DIET413_BHCS1019_JEC05_Regulation_Consolidation_2024 PDF

Regulation and Integration of Metabolism Lecture M5/5 Jane Carré Lecturer in Human Nutrition and Metabolism, SoBS [email protected]  Putting it all together Co...

Regulation and Integration of Metabolism Lecture M5/5 Jane Carré Lecturer in Human Nutrition and Metabolism, SoBS [email protected]  Putting it all together Consider the main metabolic pathways we have covered in energy metabolism.  Which ones are catabolic? Which ones are anabolic?  What effect would high activity of these pathways have on:  the reduction potential NAD(P)H/NAD(P)+?  the phosphorylation potential ATP/[ADP+Pi]?  Which pathways would you expect to be active in the FED state? Which ones in a FASTED state? In which organs?  Accumulation of metabolites typically signalling Discuss together theenergy status key metabolites that indicated each energy state: liver Energy-rich state Energy-depleted state (high energy charge) (low energy charge) Typically: Typically: Substrate-depleted: Substrate-full: TCA cycle intermediates TCA cycle intermediates Low reducing power => low NAD()H/ Reducing power => high NAD(P)+ NAD(P)H/NAD(P)+ Phosphorylating power =>high Phosphorylating power =>high ATP/ADP ATP/ADP NAD glucose-6- AMP + phosphate NAD malonyl CoA acetyl H CoA ATP citra oxaloacet te NADP ate Metabolic convergence Major fuels converge on the ‘typical’ metabolic pathways  Learning outcomes the end of this lecture you will be able to: 1. explain the need to regulate metabolic pathway flux 2. understand the concept that control of flux is shared between different enzymes in a pathway, and that enzymes with a high degree of control represent steps with regulatory potential and thus are therapeutically relevant 3. understand the concept that energy metabolism is largely controlled by energetic demand 4. outline the different ways in which metabolic regulation is achieved in cells and provide examples 5. describe key features of hormonal regulation 6. describe the metabolic role of insulin in the fed state 7. recognise key metabolic intermediates that indicate cellular energy status  Integrating whole body metabolism Key metabolic roles of different organs liver muscle adipose storage of CHO storage of CHO storage of fat Fuel reserves (glycogen) (glycogen) (TAG) reserve of amino acids Fuel mobilisation glucose output amino acid fatty acid output output o important roles of gut, brain, pancreas, kidney 6  The need for regulation of metabolism  pattern of nutrient intake is sporadic  must be able to take in macronutrient fuels, store them as necessary, oxidise them when required  anabolic and catabolic macronutrient pathways active at different times  different organs have different fuel needs  Flow (flux) of energy substrates needs to be regulated – but where?  achieved by changing activity of enzymes in metabolic pathways – but which ones? how? Figure: Frayn N and Akanji AO (2010) Integration of Metabolism 2: Macronutrients. In Nutrition and Metabolism (Susan A. Lanham-New, , Ian A. MacDonald, , Helen M. 7  Key Concept: where to regulate Metabolic pathway flux is controlled more by some enzymes than others in the pathway = flow, ie overall rate of metabolite flow through a metabolic pathway Concept of metabolic flux* control Small changes in activity of some enzymes input metabolites output affects the overall flux through the pathway more than changes in activity of others Such enzymes are said to have a relatively high degree of control over metabolic flux communicated through metabolite pools Control is shared across enzymes in a pathway and changes in activity of these enzymes may : restrict flow of metabolites through the may shift under different pathway or cellular conditions stimulate flow of metabolites  Energy metabolism is largely controlled by energy demand and responds to changes in cytosolic ATP/ADP Small changes in activity of energy demanding processes affects the overall flux through the pathway more than changes in activity of energy cytosolic ATP ATP supply ATP/ADP supply demand Energy demand is said to have a relatively high degree of control over metabolic flux Communicated through cytosolic ATP/ADP increases in energetic demand mitochondrial NADH/NAD+ also important are met by increases in ATP supply Changes in energy demand may : from energy yielding catabolic processes restrict flow of metabolites through the catabolic pathway or decreases in energetic demand stimulate flow of metabolites through anabolic are met by pathways decreases in ATP supply from energy yielding catabolic processes Control is shared across enzymes in a pathway  Key Concept: where to