Clocks & Metabolism PDF

NOTE ! These files are provided for the sole purpose of assisting BSci 3230 students to study for exams in the class. Some of the material in these files may be copyrighted, and it is not OK for you to share these files with anyone who is not a student in this class or to use them for any purpose ot...

NOTE ! These files are provided for the sole purpose of assisting BSci 3230 students to study for exams in the class. Some of the material in these files may be copyrighted, and it is not OK for you to share these files with anyone who is not a student in this class or to use them for any purpose other than to study for BSci 3230. Thanks, Carl Johnson  BSci 3230 Biological Clocks and Metabolism The obesity crisis Clocks & Metabolism in model systems (mice) Food-Entrainable Oscillator (FEO) Time-restricted Feeding (daily) Clocks & Metabolism in humans Obesity “Epidemic” in USA 2020 By race: Overall: Asians Whites Hispanics African Americans Light at Night causes Metabolic Disorders by Disruption of Daily Clock? From NASA WHO, 2008  What about Shift Work in Humans ? Shift-work Obesity Diabetes Cardiovascular disease Physiological maladaptation ? Scheer et al. PNAS 106: 4453-8 (2009) PLOS Medicine 8:12 (2011)  What about Shift Work in Humans ? = created by a T28 Forced Desynchrony protocol “misalignment” was when (leptin inhibits hunger) subjects ate and slept ~12 h out of phase from their “habitual times” “alignment” was when S/W was in phase with their prior cycles Metabolic dysfunction leads to: leptin glucose insulin arterial blood pressure sleep efficiency Scheer et al. PNAS 106: 4453-8 (2009) Biological Clocks and Metabolism in Model Systems Circadian-Controlled Gene Expression (mRNAs) in Mouse Adipose Tissues BAT = brown adipose tissue iWAT = inguinal white adipose tissue eWAT = epididymal (male gonadal) white adipose tissue Zvonic et al. Diabetes 55: 962-970 (2006)  Circadian-Controlled Gene Expression (mRNAs) in Mouse Adipose Tissues Included in the 650 genes that show circadian patterns in liver, BAT, and iWAT: Cebp-a, Cebp-g, Lpl, Ppar-a, Pgc1-b, Stat5A, Enolase 3, Pgam, Transketolase, Lipase, Dgat 1, Mod1, Pepck, lipin 1, Dbp, Rev-erb-a, Rev-erb-b, et al. Zvonic et al. Diabetes 55: 962-970 (2006) Conclusions from Studies on Mice with Mutant or knocked-out Clock Genes: Nature Medicine 12: 54-55 (2006)  Genetic Disruption of the Clock Leads to Fat Mice “Wild-type” (normal) mice: VO2 (ml/kg/h) Days Bmal1-ko mice: 2 (ml/kg/h) ml/kg/hr 5 VO Days Each trace is the mean and SD of four mice Shi et al., Current Biology 2013  Studies in Mouse Models: Mutant of the “Clock” Gene WT = wild-type CL = ClockΔ19mut (homozygous) Turek et al. 308: 1043-5 (2005)  Control of Glucose Levels in the Blood In the pancreas: pancreas Beta cells produce and secrete insulin. Insulin Body cells take up more glucose. Beta cells of Alpha cells produce and secrete pancreas are stimulated glucagon (antagonist of insulin). to release insulin into the blood. After a meal, blood glucose levels rise Liver takes up glucose and stimulate the Beta cells to release and stores it as glycogen. insulin. Insulin stimulates cells to STIMULUS: Blood glucose level transport glucose inside and to convert Rising blood glucose level (for instance, after declines to set point; stimulus for insulin it to glycogen and fat. eating a carbohydrate- rich meal) release diminishes. When blood glucose levels fall, the Homeostasis: pancreas stops releasing insulin, and Blood glucose level cells switch to using glycogen and fat (about 90 mg/100 mL) for energy. Blood glucose level STIMULUS: rises to set point; Dropping blood glucose If blood glucose falls too low, the Alpha stimulus for glucagon release