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TIME-RESTRICTED FEEDING: AN
OVERVIEW OF THE CURRENT RESEARCH
AND PRACTICALAPPLICATIONS
Jeff Rothschild, CSCS, M.S. cand.
K...
About Me
•  Currently finishing M.S. in Nutritional Science at CSULA
•  Coach College tennis
•  Work with personal trainin...
Background
Unrestricted kcal intake
24 h unrestricted
kcal
3-12 h
feeding
12-21 h
fasting
24 h fast
3-12 h
feeding
12-21 h...
Intermittent Fasting
48 h unrestricted kcal intake
24 h
unrestricted kcal
3-12 h
feeding
12-21 h
fasting
24 h fast
(or ~50...
Time-Restricted Feeding
48 h unrestricted kcal intake
24 h unrestricted
kcal
3-12 h
feeding
12-21 h
fasting
24 h fast
3-12...
Circadian rhythms
•  Bio-rhythms in the absence of external time cues for ~24h
•  Reset from environmental changes (light-...
Circadian rhythms
•  Affect food metabolism and energy balance
greater impairment of glucose tolerance than the
global kno...
Circadian rhythms
Bass and Takahashi 2010
e to glucose is intact. However, exocytosis
red, suggesting that the clock contr...
e to glucose is intact. However, exocytosis
red, suggesting that the clock controls the
age in stimulus-secretion coupling...
e to glucose is intact. However, exocytosis
red, suggesting that the clock controls the
age in stimulus-secretion coupling...
Circadian rhythms
•  External LD cycles cue
the suprachiasmatic
nucleus (SCN)
Schibler et al 2003
Circadian rhythms
•  External LD cycles cue
the suprachiasmatic
nucleus (SCN)
•  ‘Master clock’
Schibler et al 2003
Circadian rhythms
•  Feeding cycles do not
affect the SCN
•  They can independently
entrain circadian
clocks in peripheral...
Discordance…..
Time-restricted feeding windows
• Increasingly practiced
• Research has yet to be summarized
Objective
• To summarize the current literature on the
effects of TRF on body weight and other
markers of metabolic diseas...
Methods
• Daily TRF windows of 3-12 h
Methods
•  Daily TRF windows of 3-12 h
• Primary endpoints of body weight and/or
biomarkers of metabolic disease risk
Methods
•  Daily TRF windows of 3-12 h
•  Primary endpoints of body weight and/or biomarkers of
metabolic disease risk
• A...
Methods
•  Daily TRF windows of 3-12 h
•  Primary endpoints of body weight and/or biomarkers of
metabolic disease risk
•  ...
Animal research
Animal research
3-4 h TRF Light phase feeding 16-18 weeks
8-9 h TRF Dark phase feeding 16 weeks
12 h TRF
Light vs dark pha...
Animal research
3-4 h TRF Light phase feeding 16-18 weeks
8-9 h TRF Dark phase feeding 16 weeks
12 h TRF
Light vs dark pha...
Animal research
3-4 h TRF Light phase feeding 16-18 weeks
8-9 h TRF Dark phase feeding 16 weeks
12 h TRF
Light vs dark pha...
3-4 h TRF window – weight gain
•  Body weights were 17-18% lower
•  Body weight of mice on TRF-HFD
was 12% lower than AL-L...
3-4 h TRF window
Sherman et al 2011, 2012
• Two studies showing decreases in
triglycerides, total cholesterol,
TNF-α, IL-6...
8 h TRF window
• Fed mice a high-fat or normal diet during dark hrs,
16 weeks
•  Is a calorie always a calorie???
•  In th...
8 h TRF window
•  Differences in body weight
•  TRF-HFD consumed = kcals as AL-HFD but weighed 28% less
•  TRF normal diet...
8 h TRF window
•  Differences in body weight
•  TRF-HFD consumed = kcals as AL-HFD but weighed 28% less
•  TRF normal diet...
8 h TRF window
•  Total cholesterol
•  49% decrease in TC in mice on
TRF-HFD
Hatori et al 2012
8 h TRF window
•  Glucose tolerance
•  Comparable to the controls
Hatori et al 2012
8 h TRF window
•  Inflammatory markers
•  Decreased TNF-α both groups
Hatori et al 2012
12 h TRF window
12 h TRF window – body weight
•  Fed mice during 12 h light or dark phase, 5 weeks
•  Kcals and activity were not differen...
12 h TRF window – body weight
•  Fed mice during 12 h light or dark phase, 6 weeks
•  Kcals and activity were not differen...
12 h TRF window – body weight
•  Mice fed a low-fat and high-fat diet during the 12 h dark-
phase only, 16 weeks
•  No dif...
12 h TRF window - glucose
Farooq et al 2006
12 h TRF window - cholesterol
Farooq et al 2006
Summary of animal findings
Summary of animal findings
Intervention Body weight Lipids Glucose Inflammation
3-4 h TRF
8-9 h TRF
12 h TRF
-9 to -18%
↓ ...
Summary of animal findings
Intervention Body weight Lipids Glucose Inflammation
3-4 h TRF
8-9 h TRF
12 h TRF
-9 to -18%
↓ ...