regulate Enzymes with most metabolic control offer potential for regulation ant to understanding metabolism, but also clinical relevance for therapeutic targeting Metabolic regulation occurs by changing enzyme activity – but which enzymes? Some common features of enzymes that have high metabolic control First unique step of a pathway Enzyme after a branchpoint in a pathway Enzymes operating far from equilibrium – essentially irreversible Transport processes often control availability of intermediates for enzyme So activity but how is regulation of enzyme activity achieved? that’s where… 10 *Note: ‘rule-of-thumb’, but not true for all enzymes/steps that have these characteristics… not all regulated enzymes  Activity Concepts in metabolic regulation: how to regulate Metabolic pathways are regulated to: respond to environmental cues (eg nutrient availability, workload) meet metabolic needs of individual organs Discuss: In what ways can this be achieved? 11  Activity Concepts in metabolic regulation Engagement of different metabolic pathways can be achieved in various ways 1) Compartmentalisation of metabolic enzymes Different organs Different subcellular locations 2) Different enzymes catalyse ‘forward’ and ‘reverse’ metabolic pathways 3) Different isozymes respond to environmental states kinetic properties 4) Enzyme activity regulated in response to environmental metabolite concentrations states a. product inhibition/activation; substrate limitation by action of signalling enzymes; hormones b. allosteric regulation of enzymes 12 c. covalent modification of enzymes  Metabolic regulation is achieved in different ways w is regulation of enzyme activity achieved? Short-acting expression of different versions of the same (mins, hours) enzyme - isozymes substrate availability Feedback/feedforward by products/metabolic intermediates products covalent modification – eg phosphorylation fast-acting hormones Long-acting slow-acting hormones (hours, days) 13  1. Compartmentalisation of metabolism ve already seen physical separation of metabolic pathways: Tissue-specific expression of gluconeogenesis restricted to liver (& kidney) metabolic pathways fatty acid synthesis – liver, adipose ketogenesis - liver urea cycle – liver fatty acid breakdown (mitochondria) Compartmentalisation of separated from fatty acid synthesis enzymes within cells (cytosol) 14  1. Compartmentalisation of enzymes: tissue specificity eg: glucose 6 phosphatase allows gluconeogenesis in liver not muscle presence of glucose 6 phosphatase allows gluconeogenesis in liver lacking in muscle muscle lacks glucose 6 phosphatase other gluconeogenesis enzymes also lacking in muscle enzyme cannot release glucose so cannot perform gluconeogenesis directly muscle glycogen (via glycolysis) produces substrates eg alanine for liver gluconeogenesis glucose alanine to liver for gluconeogenesis alanine transamination Lecture M2  2. Alternative enzymes to catalyze ‘reverse’ process e also already seen different enzymes catalyse reverse chemistry: Activity – discuss with those around you why/how….. Gluconeogenesis is not a straightforward reversal of glycolysis Fatty acid synthesis uses different enzymes compared to fatty acid breakdown 16  revisiting Gluconeogenesis - pathway Essentially reverse of glycolysis EXCEPT for 3 key Recallsteps 3 essentially irreversible steps: hexokinase Phosphofructokinase pyruvate kinase Also, decarboxylation of pyruvate by pyruvate ruvate carboxylase acetyl CoA dehydrogenase cannot be reversed EP carboxylase acetyl CoA cannot be converted to glucose oxaloacetate citrate as OAA is withdrawn from TCA cycle means fats and some amino acids cannot be precursors to glucose synthesis from acetyl coA Lecture M2  Revisiting Gluconeogenesis - pathway Essentially reverse of glycolysis EXCEPT for 3 key steps glycolysis gluconeogenesis hexokinase glucose-6-phosphatase phosphofructoki fructose 1,6-bisphosphatase nase pyruvate kinase pyruvate carboxylase PEP carboxylase Tight regulation of gluconeogenesis over glycolysis is achieved by using different enzymes to catalyse forward and reverse reactions Overcomes Lecture M2 energetic barrier that prevents simple reversal of glycolysis  Alternative enzymes to catalyze ‘reverse’ process e also already seen different enzymes catalyze reverse chemistry: Gluconeogenesis is not a straightforward reversal of glycolysis – 3 ‘irreversible’ enzymes to overcome Fatty acid synthesis uses different enzymes to fatty acid breakdown Q: But how is activity of different pathways regulated? Which enzymes are regulated? How are pathways ‘switched on/off’? 