diminishes. level (for instance, after skipping a meal) cells release glucagon which stimulates the liver to convert glycogen back to Alpha cells of pancreas glucose. are stimulated to release glucagon into the blood. Liver breaks down glycogen and releases glucose into Glucagon blood. Insulin “Sensitivity” vs. “Resistance” as Measured with “Insulin Clamps” in Mice Insulin clamp: insulin is continuously infused at a high concentration, then glucose is infused to find the glucose infusion rate that adjusts blood glucose to the desired level. Glucose Infusion Rate sensitive to insulin (mg/Kg/min) resistant to insulin Time (min) Shi et al. Current Biology 2013 Daily Rhythms of Insulin Action CT1 CT7 CT13 CT19 wild-type insulin sensitivity is (WT) rhythmic over the day ! insulin sensitivity Insulin sensitivity is lower during the inactive time inactive phase (for mice) active time clockless (for mice) (CL) CL 13 19 25 31 Time of day Shi et al. Current Biology 2013 Daily Rhythms of Insulin Action CT1 CT7 CT13 CT19 wild-type On the other hand, in (WT) the “clockless mice,” there is no daily rhythm of insulin sensitivity, and the mice are relatively CT1 CT7 CT13 CT19 insulin resistant at all times of day–i.e., in a clockless pre-diabetic state. (CL) CL No daily rhythm Shi et al. Current Biology 2013  FEO= Food Entrainable Oscillator Grey = food is available Anticipatory activity prior to feeding Food Re-emergence of Locomotor rhythmic Anticipatory Activity anticipation of Activity feeding period during fast Disrupting/removing clock genes (e.g., Per1/2/3-ko) can affect FEO effect but doesn’t eliminate it FEO acts outside the TTFL system ?? !! Ijima et al., 2005 Pendergast et al., 2012 Pendergast and Yamazaki 2019  FEO is functional without the SCN! (SCN-X) Food Anticipatory Activity SCN is also NOT needed for FEO behavior; currently NO neuronal locus has been found for the FEO–weird ! Stephan et al., 1979 Pendergast and Yamazaki, 2019 Organization of the Mammalian Circadian System light Master clock: SCN eyes Etc. Conflicting Meal Time? liver stomach muscle Implications for jet lag and shiftwork?  The phase of the liver peripheral oscillator is set by the time of feeding; probably the action of the SCN is indirectly through the control of feeding behavior Per1:Luc rats Bioluminescence rhythms in vitro: Restricted Feeding (RF): food only available for 4 h in the middle of each day The phase of the liver clock can be uncoupled from the SCN and entrained to meal timing ! Stokkan et al., 2001  Energy Balance Calories IN Calories OUT Weight Gain Weight Loss HOW MUCH you eat Baseline Metabolism WHAT you eat HOW MUCH you WHEN you eat exercise Energy Intake Energy Expenditure  Mice under Feeding Restriction do not show changes in Calorie Intake or Activity Light (12hr) Dark (12hr) Regular Chow (NA) Regular Chow (RC) Regular Chow Restricted (NT) RC (8hr) High Fat Diet (FA) High Fat Diet (HFD) High Fat Diet Restricted (FT) HFD (8hr) Hattori et al. (2012)  Restricting High Fat Feeding to the Active Phase Prevents Obesity in Mice How?? Light (12hr) Dark (12hr) Regular Chow (NA) Regular Chow (RC) Regular Chow Restricted (NT) RC (8hr) High Fat Diet (FA) High Fat Diet (HFD) High Fat Diet Restricted (FT) HFD (8hr) Hattori et al. (2012)  Energy Balance When you eat impacts your ability to burn calories! Calories IN Calories OUT Weight Gain Weight Loss WHEN you eat Baseline Metabolism WHAT you eat HOW MUCH you HOW MUCH you eat exercise  Measuring Calories through Indirect Calorimetry Respiratory Exchange Ratio 1. What are you metabolizing? (RER) Glucose (6 C) Palmitate (16 C) 2. By knowing the amount of VO2 consumed and CO2 released, we can determine HOW much and WHICH metabolite is being used. 