Summary of animal findings
Intervention Body weight Lipids Glucose Inflammation
3-4 h TRF
8-9 h TRF
12 h TRF
-9 to -18%
↓ ...
Summary of animal findings
Intervention Body weight Lipids Glucose Inflammation
3-4 h TRF
8-9 h TRF
12 h TRF
-9 to -18%
↓ ...
Human Research
4 h TRF window
•  4h TRF every other day for 15 days in healthy men
•  Subjects were instructed to eat enough to maintain ...
4 h TRF window
•  4h TRF every other day for 15 days in healthy men
•  Subjects were instructed to eat enough to maintain ...
4 h TRF window
•  Soeters et al 2009 used the same TRF protocol, also
adjusted energy intake to prevent weight change
•  N...
4 h TRF window
•  Soeters et al 2009 used the same TRF protocol, also
adjusted energy intake to prevent weight change
•  H...
Human Research – Ramadan
Ramadan – weight change
•  Weight changes have ranged from no differences to 5%
weight loss
Ramadan – weight change
Reference Weight Change
Adlouni et al 1997
Nematy et al 2012
Ziaee et al 2006
Temizhan et al 2000
...
Ramadan – blood lipids
!"#"$"%&"
'()*+%,"(
-)
'()*+%,"(
./.
'()*+%,"(
0/.
'()*+%,"(
-1
23456%7("8(+4(9::; <=' <9>' 9?' <@A...
Ramadan – blood lipids
•  Temizhan et al found women had greater improvements in
lipid values than men, but without weight...
Ramadan – blood lipids
•  Nematy et al used the Framingham risk score to show a
significant improvement (p < 0.001) in 10 ...
Ramadan – blood lipids
•  Ziaee et al - LDL, HDL and Ø in TC and TG.
•  TG in overweight and  in normal-weight subject...
Factors to consider with Ramadan
studies….
Intake
• Total energy intake may affect blood lipid values
•  Research has shown decreases, no changes, or
even increases ...
Macros
• There are contrasting reports of whether people
change or do not change their macronutrient
intakes during Ramada...
Meal timing
•  During Ramadan, people eat during the
physiologically ‘wrong’ time
greater impairment of glucose tolerance ...
Sleep schedule
•  Sleep patterns are drastically changed to allow for
early morning meals, affecting metabolism
Seasonality
•  Ramadan takes place according to the Islamic calendar,
occurring at a different date each year
•  Differenc...
Lab testing
• Some studies have performed blood draws in the
morning while others in the late afternoon,
possibly affectin...
And finally…
•  Studies that show disparities with trends reviewed
here are few in number and generally have smaller
sampl...
Ramadan – fasting blood glucose
!"#"$"%&" '()*+%,"(-.//0(1.2&/3"
40./2%5("6(+.(7889 :7;'
<+=*$>+0"*("6(+.(?@@A :A7'(BCDE(:...
Ramadan – inflammation
•  IL-6 decreased by 55%
•  hsCRP decreased 52%
Aksungar et al 2007
Intervention Body weight Lipids Glucose
4 h TRF
8-9 h TRF
10-12 h TRF
-- --
↑, Ø Insulin
sensitivity
Ø to -5% ↓ TC, ↓ LDL,...
Intervention Body weight Lipids Glucose
4 h TRF
8-9 h TRF
10-12 h TRF
-- --
↑, Ø Insulin
sensitivity
Ø to -5% ↓ TC, ↓ LDL,...
Conclusion
• Eating patterns effect circadian rhythms
Conclusion
• Findings from animal and human studies suggest
that TRF may be an effective dietary intervention
to improve a...
Practical application
• 12-15 h daily fasting window
•  Can depend on the season
Don’t eat when it’s dark outside
Unrestricted food intake  internal
discordance
Time-restricted feeding  internal
harmony
Thank You
•  AHS, Dr Varady, Dr Jambazian, Dr Omary, Cal State LA,
UIC
Questions
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AHS13 Jeffrey Rothschild — Time-restricted Feeding, an Overview of the Current Research and Practical Applications

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Time-restricted feeding is a method of intermittent fasting which allows ad libitum energy intake within a window of 4-12 hours, inducing a 12-20h daily fasted window. A wide variety of health benefits have been seen in animal and human trials, this presentation will review the current research and suggest practical applications.

