45% Starchy foods - 33% Spiegel et al., 2004

22 Biological Relevance of Reward Stimuli with positive affective valence increase reward system activity. Increased reward system activity is expressed as increased behavior directed at the relevant stimuli. Energy Food Environmental Information Exploration Reward Positive Affect Sex Reproduction Drugs??? From Vaccarino

23 FOOD and EATING Hedonics energy regulation From Vaccarino

24 Links Between Food Reward and Drug Reward: Evidence from Individual Differences in Reward and Dopamine Sensitivity From Vaccarino

25 SLEEP CIRCADIAN RHYTHMS FUEL METABOLISM FROM THE BEGINNING

26 Discovery of the Mutant

27 Clock is a semidominant mutation

28 Discovery of Clock Gene Led to Discovery of Many Clock Genes

29 P P CK1e CRY PER BMAL CLOCK Cry/Per Liver Has Rhythm Fred W. Turek and Ravi Allada Hepatology, April 2002

30 Discovery of Clock Gene Led to Discovery of Many Clock Genes Core circadian clock genes Transcriptional translational feedback loop

31 Clock/Clock mice: Baseline sleep Reduced amplitude of sleep-wake cycle (NREM %) hr intervals +/+ clock/clock (Easton, 2004) Increased wake time (+ 2 hrs/day) % 24-hrs ** ** Wake NREM (Naylor et al., 2000)

32 Sleep in Bmal1/Mop3 -/- mice Increased total sleep time (+ 1.5 hours) Increased sleep fragmentation Impaired recovery from sleep deprivation Laposky et al., (2005), SLEEP

33 Circadian clock genes influence total sleep amount, sleep consolidation, and sleep homeostasis 24-hr Wake % 24-hr NREM % 24-hr REM % Sleep Fragmentation Bsln NREM delta power Recovery NREM Recovery REM Recovery NREM delta power Cl/Cl (Naylor et al., 2000) BMAL1/Mop3 -/- (Laposky et al., 2005) Cry 1,2 -/- (Wisor et al., 2003) Different sleep phenotypes for different circadian genes Phenotypes maintained in L:D and D:D

34 From Flies to Mice (to Humans) Core clock genes influence sleep regulatory processes Amount, consolidation, sleep architecture, sleep rebound

35 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

36 Activity and Energy Balance Turek et al., 2005

37 35 30 Increased Body Weight of Clock Mutants +/+ -/- Clock/Clock *** 25 *** 20 n=21 n=21 n=20 n=20 Female 1 Male 2 *** P < From Science 2005

38 Sleep, Circadian and Metabolic Phenotypes of the Clock mutant model Body Weight (g) Weeks on Diet +/+ Reg (n=8) Fat (n=7) Clock/Clock Reg (n=9) Fat (n=11) 10 week weight gain (g) #3 Energy homeostasis deficit +/+ Clock/Clock Regular High Fat From Science 2005

39 Metabolic parameters WT Clock P value Triglyceride (mg/dl) 136 ± ± 8 < 0.05 Cholesterol (mg/dl) 141 ± ± 6 < 0.05 Glucose (mg/dl) 130 ± ± 7 < 0.01 Insulin (ng/ml) 1.7 ± ± 0.1 N.S. Leptin (ng/ml) 3.4 ± ± 0.3 < 0.05

40 Diurnal rhythms in the mediobasal hypothalamus Wild-type = red Cl/Cl mutant = black Turek et al., Science (2005)

41 Ascending Arousal Pathways Saper et al., Nature 437:1257, 2005

42 Interactions of Circadian Regulation of Sleep and Feeding Saper et al., TINS 28: , 2005

43 Nature Medicine January 2006

In addition to obesity, ob/ob mice are hyperphagic,, and exhibit a metabolic

44 The ob/ob mouse : a genetic animal model for metabolic disorders Wild type ob/ob 1. Obesity arose from spontaneous mutation of leptin gene (ob( ob) 2. In addition to obesity, ob/ob mice are hyperphagic,, and exhibit a metabolic syndrome characterized by: -hyperglycemia -glucose intolerance -hyperinsulinemia

45 Altered sleep regulation in ob/ob mice Increased sleep time (+ 1 hour/day) Total sleep time Increased sleep fragmentation Stage Shifts 80 Ob/Con Ob/Ob Ob/Con Ob/Ob *** % recording time ** ** *** *** hr Light 12-hr Dark 24-hr Total 12-hr Light 12-hr Dark 24-hr Total Laposky et al., (2006), Am J Physiol Wild type ob/ob

46 Effect of leptin repletion on sleep in ob/ob mice Leptin normalizes NREM sleep time between genotypes minutes NREM sleep time *** *** ** ** wt ob Vehicle Leptin (3 days) 100 ug/kg/day, mini-pump) Leptin (14 days) 100 ug/kg/day, mini-pump) Sleep effects do not correlate with body weight 80 Body weight (leptin, ZT2) ** Base 3-d 14-d grams ** * *** *** 20 wt ob

47 Sleep in animal models of obesity/diabetes ob/ob mice (leptin deficient) db/db mice (leptin resistant) diet induced obesity - mice Zucker Diabetic Fatty rats

48 Sleepless in America: A Pathway to Obesity and the Metabolic Syndrome? Joseph Bass and Fred W. Turek Archives of Internal Medicine, 2005 While there is a growing awareness among some sleep, metabolic, cardiovascular, and diabetes researchers that insufficient sleep could be leading to a cascade of disorders, few in the general medical profession or in the lay public have yet made the connection. Substitute circadian dysregulation for insufficient Sleep

49 Effect of weekly reversal of the LD cycle on locomotor behavior Am. J. Physiol. 275 Penev, et al., 1998

50 Effect of weekly reversal of the LD cycle on mortality Am. J. Physiol. 275 Penev, et al., 1998

51 Chronic Disrupted Sleep/Circadian Rhythms Three fundamental discoveries in just last few years: Chronic sleep loss leads to obesity/diabetes and CVD Circadian dysregulation leads to disease and metabolic dysfunction Molecular circadian clock core machinery: EVERYWHERE

52 Circadian clock genes are everywhere!! Ishida, Kaneko and Allada (1999) PNAS, 96:

53 From: Reppert and Weaver (2002). Nature (418): 935

54 Nearly ten percent of genes have a circadian rhythm in their expression SCN Liver Pe r2 4 EAR Pe r2 4 EAR Panda et al., Cell, 2002

55 Circadian Disruption and Human Health Shiftwork/Jet lag Regulation of sleep-wake cycle Brain Tissue Specific Circadian Gene Dysregulation NEW FRONTIER Human Mental & Physical Health at Many Levels

56 Present Collaborators Collaborating Faculty: Ravi Allada JOSEPH BASS Kazu Shimomura Joseph Takahashi Martha Vitaterna Phyllis Zee AARON LAPOSKY Christine Dugovic Recent/Present/ Fellows/Students in Turek Lab: Youngsoo Kim Sue Losee-Olson Ketema Paul Jonathan Shelton Felix Nunez He (Sarina) Yang Karrie Mrazek Deanna Arble Deanna Williams Joe Owens-Ream Lili Zhou

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

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,