19  3. Regulation by different isozymes Expression of different versions of the same enzyme = isozyme (or isoenzyme) isozymes: may be tissue-specific and/or compartment-specific typically differ in terms of kinetic and/or regulatory properties Eg hexokinase versus glucokinase 20  Reminder: enzymes displacement of reactions from equilibrium and ratio of [products/reactants] acts as a ‘mass action’ thermodynamic driving force Nathaniel’s lectures: rate of enzyme reaction is proportional to substrate concentration Km of an enzyme is the substrate concentration at which half the maximal rate is achieved Enzymes may be inhibited by product Enzymes may be allosterically inhibited or activated by molecules that bind at a site other than the active site 21  Different isozymes have different regulatory features that dictate metabolic function of tissue example hexokinase glucokinase skeletal Liver, pancreas muscle Physiological range low Km – high Km – not saturated saturated at physiological at physiological range of glucose range of glucose Enzyme activity varies Enzyme with glucose maximally active concentration 22 at all glucose  Different isozymes have different regulatory features that dictate metabolic function of tissue Muscle: driven by ATP supply Pancrease: driven by ATP demand muscle cell – hexokinase pancreatic β cell – glucokinase muscle contraction blood glucose > 5 mM  ATP/ADP ↓ glucose catabolism ↑  glucose catabolism ↑ ATP/ADP ↑  ATP/ADP ↑ insulin release ↑ regulatory potential of hexokinase influences cell-specific physiology 23 4b. Feedback & feedforward regulation by metabolites: allosteric regulation feedback feedforward metabolites upstream or downstream activate or inhibit regulatory enzymes allosteric regulation Effector binds to site other than active site 24  4. Regulation by metabolite concentrations revisiting Regulation of fatty acid synthesis and breakdown itochondrial -oxidation of fatty acids fatty acid synthesis in cytosol Liver & adipose the two processes should not occur at the same time 25 Lecture M3 Next two examples relate to regulation of the balance between these processes  Regulation of CPTII by substrate availability regulation & example control Substrate availability feeds forward to stimulate continued transport regulation of balance between synthesis and breakdown atty acids: regulation of CPTII by coenzyme A Coenzyme A high levels of free CoA in matrix => continued uptake carnitine available for co-transport fatty acid oxidation facilitated low levels of free CoA in matrix => prevent uptake CPTII activity prevented in mito matrix carnitine unavailable for co-transport fatty acid oxidation slows occurs when acyl CoA production>use fed state 26 Lecture M3  revisiting Allosteric feedback regulation of CPT1 by malonyl example CoA Example of feedback control of metabolic status: regulates balance between synthesis and breakdown of fatty acids activated fatty acid bound to coenzyme Malonyl CoA precursor for fatty acid synthesis inhibits CPT1 Blocks fatty acyl CoA uptake into mitochondria signals ‘storage’ activated fatty acid transferred to prevents use of fatty acids as fuels carrier molecule carnitine for transport into mitos 27 Lecture M3  4b. allosteric regulation Allosteric regulation of phosphofructokinase allows example glycolysis to respond to energy status of cell phosphofructokinase is a key regulatory enzyme in glycolysis regulated in different ways in response to energy + status of cell 5’AMP inactivated by physiological [ATP] => product inhibition of hexokinase also inactivated by high [citrate] => high energy charge phosphofructokinase activation by 5’AMP (low energy charge) displaces allosteric inhibitory ATP ensures glycolysis activated to generate ATP & PFK is inhibited byNADH when i.e. high [ATP], fuelatneeded a high energy charge PFK is activated by high [5’AMP], i.e. at a low energy charge 28  revisiting Role of adenylate kinase and AMP in energy homeostasis ATP is produced by mitochondrial oxidative phosphorylation ATP supplied in response to energetic demand When energetic demand increases, high [ADP] => converted by adenylate kinase to AMP MP acts as cellular signal of energy status metabolic AMP sensors regulate metabolism Lecture M1  Expanding: regulation Allosteric regulation of AMP kinase cascades signal low energy charge via covalent modification of enzymes example AMP-activated kinase: a ‘master regulator’ of energy metabolism High AMP (low energy charge) indicates imbalance in fuel supply in relation to cell’s energy needs allosterically- activated AMP kinase phosphorylates other Activated by AMP proteins [LOW ENERGY covalent modification => conformational change triggers co-ordinated responses CHARGE] increases