AHS13 Jeffrey Rothschild — Time-restricted Feeding, an Overview of the Current Research and Practical Applications

  1. 1. TIME-RESTRICTED FEEDING: AN OVERVIEW OF THE CURRENT RESEARCH AND PRACTICALAPPLICATIONS Jeff Rothschild, CSCS, M.S. cand. Krista Varady, PhD Pera Jambazian, PhD
  2. 2. About Me •  Currently finishing M.S. in Nutritional Science at CSULA •  Coach College tennis •  Work with personal training clients
  3. 3. Background Unrestricted kcal intake 24 h unrestricted kcal 3-12 h feeding 12-21 h fasting 24 h fast 3-12 h feeding 12-21 h fasting Typicaldiet • 2/3 of U.S. population overweight or obese • 1/3 of U.S. adults meet criteria for metabolic synd
  4. 4. Intermittent Fasting 48 h unrestricted kcal intake 24 h unrestricted kcal 3-12 h feeding 12-21 h fasting 24 h fast (or ~500 kcal) 3-12 h feeding 12-21 h fasting NormaldietADF/ADMF •  weight loss •   LDL-C, trigs, BP and visceral fat mass •  insulin sensitivity
  5. 5. Time-Restricted Feeding 48 h unrestricted kcal intake 24 h unrestricted kcal 3-12 h feeding 12-21 h fasting 24 h fast 3-12 h feeding 12-21 h fasting ADF/ADMFTRFNormaldiet
  6. 6. Circadian rhythms •  Bio-rhythms in the absence of external time cues for ~24h •  Reset from environmental changes (light-dark, temperature and feeding cycles)
  7. 7. Circadian rhythms •  Affect food metabolism and energy balance greater impairment of glucose tolerance than the global knockout, as predicted. Islets from both global and pancreas-specific knockouts have normal insulin content, and influx of calcium in response to glucose is intact. However, exocytosis is impaired, suggesting that the clock controls the latest stage in stimulus-secretion coupling. Findings in experimental genetic models of clock-gene ablation may also have implications for understanding emerging evidence that the circadian system participates in human glucose metabolism. For instance, in genome-wide associa- tion studies, variation in the Melatonin 1b receptor (MTNR1B) and in Cry2 are both associated with blood glucose concentrations [(52) and reviewed in (53)]. MTNR1B, the cognate receptor of the circadian-regulated hor- mone melatonin, is expressed in many metabolic tissues, whereas Cry2 encodes a clock repressor. These findings un- derscore the need to incorpo- rate temporal considerations at the planning stages in future studies to account for circadian variation. Similarly, temporal considerations may aid in anal- ysis of experimental genetic models because testing at dif- ferent times and under different environmental light cycles may uncover unanticipated effects. Sleep and forced circadian misalignment: genetic models and human studies. Ties be- tween circadian disruption and metabolic disturbance have garnered attention, including large cross-sectional sampling of populations subjected to shift work. Extensive studies also indicate a correlation be- tween sleep time and body mass index (BMI). Disruption in specific phases of sleep may be connected to metabolic func- tion. Subtle tones sufficient to selectively deprive subjects of indicates that lack of orexin signaling increases susceptibility to obesity (rather than the original expectation that orexin, a potent wakefulness- inducing peptide, would induce adiposity) (57). Orexin receptor 2 mutations also account for canine narcolepsy, and orexin deficiency is a hallmark of the disease in humans (58). Activity of the orexin neuron is modulated by glucose and integrates signals downstream of leptin-responsive neurons within the arcuate nucleus. Leptin also affects sleep, possibly independently of effects on body weight, raising the need to further define leptin actions in this process (59). Manipulation of orexin signaling, an integrator of energetic and pulation that is intended to simulate deleterious effects of jet lag or shift work, caused impaired glucose tolerance and hypoleptinemia. Whether circadian disruption might also affect endocrine pancreas insulin secretion, hepatic gluconeogenesis, and glucose disposal in skeletal muscle in humans awaits further study; however, these results empha- size the clinical linkages between circadian function and metabolic homeostasis. Coupling and Outputs: How Do Clocks Sense and Respond to Nutrient Signals? Under homeostatic conditions, the clock acts as a driver of metabolic physiology (Fig. 3). However, Sleep deprivation Prolonged wakefulness High-fat diet Pancreas Insulin secretion Fat Lipogenesis Adiponectin production Muscle Fatty acid uptake Glycolytic metabolism Liver Glycogen synthesis Cholesterol synthesis Bile acid synthesis SLEEP FASTING Insulin s ecretion SympathetictoneGlucocorticoids Growth hormone Melatoninsecretion Insulin resistance Insulin s ecretion WAKE FEEDING Leptin secretion Gluconeoge nesis Liver Gluconeogenesis Glycogenolysis Mitochondrial biogenesis Muscle Oxidative metabolism Pancreas Glucagon secretion Fat Lipid catabolism Leptin secretion Fig. 3. The clock partitions behavioral and metabolic processes according to time of day. The clock coordinates ap- propriate metabolic responses within peripheral tissues with the light/dark cycle. For example, the liver clock promotes gluconeogenesis and glycogenolysis during the sleep/fasting period, whereas it promotes glycogen and cholesterol synthesis during the wake/feeding period. Proper functioning of peripheral clocks keeps metabolic processes in synchrony SPECIALSECTION onDecember2,2010www.sciencemag.orgDownloadedfrom Bass and Takahashi 2010