3. Plugging these factors into a heat equation tells us the calories burned! (= energy expenditure) Journal of Obesity, 2006  Energy Expenditure is Higher in the Restricted Feeding Groups RER= Respiratory Exchange Ratio= VCO2/VO2 (RER indirectly determines the relative contribution of carbohydrates and lipids to overall energy expenditure) Active period (night): mostly carbs; Inactive period (day): mostly lipids Light (12hr) Dark (12hr) Regular Chow (NA) Regular Chow (RC) Regular Chow Restricted (NT) RC (8hr) High Fat Diet (FA) High Fat Diet (HFD) High Fat Diet Restricted (FT) HFD (8hr) Hattori et al. (2012) Biological Clocks and Metabolism in Humans Using Mobile Apps to Answer Circadian Questions! Gill and Panda, 2015 Feeding time and eating duration are highly variable in humans Recorded Feeding events (3 weeks) Gill and Panda, 2015 Baseline: regular feeding habits Restricting Eating Duration affects Caloric Intake restricted to 12 hours Intervention: feeding Reported subjects under 12-h feeding time restriction (NOT calorie restriction) saw on average a 20% reduction in Calories consumed! Gill and Panda, 2015 Time-Restricted Feeding Explosion!  Simulated Shiftwork Schedule impacts Metabolic Rate Daily energy expenditure based Baseline on individual resting metabolic rate measured in a 1 human “indirect calorimeter” 2 Nightshift Day# 3 Wake Sleep Not much difference in energy expenditure in daytime (wake time) after shift, but significantly less energy expenditure during night while asleep. If the shifters are burning less but eating as much, they’ll accumulate more fat. Quote from the paper: “nightshift work reduces total daily energy expenditure, thereby contributing to unwanted weight gain & obesity.” McHill et al., 2014  Meal Timing Work in the Johnson Lab Supplementary Figure S6 Supplementary Figure S6 Kelly et al. 2020 Suboptimal meal timing can impact lipid oxidation and thereby weight gain/loss Kelly et al. 2020 Suboptimal meal timing can impact lipid oxidation and thereby weight gain/loss RC HF HF RC HF HF Inactive Active Inactive Active Lipid Oxidation HF 6h early night HF 6h late night 0 1 2 Days on Feeding Regime B L D S B L D S Active Sleep Active Sleep Lipid Oxidation B-L-D L-D-S 0 1 2 Days on Feeding Regime Kelly et al. 2020 Another Cool Example for TRF: IV feeding in the hospital Children recovering in the hospital from hematopoietic stem cell transplantation (HSCT) are fed by IV. If the IV feeding is restricted to the daytime only (“Intervention” group), patients recover more quickly & are Duration of IV feeding discharged earlier from the hospital than the group that is fed by IV continuously (“Control” group). Also, some patients fed continuously develop hyperglycemia, whereas this was not observed in the TRF group. Wang et al. J Clin Invest. 2023;133(4):e167275  Bottom Line Metabolism is regulated through the circadian clock Feeding at irregular times can lead to dyssynchrony of peripheral oscillators associated with metabolism Metabolic dys-synchrony leads to weight gain and lowers the amount of calories burned Eating before bedtime can delay the clock-controlled switch into “lipid burning” mode and promote fat accumulation  Food for Thought Consider a student who starts a regimen of studying late into the evening/night. The student likes to indulge in late-night snacks (sporadically from 8-11PM) during this studying period to ease the pain of studying but insists on decaf coffee to maintain their sleep schedule. What might be a consequence of this regimen? If humans are more “insulin resistant” at night when they are normally sleeping, what is the consequence to the normal glucose/insulin relationship for persons suffering from ”Night Eating syndrome?”