Circadian Rhythms,

Time-restricted Eating,
and Cardiometabolic Health

Emily Manoogian, PhD

Satchidananda Panda Lab
Regulatory Biology, Salk Institute

WCIRDC 2019
Outline

• Brief introduction to circadian rhythms

• Time-restricted feeding (TRF) in mice

• Translating TRF to humans

Environmental Endogenous Rhythms Rhythmic Output
Cues (molecular clocks and internal networks)
• Behavior
• Sleep
• Eating patterns
• Activity patterns
Light • Cognitive ability

• Physiology
• Body temperature
Food • Heart rate
• Enzyme production
• Hormone release
• Metabolism

• Cell function
 Time-Restricted
Feeding/Eating
Note: Time-Restricted Feeding (TRF) is the termed used in animal studies.
Time-Restricted Eating (TRE) is used when referring to human studies.
 Standard Diet High-fat diet

Obese & Associated

Healthy
(low fat mass, normal Diseases
blood sugar, cholesterol, (increased fat mass, high
Insulin, leptin) blood sugar, cholesterol,
Insulin, leptin)
 Can eat whenever they want. Fatty Liver

Body weight
Weeks

Can only eat 8-12 hours a day. Healthy Liver

Time-Restricted Feeding in Mice

Modified from Zarrinpar, Chaix, and Panda 2016

myCircadianClock
Feedogram (raster plot of eating events)

6am Noon 6pm Midnight

Gill and Panda, 2015

 6am Noon 6pm Midnight
Mon
Tue
Wed
Thu
Fri
Sat
Sun
Mon
Tue
Wed
Thu
Fri
Sat
Sun
Mon
Tue
Wed
Thu
Fri
Gill and Panda, 2015
Gill and Panda, 2015
Gill and Panda, 2015
Eating Duration

50% Adults eat for >15h

40

100
30

% of All Subjects

Cumulative %
20
50

10

0
11 12 13 14 15 16 17 18
Eating Duration Bin Center (h)

Gill and Panda, Cell Metabolism 2015

10-hr TRE Intervention in 8 participants
10-11 hr TRE ~5% Weight loss Improved Energy and Sleep
Decreased Hunger

Gill and Panda, Cell Metabolism 2015

• 5 Wk randomized
Crossover

• 8 overweight men

• Meals were provided.

Meta-Analysis of Intermittent Fasting studies (3 TRE)

BMI Fasting Glucose HOMA-IR

Pre

Post

Favor Favor Favor Favor Favor Favor

Intervention Control Intervention Control Intervention Control

Cho et al., 2019

Intermittent Fasting VS TRE

Intermittent Fasting TRE

• Caloric Restriction • No Caloric Restriction

• Frequency of fasting may vary • Practiced daily
(daily, weekly, monthly, etc) • Consistent eating window
• Not intended to support the supports circadian system
circadian system (time of eating
window changes)
 Can Time-Restricted Eating
manage metabolic syndrome?
• 16 of 19 participants were
on medication.

• Only trial that has assessed

TRE as a treatment for
metabolic syndrome.

• Cannot me assessed in
preclinical animal models.
Participants
• 19 Participants
• Male = 14, Female = 5
• Age: 39-79 yr; Median = 58
• Metabolic syndrome (3 of 5 factors):
• Elevated Waist circumference (>108cm men; >88 cm women)
• Elevated Triglycerides (>150 mg/dl)
• Elevated Fasting Glucose (>100 mg/dl)
• Elevated Blood Pressure (>130/85 mm/Hg)
• Low HDL (<40)
• Metabolic syndrome affects about a third of adults in the United States.
• For Men: 50-69 yr = 40-50%; 70+ yr = 56-59%
• For Women: 50-69 yr = 43=57% ; 70 + yr = 62-69%

Wilkinson and Manoogian et al., Cell Metabolism, 2019

16 of 19 participants were on at least one medication

Number of
Medication
Participants (%)

Statin 15 (79%)
Anti-hypertensive 12 (63%)
Omega-3 4 (21%)
Ezetimibe 2 (11%)
Fibrate 1 (5%)
Niacin 1 (5%)
Metformin 1 (5%)
Sulfonyl-urea 1 (5%)

Wilkinson and Manoogian et al., Cell Metabolism, 2019

Timeline: 10-hr TRE to manage metabolic syndrome

Baseline
• 1st Visit (Day 1): Assays (Blood Tests, Vitals,
PSQI), CGMs applied and Actiwatches provided.
Trained on the myCircadianClock (mCC) app.
• 2nd Visit: CGM is removed and watch is returned.
Intervention
• 3rd Visit (7-10 days before end of intervention):
CGM is applied, and actiwatch is provided.
• 4th Visit: Assays at baseline are repeated.
CGM is removed and watch is returned.