  8. 8. Circadian rhythms Bass and Takahashi 2010 e to glucose is intact. However, exocytosis red, suggesting that the clock controls the age in stimulus-secretion coupling. dings in experimental genetic models of ene ablation may also have implications derstanding emerging evidence that the n system participates in human glucose ism. For instance, in genome-wide associa- dies, variation in the Melatonin 1b receptor 1B) and in Cry2 are both associated with glucose concentrations nd reviewed in (53)]. 1B, the cognate receptor circadian-regulated hor- melatonin, is expressed ny metabolic tissues, s Cry2 encodes a clock or. These findings un- e the need to incorpo- mporal considerations lanning stages in future to account for circadian n. Similarly, temporal rations may aid in anal- experimental genetic because testing at dif- mes and under different mental light cycles may unanticipated effects. p and forced circadian nment: genetic models man studies. Ties be- ircadian disruption and lic disturbance have d attention, including oss-sectional sampling ulations subjected to ork. Extensive studies dicate a correlation be- sleep time and body dex (BMI). Disruption fic phases of sleep may ected to metabolic func- Orexin receptor 2 mutations also account for canine narcolepsy, and orexin deficiency is a hallmark of the disease in humans (58). Activity of the orexin neuron is modulated by glucose and integrates signals downstream of leptin-responsive neurons within the arcuate nucleus. Leptin also affects sleep, possibly independently of effects on body weight, raising the need to further define leptin actions in this process (59). Manipulation of orexin signaling, an integrator of energetic and pancreas insulin secretion, hepatic gluconeogenesis, and glucose disposal in skeletal muscle in humans awaits further study; however, these results empha- size the clinical linkages between circadian function and metabolic homeostasis. Coupling and Outputs: How Do Clocks Sense and Respond to Nutrient Signals? Under homeostatic conditions, the clock acts as a driver of metabolic physiology (Fig. 3). However, Sleep deprivation Prolonged wakefulness High-fat diet Pancreas Insulin secretion Fat Lipogenesis Adiponectin production Muscle Fatty acid uptake Glycolytic metabolism Liver Glycogen synthesis Cholesterol synthesis Bile acid synthesis SLEEP FASTING Insulin s ecretion SympathetictoneGlucocorticoids Growth hormone Melatoninsecretion Insulin resistance Insulin s ecretion WAKE FEEDING Leptin secretion Gluconeogenesis Liver Gluconeogenesis Glycogenolysis Mitochondrial biogenesis Muscle Oxidative metabolism Pancreas Glucagon secretion Fat Lipid catabolism Leptin secretion Fig. 3. The clock partitions behavioral and metabolic processes according to time of day. The clock coordinates ap- propriate metabolic responses within peripheral tissues with the light/dark cycle. For example, the liver clock promotes onDecember2,2010www.sciencemag.orgDownloadedfrom
  9. 9. e to glucose is intact. However, exocytosis red, suggesting that the clock controls the age in stimulus-secretion coupling. dings in experimental genetic models of ene ablation may also have implications derstanding emerging evidence that the n system participates in human glucose ism. For instance, in genome-wide associa- dies, variation in the Melatonin 1b receptor 1B) and in Cry2 are both associated with glucose concentrations nd reviewed in (53)]. 1B, the cognate receptor circadian-regulated hor- melatonin, is expressed ny metabolic tissues, s Cry2 encodes a clock or. These findings un- e the need to incorpo- mporal considerations lanning stages in future to account for circadian n. Similarly, temporal rations may aid in anal- experimental genetic because testing at dif- mes and under different mental light cycles may unanticipated effects. p and forced circadian nment: genetic models man studies. Ties be- ircadian disruption and lic disturbance have d attention, including oss-sectional sampling ulations subjected to ork. Extensive studies dicate a correlation be- sleep time and body dex (BMI). Disruption fic phases of sleep may ected to metabolic func- Orexin receptor 2 mutations also account for canine narcolepsy, and orexin deficiency is a hallmark of the disease in humans (58). Activity of the orexin neuron is modulated by glucose and integrates signals downstream of leptin-responsive neurons within the arcuate nucleus. Leptin also affects sleep, possibly independently of effects on body weight, raising the need to