fuel mobilisation For info increases capacity for fuel oxidation – eg mitochondrial biogenesis AMP produced by adenylate kinase when ADP rises (energy 30 demand>supply) 4d. Hormones stimulus such as the blood concentration of: metabolic fuels other hormones neuronal control. release of hormone from the endocrine gland in which it is made circulates in the bloodstream acts only on target cells that have receptors for the hormone 31  Hormone binding to receptors causes a signalling cascade that results in cellular responses Two types of hormone response Fast-acting: changes in activity of existing enzymes due to covalent modification. Receptor releases second messengers Direct/indirect activation of an enzyme that catalyses a covalent modification of an enzyme eg kinase activated => phosphorylates target Increases or decreases activity of enzyme Slow-acting: changes in rate of synthesis of enzymes second messengers bind to regulatory regions of DNA alter rate of transcription of one or more genes32 Source: simplewikipedia.com  Key hormones regulating macronutrient metabolism Pancreatic hormones insulin glucagon Intestinal hormone incretins Adrenal glands Catecholamines (adrenaline, noradrenaline) cortisol Pituitary gland growth hormone Thyroid gland thryoid hormone Adipocyte hormones leptin 33 Lanham-New Chapter 4  Integrating whole body metabolism Key metabolic roles of different organs liver muscle adipose storage of CHO storage of CHO storage of fat Fuel reserves (glycogen) (glycogen) (TAG) reserve of amino acids Fuel mobilisation glucose output amino acid fatty acid output output o important roles of gut, brain, pancreas, kidney 34  Insulin is a fast-acting hormone of the fed state Anabolic hormone encourages the storage of carbohydrate, fat and protein enerally mediated by stimulating synthesis and inhibiting catabolic bre liver muscle adipose glucose uptake, uptake, use uptake, use & storage storage of glucose of glucose glucose output amino acid fatty acid output output *Glycolysis not inhibited by BHCS2022, BHCS2025 insulin – stimulated - ATP te: also depends on glucagon concentration required for anabolism35  Insulin is a fast-acting hormone of the fed state Anabolic hormone encourages the storage of carbohydrate, fat and protein enerally mediated by stimulating synthesis and inhibiting catabolic bre *Glycolysis not inhibited by insulin – stimulated - ATP required BHCS2022, BHCS2025 for anabolism 36 ote: also depends on glucagon  Fast-response example Activation of glycogen synthesis in the fed liver muscle state by insulin Insulin released from pancreas in response to rising blood glucose and amino acids (fed state) stimulates insulin receptor response results in dephosphorylation of glycogen synthase insulin insuli (activation) n dephosphorylation glycogen phosphorylase (inactivation) leads to fuel storage in fed state Lecture M2 37  Fast-response Activation of glycogen breakdown by adrenaline example liver muscle Adrenaline ‘fight or flight’ mobilises glycogen Bender DA 2022 stimulates a beta-adrenergic receptor response adrenaline adrenaline results in glucagon glucagon phosphorylation of glycogen synthase (inactivation) phosphorylation glycogen phosphorylase (activation) 38 Lecture Glucagon M2 Outcome: hormonemuscle elicits supply of substrates the same response –for liver gluconeogenesis  Energy metabolism is largely controlled by energy demand and responds to changes in cytosolic ATP/ADP Small changes in activity of energy demanding processes affects the overall flux through the pathway more than changes in activity of energy cytosolic ATP ATP supply ATP/ADP supply demand Energy demand is said to have a relatively high degree of control over metabolic flux Communicated through cytosolic ATP/ADP increases in energetic demand mitochondrial NADH/NAD+ also important are met by increases in ATP supply Changes in energy demand may : from energy yielding catabolic processes restrict flow of metabolites through the catabolic pathway or decreases in energetic demand stimulate flow of metabolites through anabolic are met by pathways decreases in ATP supply from energy yielding catabolic processes Control is shared across enzymes in a pathway  Energy metabolism is largely controlled by energy demand and responds to changes in cytosolic ATP/ADP ATP cytosolic ATP Supply ATP/ADP demand (fuel oxidation) (work) increases in energetic demand are met by g exercise stimulation of fuel oxidation increases in ATP supply from energy yielding catabolic processes decreases in energetic demand are met by decreases in ATP supply from energy yielding catabolic processes Regulation of the use of metabolic