• End of Week 2: Participants are instructed to

select a 10-hour eating window and start 12-
weeks of TRE .
Wilkinson and Manoogian et al., Cell Metabolism, 2019
 a b

Continuous Glucose Monitor (CGM) Phillips Actiwatch

Abbott Freestyle LibrePro.
Feasibility: Eating Window and Adherence

95% Eating Window Logging Adherence

(hours) (at least 2 items over >/= 5 hr interval)

Baseline Baseline 90.24% (8.98%)

15.13 (1.3) Mean (SD)
Mean (SD)
Intervention Intervention 84.45 %
10.78 (1.18)
Mean (SD) Mean (SD) (12.17)
Change
-4.35 (1.32)
Mean (SD)
Adherence to eating within the
% Change -29% eating window on days logged

p-value 8.847E-11 Intervention 90.4% (8.75%)

Mean (SD)

Wilkinson and Manoogian et al., Cell Metabolism, 2019

Why do we use the
95% eating interval?
 Variability of First
and Last Calorie
Daily Eating
0 6 12 18 24 Duration (Hours)
Thursday 11.45 h
Friday 12.82 h
Saturday 13.22 h
Sunday 8.58 h
Monday 13.77 h
Tuesday 12.85 h
Wednesday 13.48 h
Thursday 11.83 h
Friday 17.87 h
Saturday 12.70 h
Sunday 12.68 h
Monday 14.55 h
Tuesday 12.73 h

Wednesday 13.37h
Daily Average:
0 3 6 9 12 15 18 21 24 12.99 Hours
14.19 hours
6:36am 95% interval 8:47pm
 Variability of First
and Last Calorie Daily Eating
0 6 12 18 24 Duration (Hours)
Thursday 8.08 h
Friday 9.88 h
Saturday 8.55 h
Sunday 7.80 h
Monday 8.83 h
Tuesday 9.08 h
Wednesday 8.80 h
Thursday 8.70 h
Friday 8.57 h
Saturday 7.40 h
Sunday 8.53 h

Monday 9.25 h

Tuesday 9.65 h

Wednesday 9.05 h
Daily Average:
0 3 6 9 12 15 18 21 24 8.73 Hours
9.67 hours
10:01am 95% interval 8:41pm
A

Time of the day (hours) Wilkinson and Manoogian et al., Cell Metabolism, 2019
 Time of calorie intake during baseline (orange) and intervention (blue)
04:00
Participants did not skip meals, but rather delayed breakfast (by 2.09±1.20 hours)
and advanced dinner (2.08±1.32 hours) relative to baseline.
24:00
Time of Day

20:00

16:00

12:00

08:00

04:00
Wilkinson and Manoogian et al., Cell Metabolism, 2019
Time between sleep and calorie intake increased

Change
TRE
TRE- p-value
(hrs)

Participants
Baseline
Time between wake and
first calorie 3.64±1.22 +1.81±0.96 p=7.72E-7
Time between last
calorie and sleep onset 4.02±1.19 +1.53±1.18 p=6.48E-5
n=17, Orange = Baseline; Blue = Intervention

0 2.5 5 5 2.5 0
Wake to Last cal to
Wilkinson and Manoogian et al., Cell Metabolism, 2019 1st cal (hrs) sleep (hrs)
Variation in meal and wake timing decreased

Change % Change
Baseline TRE
TRE-Baseline of p-value
(Variance in Hours) Variance

Participants
First Calorie (●)* 2.77 1.63 -1.13 -40.96% 0.001
Last Calorie (■)* 4.12 2.30 -1.82 -44.23% 0.0001
Wake (▲)* 3.42 2.21 -1.22 -35.53% 0.035
Sleep Onset (▼)* 3.05 2.05 -0.99 -32.63% 0.142
n=19 unless noted: *n=18
Orange = Baseline; Blue = Intervention

Wilkinson and Manoogian et al., Cell Metabolism, 2019

Changes in factors of metabolic syndrome

. *p<0.05, **p<0.01

Post-
Baseline Change
Intervention % Change p-value
Mean (SD) Mean (SD)
Mean (SD)
Systolic BP (mmHg) ** 128 (8.89) 123 (13.35) -5.1 (9.51) -4% 0.041
Diastolic BP (mmHg) ** 78 (8.74) 72 (10.75) -6.5 (7.94) -8% 0.004
Waist Circumference (cm) 109 (11.21) 105 (14.79) -4.5 (6.72) -4% 0.010
HDL-C (mg/dL) 47 (12.49) 45 (12.42) -1.5 (3.19) -3% 0.051
Triglycerides (mg/dL) 161 (87.30) 159 (94.24) -2.6 (57.68) -2% 0.845
Fasting glucose (mg/dL) 107 (18.01) 101 (11.60) -5.7 (13.54) -5% 0.081
n = 19 unless noted: *n=18, **n=17, ***n=16 Wilkinson and Manoogian et al., Cell Metabolism, 2019
Changes in cholesterol