further define leptin actions in this process (59). Manipulation of orexin signaling, an integrator of energetic and pancreas insulin secretion, hepatic gluconeogenesis, and glucose disposal in skeletal muscle in humans awaits further study; however, these results empha- size the clinical linkages between circadian function and metabolic homeostasis. Coupling and Outputs: How Do Clocks Sense and Respond to Nutrient Signals? Under homeostatic conditions, the clock acts as a driver of metabolic physiology (Fig. 3). However, Sleep deprivation Prolonged wakefulness High-fat diet Pancreas Insulin secretion Fat Lipogenesis Adiponectin production Muscle Fatty acid uptake Glycolytic metabolism Liver Glycogen synthesis Cholesterol synthesis Bile acid synthesis SLEEP FASTING Insulin s ecretion SympathetictoneGlucocorticoids Growth hormone Melatoninsecretion Insulin resistance Insulin s ecretion WAKE FEEDING Leptin secretion Gluconeogenesis Liver Gluconeogenesis Glycogenolysis Mitochondrial biogenesis Muscle Oxidative metabolism Pancreas Glucagon secretion Fat Lipid catabolism Leptin secretion Fig. 3. The clock partitions behavioral and metabolic processes according to time of day. The clock coordinates ap- propriate metabolic responses within peripheral tissues with the light/dark cycle. For example, the liver clock promotes onDecember2,2010www.sciencemag.orgDownloadedfrom Circadian rhythms
  10. 10. e to glucose is intact. However, exocytosis red, suggesting that the clock controls the age in stimulus-secretion coupling. dings in experimental genetic models of ene ablation may also have implications derstanding emerging evidence that the n system participates in human glucose ism. For instance, in genome-wide associa- dies, variation in the Melatonin 1b receptor 1B) and in Cry2 are both associated with glucose concentrations nd reviewed in (53)]. 1B, the cognate receptor circadian-regulated hor- melatonin, is expressed ny metabolic tissues, s Cry2 encodes a clock or. These findings un- e the need to incorpo- mporal considerations lanning stages in future to account for circadian n. Similarly, temporal rations may aid in anal- experimental genetic because testing at dif- mes and under different mental light cycles may unanticipated effects. p and forced circadian nment: genetic models man studies. Ties be- ircadian disruption and lic disturbance have d attention, including oss-sectional sampling ulations subjected to ork. Extensive studies dicate a correlation be- sleep time and body dex (BMI). Disruption fic phases of sleep may ected to metabolic func- Orexin receptor 2 mutations also account for canine narcolepsy, and orexin deficiency is a hallmark of the disease in humans (58). Activity of the orexin neuron is modulated by glucose and integrates signals downstream of leptin-responsive neurons within the arcuate nucleus. Leptin also affects sleep, possibly independently of effects on body weight, raising the need to further define leptin actions in this process (59). Manipulation of orexin signaling, an integrator of energetic and pancreas insulin secretion, hepatic gluconeogenesis, and glucose disposal in skeletal muscle in humans awaits further study; however, these results empha- size the clinical linkages between circadian function and metabolic homeostasis. Coupling and Outputs: How Do Clocks Sense and Respond to Nutrient Signals? Under homeostatic conditions, the clock acts as a driver of metabolic physiology (Fig. 3). However, Sleep deprivation Prolonged wakefulness High-fat diet Pancreas Insulin secretion Fat Lipogenesis Adiponectin production Muscle Fatty acid uptake Glycolytic metabolism Liver Glycogen synthesis Cholesterol synthesis Bile acid synthesis SLEEP FASTING Insulin s ecretion SympathetictoneGlucocorticoids Growth hormone Melatoninsecretion Insulin resistance Insulin s ecretion WAKE FEEDING Leptin secretion Gluconeogenesis Liver Gluconeogenesis Glycogenolysis Mitochondrial biogenesis Muscle Oxidative metabolism Pancreas Glucagon secretion Fat Lipid catabolism Leptin secretion Fig. 3. The clock partitions behavioral and metabolic processes according to time of day. The clock coordinates ap- propriate metabolic responses within peripheral tissues with the light/dark cycle. For example, the liver clock promotes onDecember2,2010www.sciencemag.orgDownloadedfrom Circadian rhythms
  11. 11. Circadian rhythms •  External LD cycles cue the suprachiasmatic nucleus (SCN) Schibler et al 2003
  12. 12. Circadian rhythms •  External LD cycles cue the suprachiasmatic nucleus (SCN) •  ‘Master clock’ Schibler et al 2003
  13. 13. Circadian rhythms •  Feeding cycles do not affect the SCN •  They can independently entrain circadian clocks in peripheral organs
  14. 14. Discordance…..
  15. 15. Time-restricted feeding windows • Increasingly practiced • Research has yet to be summarized
  16. 16. Objective • To summarize the current literature on the effects of TRF on body weight and other markers of metabolic disease risk in animals and humans.