fuels in muscle during aerobic exercise Muscle is composed of fibres with different metabolic features – oxidative (slow-twitch, T1) or glycolytic (fast-twitch, TIIB) Glucose is main fuel for resting muscle in fed state => Anaerobic glycolysis due to poor perfusion Moderate aerobic exercise (gentle jogging, brisk walking) => Plasma non-esterified fatty acids NEFA Prolonged aerobic exercise at relatively high intensity (eg major fuel marathon running) Increased reliance on stores of glycogen and TAG, with glucose from gluconeogenesis (liver) As exercise continues, plasma NEFA more important 41  ATP yields from fuel sources ATP/mol substrate theoretical maximum yield anaerobic glycolysis 2 Max n reducing equivalents substrate level phosphorylation aerobic glycolysis 32-34 Max formation/use of pmf in OXPHOS -fatty acid oxidation 110-126 factors affecting actual yield from OXPHOS include how much of pmf is available for ATP synthesis benefits of low molar affected by uncoupling of efficiency? oxphos  Metabolic flexibility Ability of cells to adapt to conditions by engaging different energy yielding pathways anaerobic aerobic glycolysis, fatty acid oxidation analogy: analogy: low gear high gear slower turnover rapid turnover low yield => rapid turnover high yield => slower inefficient turnover rapid response to demand more efficient sustainable? longer lasting (blade size represents ATP yiel  Integrating metabolism ts: etabolism and glucose metabolism are intimately related one predominates, the other is minimised ved through hormonal regulation – insulin suppresses fat mobilisation, stimulates glucose use an ved through metabolite regulation – eg fatty acids inhibit glucose oxidation in muscle 44  Summary 1. explain the need to regulate metabolic pathway flux 2. understand the concept that control of flux is shared between different enzymes in a pathway, and that enzymes with a high degree of control represent steps with regulatory potential and thus are therapeutically relevant 3. understand the concept that energy metabolism is largely controlled by energetic demand 4. outline the different ways in which metabolic regulation is achieved in cells and provide examples 5. describe key features of hormonal regulation 6. describe the metabolic role of insulin in the fed state 7. recognise key metabolic intermediates that indicate cellular energy status 8. describe the regulation of macronutrient metabolism in some key organs/tissues 45  Accumulation of metabolites typically signalling Discuss together theenergy status key metabolites that indicated each energy state Energy-rich state Energy-depleted state (high energy charge) (low energy charge) NAD glucose-6- AM + phosphate P NAD malonyl acetyl H CoA CoA citrat ATP e NADPH  Summary 1. explained the need to regulate metabolic pathway flux 2. outlined the concept that control of flux is shared between different enzymes in a pathway, and that enzymes with a high degree of control represent steps with regulatory potential and thus are therapeutically relevant 3. outlined the different ways in which metabolic regulation is achieved in cells and provided examples 4. described key features of hormonal regulation 5. described the metabolic role of insulin in the fed state 6. recognised key metabolic intermediates that indicate cellular energy status 7. described the regulation of macronutrient metabolism in some key organs/tissues 47  Reading Bender, David A., and Shauna M. C. Cunningham (2021), In Introduction to Nutrition and Metabolism, 6th Edition, Taylor & Francis Group. ProQuest Ebook Central, Chapter 10 https://ebookcentral.proquest.com/lib/plymouth/detail.action?docID=6421442. Frayn K & Abayomi AO (2011) Chapter 4, In Introduction to Human Nutrition, In Susan A. Lanham-New, et al (eds), Second Edition, John Wiley & Sons, Incorporated, 2019. ProQuest Ebook Central, https://ebookcentral.proquest.com/lib/plymouth/detail.action?docID=5916540 48  What next? Read the textbook recommended reading Try to consolidate your notes – use tables to summarise key information and compare systems/pathways Use slide headers for take-home messages dentify key enzymes and highlight focus metabolites – draw schemes to show roles/regulation Try to focus on common concepts underpinning the metabolic pathways Key aspects key steps location inputs/outputs regulation & control 49  Conceptual understanding Consider the main metabolic pathways we have covered in energy metabolism.  Which ones are catabolic? Which ones are anabolic?  What effect would high activity of these pathways have on:  the reduction potential NAD(P)H/NAD(P)+?  the phosphorylation potential ATP/[ADP+Pi]?  