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KIN 404 SEC 4:TEST 4 NOTES - Regulation of energy expenditure.docx

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KIN 404
Russ Tupling

REGULATION OF ENERGY EXPENDITURE  For 2 adults of similar size/age, TDEE can vary by ~ 1500 kcal/day.  Weight gain results wen EE is inappropriately low for the caloric intake of a person. Measures of metabolic rate:  Basal metabolic rate (BMR) – laying awake but resting (ideally right after waking up), stress free, not digesting food, absence of thermoregulatory heat production o Measured directly by calorimetry, and indirectly by measuring oxygen uptake  Resting metabolic rate (RMR) – similar to BMR but not measured in morning after sleep (10% higher)  Minimal metabolic rate – metabolic rate in various conditions that cause rate to fall below BMR o Sleep = decreases it by 10%, anesthesia, continued starvation (leptin decreases energy)  Field metabolic rate – TDEE is higher than BMR due to energy requirements of feeding, cold exposure and muscle use.  Maximal metabolic rate – maximal steady state metabolic rate during hard exercise (20X BMR- athlete; 12X BMR – sedentary) Energy use in adult human body  Of total energy intake, most is used up but some is lost in urine and feces.  Of the total energy used, most is lost as heat, some used in growth, reproduction and work.  Of total energy lost, most of it is due to BMR, muscle use, food TEF, cold/diet. o BMR – 60-70%  Mitochondrial proton leak – 20%  Protein synthesis – 25-30%  Na/K ATPase – 19-28%  Ca ATPase – 4-8%  Gluconeogenesis – 7-10%  Ureagenesis – 3%  Actomyosin ATPase – 2-8% o Physical activity – 15-30% (>50% in highly active individuals)  Exercise – purposeful physical activity undertaken for sport. Avg ~ 100kcals/day  NEAT – occupation, leisure, sitting, talking etc. Avg 450 – 2000 kcals/day o TEF – 8-12%  Typically stimulates metabolic rate by ~25% with peak stimulation 1-2 hrs after a meal in humans. Frequent eating has cumulative effect.  Metabolism of ingested amino acids in liver for glucose, fat, urea, and protein synthesis (~35-35%) = active process  Swallowing, digesting, and absorption of food, enzyme secretion (~25-30%)  SNS activation (~30-40%) o Other – 2-3%  Nucleic acid synthesis  Substrate cycling  Brain contributes very little to body mass, but contributes a lot to BMR because of the increased number of cells present in humans, thus more activity (not in rats)  Skeletal muscle contributes to both body mass and BMR in humans and rats Overview of the acute control of brown adipose tissue (BAT)  VMN – ventromedial hypothalamic nucleus  SNS to release norepinephrine (NE)  Beta-3 adregenic receptor on BAT and increases CAMP  cAMP activates PKA which phosphorylates and activates HSL  HSL hydrolyses triglycerides  Lipolysis releases FFA from TG  FFA is substrate for thermogenesis and activator of UCP1 o FFA gets taken up in mitochondria and undergoes beta-oxidation  TEF is not the same as adaptive thermogenesis, although both activated by SNS o TEF always happens, but adaptive thermogenesis is the net + energy balance due to chronic increase in intake of energy that leads to adaptations over time.  Thermogenesis is due to activation of UCP1 through lipolysis o Experiments with BAT isolated from UCP1 ablated mice show that in the absence of UCP1, no thermogenesis can be induced in BAT by NE.  NE leads to response in WT, but no response in UCP1-KO o Stimulation of lipolysis stimulates thermogenesis, and the thermogenic process in BAT can be mimicked by the addition of fatty acids (also UCP1 dependent)  Lipolysis is NE induced in brown adipocytes  All manipulations that induce lipolysis in BAT also induce thermogenesis.  HSL- hormone sensitive lipase o Contained in BAT. o NE induces phosphorylation of this enzyme in order to activate lipolysis o Artificial TG emulsions are not endowed with perilipin – protein that normally covers the TG droplets within the cell  Protects the TG against HSL activity.  