  17. 17. Methods • Daily TRF windows of 3-12 h
  18. 18. Methods •  Daily TRF windows of 3-12 h • Primary endpoints of body weight and/or biomarkers of metabolic disease risk
  19. 19. Methods •  Daily TRF windows of 3-12 h •  Primary endpoints of body weight and/or biomarkers of metabolic disease risk • A minimum of 14 d following a TRF protocol
  20. 20. Methods •  Daily TRF windows of 3-12 h •  Primary endpoints of body weight and/or biomarkers of metabolic disease risk •  A minimum of 14 d following a TRF protocol • More than 60 studies on Ramadan were found •  Eight included based on largest sample sizes (n ≥ 32), and inclusion of four or more relevant parameters
  21. 21. Animal research
  22. 22. Animal research 3-4 h TRF Light phase feeding 16-18 weeks 8-9 h TRF Dark phase feeding 16 weeks 12 h TRF Light vs dark phase Low-fat vs high-fat during dark phase 4-6 weeks 16 weeks
  23. 23. Animal research 3-4 h TRF Light phase feeding 16-18 weeks 8-9 h TRF Dark phase feeding 16 weeks 12 h TRF Light vs dark phase Low-fat vs high-fat during dark phase 4-6 weeks 16 weeks
  24. 24. Animal research 3-4 h TRF Light phase feeding 16-18 weeks 8-9 h TRF Dark phase feeding 16 weeks 12 h TRF Light vs dark phase Low-fat vs high-fat during dark phase 4-6 weeks 16 weeks •  Mice normally consume 60-80% of their daily caloric intake during the dark-phase
  25. 25. 3-4 h TRF window – weight gain •  Body weights were 17-18% lower •  Body weight of mice on TRF-HFD was 12% lower than AL-LFD in spite of the same energy intake Sherman et al 2012
  26. 26. 3-4 h TRF window Sherman et al 2011, 2012 • Two studies showing decreases in triglycerides, total cholesterol, TNF-α, IL-6 and NF-kb • Increased insulin sensitivity TNF-αIL-6
  27. 27. 8 h TRF window • Fed mice a high-fat or normal diet during dark hrs, 16 weeks •  Is a calorie always a calorie??? •  In the context of circadian biology, maybe not NA = normal chow (13% fat) ad lib NT = normal chow 8 h TRF FA = high fat (61% fat) ad lib FT = high fat 8 h TRF Hatori et al 2012
  28. 28. 8 h TRF window •  Differences in body weight •  TRF-HFD consumed = kcals as AL-HFD but weighed 28% less •  TRF normal diet weighed less than AL though the difference did not reach statistical significance NA = normal chow (13% fat) ad lib NT = normal chow 8 h TRF FA = high fat (61% fat) ad lib FT = high fat 8 h TRF Hatori et al 2012
  29. 29. 8 h TRF window •  Differences in body weight •  TRF-HFD consumed = kcals as AL-HFD but weighed 28% less •  TRF normal diet weighed less than AL though the difference did not reach statistical significance NA = normal chow (13% fat) ad lib NT = normal chow 8 h TRF FA = high fat (61% fat) ad lib FT = high fat 8 h TRF Hatori et al 2012
  30. 30. 8 h TRF window •  Total cholesterol •  49% decrease in TC in mice on TRF-HFD Hatori et al 2012
  31. 31. 8 h TRF window •  Glucose tolerance •  Comparable to the controls Hatori et al 2012
  32. 32. 8 h TRF window •  Inflammatory markers •  Decreased TNF-α both groups Hatori et al 2012
  33. 33. 12 h TRF window
  34. 34. 12 h TRF window – body weight •  Fed mice during 12 h light or dark phase, 5 weeks •  Kcals and activity were not different •  Dark-phase fed weighed 13% less than light-phase fed •  Less visceral fat Salgado-Delgado et al 2010
  35. 35. 12 h TRF window – body weight •  Fed mice during 12 h light or dark phase, 6 weeks •  Kcals and activity were not different •  Dark-phase fed weighed 19% less than light-phase fed Arble et al 2009
  36. 36. 12 h TRF window – body weight •  Mice fed a low-fat and high-fat diet during the 12 h dark- phase only, 16 weeks •  No differences in kcals or activity •  TRF showed decreased weight gain, independent of the diet Tsai et al 2012
  37. 37. 12 h TRF window - glucose Farooq et al 2006
  38. 38. 12 h TRF window - cholesterol Farooq et al 2006
  39. 39. Summary of animal findings
  40. 40. Summary of animal findings Intervention Body weight Lipids Glucose Inflammation 3-4 h TRF 8-9 h TRF 12 h TRF -9 to -18% ↓ TC, ↓ LDL, ↓ HDL, ↓ TG ↓ Insulin resistance ↓ Il-6, ↓ TNF-a, ↓ CRP, ↓ NFkb Ø to -28% ↓ TC ↑ Insulin sensitivity ↓ Il-6, ↓ TNF-a Ø to -19% ↓ TC, ↓ TG ↓ Glucose --
  41. 41. Summary of animal findings Intervention Body weight Lipids Glucose Inflammation 3-4 h TRF 8-9 h TRF 12 h TRF -9 to -18% ↓ TC, ↓ LDL, ↓ HDL, ↓ TG ↓ Insulin resistance ↓ Il-6, ↓ TNF-a, ↓ CRP, ↓ NFkb Ø to -28% ↓ TC ↑ Insulin sensitivity ↓ Il-6, ↓ TNF-a Ø to -19% ↓ TC, ↓ TG ↓ Glucose --
  42. 42. Summary of animal findings Intervention Body weight Lipids Glucose Inflammation 3-4 h TRF 8-9 h TRF 12 h TRF -9 to -18% ↓ TC, ↓ LDL, ↓ HDL, ↓ TG ↓ Insulin resistance ↓ Il-6, ↓ TNF-a, ↓ CRP, ↓ NFkb Ø to -28% ↓ TC ↑ Insulin sensitivity ↓ Il-6, ↓ TNF-a Ø to -19% ↓ TC, ↓ TG ↓ Glucose --