Which pathways would you expect to be active in the FED state? Which ones in a FASTED state?  Activity Subdivision of metabolism Catabolic pathways: Anabolic pathways: Breakdown of macromolecules Energy exergoni fuel/substrate yielding c oxidations Produce ATP and/or synthesis of endergonic NAD(P)H macromolecules/compounds Energy-requiring reduction Consume ATP and/or NAD(P Substrates are precursor  Accumulation of metabolites typically signalling Discuss together theenergy status key metabolites that indicated each energy state: liver Energy-rich state Energy-depleted state (high energy charge) (low energy charge) NAD glucose-6- AM + phosphate P NAD malonyl acetyl H CoA CoA ATP citrat oxaloaceta e NADPH te  Active consolidation anaerobic vs aerobic glycolysis (respiration) Aerobic glycolysis (respiration) Anaerobic glycolysis ATP (ATP/mol glucose) reducing power (NADH/mol glucose) end product(s) supply of re-cycled NAD+ when used which tissues step: Can you incorporate similar key information on fatty acid metabolism? (you may wish to change the list of features)  Other suggestions for active consolidation Metabolic convergence and regulation a scheme showing key metabolic interactions of each of the following focus met pyruvate eg Fatty acid synthesis fed liver acetyl coA citrate +ACC glucose-6-phosphate metabolite etc oxaloacetate 1) key regulatory signals (2) metabolic conditions (3) organ(s) (4) key enzymes  MCQs 15 MCQ questions on chemistry 15 MCQ questions on metabolism Strategies Gluconeogenesis is the synthesis of glucose from non- carbohydrate sources. Gluconeogenesis operates as a try the cover up test – is your answer ther reverse of glycolysis apart from 3 irreversible steps, where use reasoning: alternative enzymes are required. what do you know? All of the metabolic intermediates listed below can what can you eliminate? be used as a precursor for gluconeogenesis EXCEPT which ONE? clues in the leader? A. acetyl CoA B. alanine C. glycerol D. lactate E. pyruvate 55  MCQs 15 MCQ questions on chemistry 15 MCQ questions on metabolism Strategies try the cover up test – is your answer ther The driving force that increases the rate of a metabolic pathway when the concentrations of products and reactants are held far use reasoning: from equilibrium is called: what do you know? A. Mass action what can you eliminate? B. Electrochemical potential C. Free energy clues in the leader? D. Redox potential E. Phosphorylation potential 56  MCQs 15 MCQ questions on chemistry 15 MCQ questions on metabolism Strategies try the cover up test – is your answer ther CPT1 carries activated fatty acids into the mitochondrial use reasoning: matrix during β-oxidation. what do you know? Inhibition of CPT1 by malonyl CoA, a metabolic what can you eliminate? intermediate of fatty acid synthesis, is an example of what type of metabolic regulation? clues in the leader? A. Hormonal regulation B. Allosteric feedback C. Covalent modification D. Substrate inhibition E. Isozyme expression 57  MCQs 15 MCQ questions on chemistry 15 MCQ questions on metabolism Strategies Phosphofructokinase is a key regulatory enzyme of try the cover up test – is your answer ther glycolysis and is regulated in response to the energy state of the cell. use reasoning: what do you know? Which of the following metabolic intermediates what can you eliminate? inhibits the enzyme phosphofructokinase? clues in the leader? A. ADP B. NAD+ C. 5'AMP D. citrate E. fructose-1,6-bisphosphate 58  Example MCQs: Metabolism Transfer concept => new context Q3. Strategies Active transport of calcium ions Ca2+ across the endoplasmic reticulum membrane occurs against their try the cover up test – is your answer ther concentration gradient (from low to high Ca 2+ concentration) and involves the hydrolysis of ATP. use reasoning: Which one of the statements below best describes what do you know? the role of ATP in this transport process? what can you eliminate? P hydrolysis makes the overall Gibbs Free energy of the transport process more positive Some clues in the leader: ydrolysis drives transport of calcium ions down their electrochemical gradient ions, against gradient is calcium transport favourable? ing with ATP hydrolysis helps the endergonic transport process to take place exergonic/endergonic? is ATP hydrolysis favourable? ing with ATP hydrolysis helps the exergonic transport process to take place exergonic/endergonic high [Ca ] 2+ E. Coupling with calcium ion transport drives ATP hydrolysis ATP ADP+Pi low [Ca2+]  Fast-response Uncoupling of OXPHOS in BAT in response to example adrenaline Inter-organ crosstalk between fat and CHO metabolism CHO and hepatic lipogenesis 61