PKA phosphorylates perilipin and dissociates it from the TG droplet, making it freely exposed to attack by HSL o Perilipin-deficient mice = high basal lipolysis that can’t be further activated by adrenergic stimulation, and increased BMR o Perilipin deficient animals = BAT appears very lipid depleted. o KO perilipin = lean but don’t become obese, increased EE  Thermogenesis in BAT at a given moment is determined by the degree of activation at that moment (y-axis) and can alter within seconds, but the capacity for thermogenesis is determined by the degree of recruitment of the tissue (x-axis) which needs days or weeks to be significantly altered. o When you wake up and not eaten (BMR), its inactive o Once you eat or get cold, you increase activation o Chronic overfeeding leads to the recruitment of more BAT and some white adipose tissue also gets activated. Therefore BAT hypertrophy. o BAT even at BMR burn more energy compared to WAT. Sites of FDG uptake corresponding to BAT in adult humans  FDG PET- fluorodeoxyglucose positron emission tomography – used to look for tumors o Tumors are very glycosidic and take up a lot of glucose. o Test – get people to fast, then inject them with FDG, and the cells that rely on glucose will take it up from the blood = brain, bladder, heart  CT – computer tomography – visualizes density and composition of tissues o Found that the dense mass was not muscle but adipose tissue, humans have BAT o Is the staining different in warm vs cold temp?  Cold-induced BAT activation in adult humans.  Warm temp = no need to activate SNS to adapt for thermogenesis  Cold temp = tissue becomes activated and takes up more glucose  Sympathetic control of BAT activity in adult humans  Same experiment carried out under cold/normal conditions but now with the use of propranol (beta blocker) o Completely blocks glucose uptake and UCP1 is not activated = humans have stores of BAT Articles:  Mice overexpressing human UCP3 in skeletal muscle = hyperphagic (eat more) and lean o Complete prevention of diet-induced diabetes  Skeletal muscle respiratory uncoupling (overexpressed UCP1 – found only in BAT)= prevents diet-induced obesity and insulin resistance in mice Conclusion: Promoting inefficient metabolism in muscle represents a potential treatment for obesity and its complications = Increasing mitochondrial uncoupling proteins promotes inefficient metabolism in muscle.  Mice lacking mitochondrial uncoupling proteins = cold sensitive but not obese (room temp)  Genetic ablation of BAT in transgenic mice = development of obesity Conclusion: UCP1 is not the only system involved in thermogenesis even within BAT so there may be other energy consuming processes that can be targeted for promoting inefficient metabolism. Prof’s research – looking for another non-UCP1 site for inefficient metabolism  What contribution do Ca pumps have on total EE? o At rest, cytosolic Ca levels must remain low. Pumps need energy to pump Ca against concentration gradient. 1ATP used to pump 2Ca into SR = efficient o Inefficieny = less Ca being pumped for every ATP used.  Experiment: EDL stimulated to contract normally o Measured the amount of force consumed and ATP used in contraction. o Repeated experiment using drug that inhibits myosin-ATPase to tease out how much energy was used by myosin and which aren’t (Ca-ATPase) o Ca was still being released even when muscle was not contracting o Study assumed 5% of total skeletal muscle ATP consumption o ATP consumption in resting mouse muscle measured at 40-45% o Skeletal muscle accounts for 20-30% of whole body RMR  Ca pump activity could account for 18% of TDEE o Studies show that Ca pumps contribute 30-40% to the overall muscle ATP use.  Myosin ATPase – 60%, Ca ATPase – 30%, Na ATPase – 10% Assessing contribution of SERCA activity to RMR  Experiment: As the muscle sits at rest and uses up ATP for its basal metabolic processes, the muscle is consuming oxygen. Therefore, oxygen content of the bath decreases and that’s what’s measured.  Indirect method: inhibit Ca leak which indirectly inhibits Ca pumps because the pump would not need the actin to pump the Ca back in.  