  43. 43. Summary of animal findings Intervention Body weight Lipids Glucose Inflammation 3-4 h TRF 8-9 h TRF 12 h TRF -9 to -18% ↓ TC, ↓ LDL, ↓ HDL, ↓ TG ↓ Insulin resistance ↓ Il-6, ↓ TNF-a, ↓ CRP, ↓ NFkb Ø to -28% ↓ TC ↑ Insulin sensitivity ↓ Il-6, ↓ TNF-a Ø to -19% ↓ TC, ↓ TG ↓ Glucose -- Eating at the physiologically ‘wrong’ time can lead to increased weight gain, visceral fat, blood lipids and inflammation along with decreased glycemic control
  44. 44. Human Research
  45. 45. 4 h TRF window •  4h TRF every other day for 15 days in healthy men •  Subjects were instructed to eat enough to maintain body weight Halberg et al 2005
  46. 46. 4 h TRF window •  4h TRF every other day for 15 days in healthy men •  Subjects were instructed to eat enough to maintain body weight •  Insulin-mediated whole body glucose uptake rates increased 16% •  Insulin-induced inhibition of lipolysis became more prominent •  No changes in IL-6 or TNF-α Halberg et al 2005
  47. 47. 4 h TRF window •  Soeters et al 2009 used the same TRF protocol, also adjusted energy intake to prevent weight change •  No improvements in peripheral or hepatic insulin sensitivity, or any changes in insulin-induced suppression of lipolysis
  48. 48. 4 h TRF window •  Soeters et al 2009 used the same TRF protocol, also adjusted energy intake to prevent weight change •  However, these participants consumed 40% of their daily energy intake from liquid meals, which may cause different gastric, pancreatic, and biliary responses than consumption of solid meals
  49. 49. Human Research – Ramadan
  50. 50. Ramadan – weight change •  Weight changes have ranged from no differences to 5% weight loss
  51. 51. Ramadan – weight change Reference Weight Change Adlouni et al 1997 Nematy et al 2012 Ziaee et al 2006 Temizhan et al 2000 Fakhrzadeh et al 2003 Ravanshad et al 1999 -3% -2% -2% -5% Men, NC Women -1.8% Men, NC Women NC
  52. 52. Ramadan – blood lipids !"#"$"%&" '()*+%,"( -) '()*+%,"( ./. '()*+%,"( 0/. '()*+%,"( -1 23456%7("8(+4(9::; <=' <9>' 9?' <@A' B+C*$D+3"*("8(+4(>AA@ <>?'(EFGH( <>:'(EIG( <@;' >9'(EFGH( @9'(EIG <@;'(EFGH( <9:'(EIG J"K+8L("8(+4(>A9> <M' <9>' 99' <9:' -"K7D*+%("8(+4(>AAA <='(EFGH( <9A'(EIG <99'(EFGH( <9>'(EIG @'(EFGH(( >'(EIG <9:(EFGH( <>:'(EIG N+$"("8(+4(>A99 <O' <:' 9M' <?' 2CP6%,+$("8(+4(>AA; J) J) J) J) !+Q+%P*+3("8(+4(9::: J) J) N7+""("8(+4(>AAO J) ?' <:' J)
  53. 53. Ramadan – blood lipids •  Temizhan et al found women had greater improvements in lipid values than men, but without weight loss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
  54. 54. Ramadan – blood lipids •  Nematy et al used the Framingham risk score to show a significant improvement (p < 0.001) in 10 years coronary heart disease risk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
  55. 55. Ramadan – blood lipids •  Ziaee et al - LDL, HDL and Ø in TC and TG. •  TG in overweight and  in normal-weight subjects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
  56. 56. Factors to consider with Ramadan studies….
  57. 57. Intake • Total energy intake may affect blood lipid values •  Research has shown decreases, no changes, or even increases in energy intake during Ramadan
  58. 58. Macros • There are contrasting reports of whether people change or do not change their macronutrient intakes during Ramadan fasting
  59. 59. Meal timing •  During Ramadan, people eat during the physiologically ‘wrong’ time greater impairment of glucose tolerance than the global knockout, as predicted. Islets from both global and pancreas-specific knockouts have normal insulin content, and influx of calcium in response to glucose is intact. However, exocytosis is impaired, suggesting that the clock controls the latest stage in stimulus-secretion coupling. Findings in experimental genetic models of clock-gene ablation may also have implications for understanding emerging evidence that the circadian system participates in human glucose metabolism. For instance, in genome-wide associa- tion studies, variation in the Melatonin 1b receptor (MTNR1B) and in Cry2 are both associated with blood glucose concentrations [(52) and reviewed in (53)]. MTNR1B, the cognate receptor of the circadian-regulated hor- mone melatonin, is expressed in many metabolic tissues, whereas Cry2 encodes a clock repressor. These findings un- derscore the need to incorpo- rate temporal considerations at the planning stages in future studies to account for circadian variation. Similarly, temporal considerations may aid in anal- ysis of experimental genetic models because testing at dif- ferent times and under different environmental light cycles may uncover unanticipated effects. Sleep and forced circadian misalignment: genetic models and human studies. Ties be- tween circadian disruption and metabolic disturbance have garnered attention, including large cross-sectional sampling of populations subjected to shift work. Extensive studies also indicate a correlation be- tween sleep time and body mass index (BMI). Disruption in specific phases of sleep may be connected to metabolic func- tion. Subtle tones sufficient to selectively deprive subjects of slow-wavesleepwithoutproduc- indicates that lack of orexin signaling increases susceptibility to obesity (rather than the original expectation that orexin, a potent wakefulness- inducing peptide, would induce adiposity) (57). Orexin receptor 2 mutations also account for canine narcolepsy, and orexin deficiency is a hallmark of the disease in humans (58). Activity of the orexin neuron is modulated by glucose and integrates signals downstream of leptin-responsive neurons within the arcuate nucleus. Leptin also affects sleep, possibly independently of effects on body weight, raising the need to further define leptin actions in this process (59). Manipulation of orexin signaling, an integrator of energetic and pulation that is intended to simulate deleterious effects of jet lag or shift work, caused impaired glucose tolerance and hypoleptinemia. Whether circadian disruption might also affect endocrine pancreas insulin secretion, hepatic gluconeogenesis, and glucose disposal in skeletal muscle in humans awaits further study; however, these results empha- size the clinical linkages between circadian function and metabolic homeostasis. Coupling and Outputs: How Do Clocks Sense and Respond to Nutrient Signals? Under homeostatic conditions, the clock acts as a driver of metabolic physiology (Fig. 3). However, Sleep deprivation Prolonged wakefulness High-fat diet Pancreas Insulin secretion Fat Lipogenesis Adiponectin production Muscle Fatty acid uptake Glycolytic metabolism Liver Glycogen synthesis Cholesterol synthesis Bile acid synthesis SLEEP FASTING Insulin s ecretion SympathetictoneGlucocorticoids Growth hormone Melatoninsecretion Insulin resistance Insulin s ecretion WAKE FEEDING Leptin secretion Gluconeoge nesis Liver Gluconeogenesis Glycogenolysis Mitochondrial biogenesis Muscle Oxidative metabolism Pancreas Glucagon secretion Fat Lipid catabolism Leptin secretion Fig. 3. The clock partitions behavioral and metabolic processes according to time of day. The clock coordinates ap- propriate metabolic responses within peripheral tissues with the light/dark cycle. For example, the liver clock promotes gluconeogenesis and glycogenolysis during the sleep/fasting period, whereas it promotes glycogen and cholesterol synthesis during the wake/feeding period. Proper functioning of peripheral clocks keeps metabolic processes in synchrony with the environment, which is critical for maintaining health of the organism. Different tissues exhibit distinct clock- SPECIALSECTION onDecember2,2010www.sciencemag.orgDownloadedfrom
  60. 60. Sleep schedule •  Sleep patterns are drastically changed to allow for early morning meals, affecting metabolism
  61. 61. Seasonality •  Ramadan takes place according to the Islamic calendar, occurring at a different date each year •  Differences in latitude may lead to fasting times of 8-16 hrs
  62. 62. Lab testing • Some studies have performed blood draws in the morning while others in the late afternoon, possibly affecting results
  63. 63. And finally… •  Studies that show disparities with trends reviewed here are few in number and generally have smaller sample sizes of 8-25 people •  This review included studies with sample sizes of 32-91 people
  64. 64. Ramadan – fasting blood glucose !"#"$"%&" '()*+%,"(-.//0(1.2&/3" 40./2%5("6(+.(7889 :7;' <+=*$>+0"*("6(+.(?@@A :A7'(BCDE(:?9'(BFD !+G+%3*+0("6(+.(7888 :?9' H5+""("6(+.(?@@I :7@' J"K+6L("6(+.(?@7? J) M"K5>*+%("6(+.(?@@@ 7N'(BCDE(??'(BFD
  65. 65. Ramadan – inflammation •  IL-6 decreased by 55% •  hsCRP decreased 52% Aksungar et al 2007
  66. 66. Intervention Body weight Lipids Glucose 4 h TRF 8-9 h TRF 10-12 h TRF -- -- ↑, Ø Insulin sensitivity Ø to -5% ↓ TC, ↓ LDL, ↑ HDL, ↓ TG ↓ ↑ FBG -2 to -3% ↓ TC, ↓ LDL, ↑ HDL, ↓ TG ↓ FBG Summary of human findings
  67. 67. Intervention Body weight Lipids Glucose 4 h TRF 8-9 h TRF 10-12 h TRF -- -- ↑, Ø Insulin sensitivity Ø to -5% ↓ TC, ↓ LDL, ↑ HDL, ↓ TG ↓ ↑ FBG -2 to -3% ↓ TC, ↓ LDL, ↑ HDL, ↓ TG ↓ FBG Summary of human findings
  68. 68. Conclusion • Eating patterns effect circadian rhythms
  69. 69. Conclusion • Findings from animal and human studies suggest that TRF may be an effective dietary intervention to improve a variety of metabolic risk factors •  Plasma lipids •  Fasting glucose and insulin •  Insulin sensitivity •  Inflammatory cytokines
  70. 70. Practical application • 12-15 h daily fasting window •  Can depend on the season
  71. 71. Don’t eat when it’s dark outside
  72. 72. Unrestricted food intake  internal discordance
  73. 73. Time-restricted feeding  internal harmony
  74. 74. Thank You •  AHS, Dr Varady, Dr Jambazian, Dr Omary, Cal State LA, UIC
  75. 75. Questions

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