Baseline Post-
Change
Mean Intervention % Change p-value
Mean (SD)
(SD) Mean (SD)
Total Cholesterol (mg/dL) 181 (35.80) 168 (39.65) -13.2 (24.29) -7% 0.030
LDL-C (mg/dL) ** 104 (32.30) 92 (37.82) -11.9 (19.01) -11% 0.016

n = 19 unless noted: *n=18, **n=17, ***n=16 Wilkinson and Manoogian et al., Cell Metabolism, 2019
Decreased weight and body fat

. *p<0.05,
**p<0.01,
***p<0.001

Post-
Baseline Change
Intervention % Change p-value
Mean (SD) Mean (SD)
Mean (SD)
Weight (lbs) 216 (43.50) 208 (40.51) -7.3 (7.06) -3.4% <0.001
BMI 33 (4.76) 32 (4.44) -1.1 (0.97) -3% <0.001
%Body Fat 37 (4.19) 36 (4.02) -1.0 (0.91) -3% <0.001
Visceral Fat Rating 17 (5.97) 16 (5.89) -0.6 (0.77) -3% 0.0004
n = 19 unless noted: *n=18, **n=17, ***n=16 Body composition measured with a TANITA Scale
Wilkinson and Manoogian et al., Cell Metabolism, 2019
Changes in glucose regulation

Post-
Baseline Change
Intervention % Change p-value
Mean (SD) Mean (SD)
Mean (SD)
Fasting glucose
107 (18.01) 101 (11.60) -5.7 (13.54) -5% 0.081
(mg/dL)
Fasting Insulin 18 (13.36) 14 (8.03) -3.6 (8.01) -21% 0.064
HbA1c (%) 5.7 (0.45) 5.6 (0.40) -0.14% -2% 0.058

n = 19 unless noted: *n=18, **n=17, ***n=16 Wilkinson and Manoogian et al., Cell Metabolism, 2019
Continuous Glucose Monitors (N=1): Pre vs Post TRE

13.80 hr eating interval

(~5:15am-7pm)

No changes in food quality. No change in activity. No increase

in time in bed, but increase in sleep time and sleep quality.

9.80 hr eating interval (9am-7pm) Wilkinson and Manoogian et al., Cell Metabolism, 2019
 Continuous Glucose
myCircadianClock Actiwatch
Monitor
 Food Logs
Glucose

Glucose
Actigraphy
• Follow up on our Pilot – NIDDK RO1
• 118 participants (Recruiting now)
• 3- month Randomized control trial
• All on Mediterranean Diet
• ½ randomized to self-selected 10-hr TRE
• 1-year optional follow up
• Adults (M/F), Metabolic Syndrome, Including elevated fasting
glucose
Timeline: 10 hr TRE to manage metabolic syndrome

14 hours+ eating interval ≤10 hour eating interval

Week 1 Week 2 Time Restrictive Eating (TRE) intervention Week 13 Week 14

• 14-week study (2-week baseline, 12-week

intervention)
• Assays: DXA, Muscle Biopsy, Blood Tests,
Vitals, CGMs, Actigraphy, Questionnaires, and
optional Liver MRI
Summary

• Long duration eating is common in modern society: Over 50% of

adult participants (n= 156) had a daily eating window of > 15 h.

• 10- hour TRE in humans can lead to weight loss and

cardiometabolic benefits, even for those already on medication.

• Further studies are needed and ongoing.

Acknowledgments
Panda Lab Taub Lab (UCSD)
Satchin Panda Data Team Pam Taub
Hiep Le Jason Fleischer Michael Wilkinson
Amandine Chaix Katherine Wang Adena Zadourian
Hugo Calliargo Joey Zhang Hannah Lo
Xiaoyan Zhu Ashley Rosander
“Clock People” Team Aryana Pazargadi
Girish Melkani
Savannah Fakhouri
Terry Lin
Azeen Shoghi
Shaunuk Deota
Nikko Gutierrez
Michael Lam
Nathan Le
Tiara Valledor
Previous Advisors
Lance Kriegsfeld
Mikael Fakhoury
Eric Bittman

Funding: Larry Hillblom Foundation, UCSD, Helmsley Foundation,

Glenn Center for Aging, Salk Innovation Award, Salk Women and Science, NIDDK