High concentration of MgCl2 = binds to Ca release channels and maintains it in the closed state o Prevents Ca from leaking out of the channel  Reduction of VO2 content in comparison to control was 41% soleus (slow twitch), 46% EDL (fast) o ATP consumption contributes >5% significantly more (~40-50%) Adaptive thermogenesis  Variable, regulated by the brain  Responds to temperature and diet  Occurs in brown adipocyte mitochondria o Cold or excess energy is sensed in the brain o Sympathetic nerves are activated – chronic elevation of SNS activity = good for adaptive thermogenesis but bad for CVD and high BP o NE binds to beta-adrogenic receptor (B-AR) on BAT  Activates cAMP  Activates PKA o Stimulates lipolysis, activates UCP1 and generates heat/burns energy Altering SR Ca transport efficiency  Physiologically – phospholamban, sarcolipin, HUFAs and cold acclimation all decrease efficiency of Ca pumps. o Cold increases thyroid hormone which decreases SERCA pump efficiency. o T3 levels also increase heat/EE  Pharmacologically – hyper/hypothyroid, tamoxifen, curcumin = decrease Ca pump efficiency o Fluoride increases Ca pump efficiency Sarcolipin (SLN)  Integral membrane protein, 31 aa  Interaction within Ca binding domain of SERCA  SERCA regulator o Affects rate and efficiency of Ca pumping (reduces it) = reduces affinity of Ca binding sites o Inhibits uptake more than ATPase activity = more ATPase is required. Articles  SLN uncouples hydrolysis of ATP from accumulation of Ca by the Ca-ATPase of skeletal-muscle SR o Took artificial membranes and reconstituted them with pure proteins with different rations of SERCA to SLN and they measured Ca uptake. o The more SLN was reconstituted, the more uncoupling they got  The presence of SLN results in increased heat production by Ca-ATPase o Same prep in artificial membrane o Proposed a model where SLN causes slippage during Ca pumping. o The reaction cycle of SERCA:  E1 confirmation – ATP is hydrolyzed, ADP is released  Ca binds at the binding site with high affinity  Cytoplasmic gate is open, lumen gate is closed  Ca binding site faces cytoplasm  E2 confirmation – free energy released by ATP hydrolysis is used to drive the conformational change.  Cytoplamsic gates close, lumen gates open  Cytoplasmic gates close before Ca can get through the pump and it slips out back into the cytosol.  SLN leads to slippage and promotes inefficient Ca pumping  Ca no longer binds with high affinity therefore released in cytoplasm  Coupling ratio < 2Ca: 1ATP and increased heat release Transgenic mouse models (SLN KO)  Breed mice that have 1 copy of the mutated gene and 1 normal gene (f1 generation will be bred by Mendelian genetics, so you always have to test the offsprings) o WT will only have the WT allele, o Heterozygotes will express both alleles o KO will only have the targeting allele  No mRNA in KO mice  Diaphragm, soleus, WG, Artia = tissues that express high levels of SLN  In EDL, KO and WT should be similar.  SLN ablation increases Ca transport efficiency in soleus (High SLN) o Measured Ca uptake by transport o Measured ATPase activity by ATP hydrolysis  For the same amount of Ca uptake, the KO mice required less ATP to achieve it = coupling ratio in KO mice higher = more efficient o Physiological levels of SLN in skeletal muscle reduces the efficiency of Ca transport (WT vs KO)  Conclusion: mice with varying levels of SLN expression are ideal for studying the effects of altered Ca pump efficiency on metabolic rate, energy balance and susceptibility to diet-induced obesity.  The relative contribution of SERCA to resting soleus VO2 is lower in chow-fed SLN KO mice o Lower in KO because more efficient but not statistically significant o Difference in % reduction in VO2 when MgCl2 is used:  45% in WT, 35% in KO.  Less in KO because SERCA pumps use less energy to RMR because they are more efficient o The resting VO2 metabolic rate did not go down as expected because it could be due to some other mechanism kicking in to compensate. o Skeletal muscle contributes ~ 30% of total body BMR. If there was a significant difference here, it would be expected to be noted at the whole body level  Body weight, whole body VO2, food intake and activity are not different between SLN KO and WT chow-fed mice. o
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