L1 Metabolism Metabolic Overview

Overview

The opening lecture of the Metabolism and Nutrition module sets up both the administration of the module and the conceptual scaffolding for everything that follows. It first maps how metabolism connects to disease (inherited enzyme defects, disorders of regulation, and ischaemia), then uses obesity and diabetes as the worked example of why metabolism matters clinically in New Zealand. It shows that obesity looks arithmetically simple as an energy balance but is actually contested, running through the genetic, endocrine, dietary and metabolic adaptation hypotheses. It then lays out the core biochemistry the module will build on: the central interconversions between carbohydrate, fat and protein, the anabolic and catabolic pathways that link them, the size of the body’s fuel stores, which tissues use which fuels, and how the liver, adipose tissue, muscle, brain and kidney trade fuels in the fed state, between meals and in starvation.

Module structure and administration

• Composition: approximately 35 lectures, 3 labs, 4 tutorials and 2 cases.
• Input from 11 departments and centres, including Anatomy, Biochemistry, Human Nutrition, Kōhatu Centre for Hauora Māori, Medicine, Pathology, Pharmacology, Physical Education, Psychological Medicine and Surgical Sciences.
• Topics covered: metabolism of protein, glucose and fats in the normal state; the same in disease (diabetes, gout, trauma and similar); short-term and long-term consequences of metabolic conditions; metabolic syndrome and insulin resistance; the involvement of gout, hypertension and heart disease; the genetics of complex diseases such as diabetes and gout; medicines used in these conditions; the role of nutrition and diet; the role of exercise; psychological ramifications; cultural ramifications.
• The material is organised by the question each discipline answers:
  • What it is: Biochemistry, Genetics, Pathology.
  • What can be done about it: Pharmacology, Physical Education, Psychology, Biochemistry, Human Nutrition, Hauora Māori, Pacific Health.
  • What does it mean: Culture, Faith, Sociology, Anthropology, Hauora Māori, Pacific Health.
• Overarching goal: given a patient’s history, clinical signs and symptoms, physical examination and the results of biochemical analysis of blood and/or urine or specialised metabolic tests, discern whether aspects of metabolism might have a role in the patient’s condition, identify what those aspects might be, explain what is occurring in the patient, and suggest further investigations or treatment.
• Timetable: lectures run in weeks 9 to 13 (Metabolic Overview, regulation and dysregulation of fuel metabolism, genetics of diabetes and obesity, diet in health and disease, diabetes update, heritability in metabolic disorders, hypoglycaemia 1 and 2, gluconeogenesis and the response to trauma, lipogenesis/lipolysis/ketogenesis, antioxidants and oxidative stress, metabolic syndrome, BMI and diabetes in children, genome damage and repair, bariatric surgery, a type 1 diabetes patient presentation, nitrogen balance and shuttling, childhood obesity, excretion of nitrogen compounds, inborn errors of metabolism, neuroendocrine control of appetite, amino acids in normal function, alcohol, nutritional management of type 1 and 2 diabetes, intimate partner violence, Hauora Māori and diabetes, metabolism and genetics of gout, direct-to-consumer genetic tests, approach to the patient with type 2 diabetes, sports and exercise nutrition). Labs (weeks 9 to 14) are genetic testing in an eye clinic, glucose and insulin, metabolism and nitrogen, and genetics in obesity and diabetes. Module tutorials (Metabolism 1 to 3 and type 2 diabetes) and case tutorials run in weeks 10 to 13 in groups A to D.
• Linked cases: Case 18 (weight loss and polydipsia), Case 19 (weight gain and insulin resistance), Case 20 (haematuria).
• Assessment is by SAQ and MCQ, and a larger number of topics will continue to be assessed.
• Contacts: Shar Snoeck (sharleen.rae-whitcombe@otago.ac.nz) for labs, tutorials and attendance. For the lecturer, before and after class is a very good time; email is not optimal.
• Moodle resources: module outcomes and goals, resources, linkages, lectures, the metabolism handout from BIOC192, the liver cell diagram, and the tutorial manual.
• It is probably not necessary to buy a biochemistry textbook because free-access web resources exist (http://themedicalbiochemistrypage.org/) and useful texts are on reserve in the Medical Library: Campbell and Farrell (2015) Biochemistry 8th ed (introductory overview), or Baynes and Dominiczak (2014) Medical Biochemistry 4th ed (principles rather than facts, pathways and regulation in physiological and pathological context), or Champe, Harvey and Ferrier (2013) Lippincott’s Illustrated Reviews: Biochemistry 6th ed (well illustrated, concept maps and summaries), and Harrison’s Textbook of Medicine 19th ed or similar.

How metabolism connects to disease

Three broad routes link metabolism to clinical disease.

1. Genetically inherited disorders: absence or abnormal function of enzymes or regulatory proteins, caused by mutations.
2. Problems involving regulation: hypermetabolic states (for example thyroid), trauma, cancer cachexia, metabolic syndrome, diabetes, hypercholesterolaemia, hypertriglyceridaemia, gout.
3. Problems involving ischaemia (insufficient fuels and oxygen): heart attack, stroke, peripheral vascular disease.

Clinical language and professional conduct

Diabetes, metabolic syndrome and obesity are topical and important. These terms have a specific clinical meaning and will be encountered professionally, so it is important to become comfortable with them and their clinical use, and to be familiar with aspects surrounding their use in society. They can also feel confronting and can be misunderstood and misused, especially in a nonclinical setting. Within the module the expectation is to treat each other with respect and sensitivity, with no tolerance for insensitive, inaccurate or unfair use of any of these terms.

Scale and clinical impact of obesity and diabetes

• Public attention is enormous: more than 300 million Google hits, with current coverage spanning global rises in diabetes and obesity, childhood obesity linked to higher risk for most type 2 diabetes subtypes in adulthood (people with a genetic risk factor for childhood obesity having an increased likelihood of developing most subtypes of type 2 diabetes as adults), brown fat as a therapeutic target, and the commercial scale of diabetes drugs (Mounjaro first-quarter sales expected around $433 million).
• New Zealand obesity: 1 in 3 adults (34.3%) are obese; health care costs attributable to obesity are $686 million per year, which is 4.5% of total yearly health care costs.
• New Zealand diabetes: estimated prevalence 4.2% of the population, about 292,400 people.
• These are two of the most common conditions you are likely to see in practice.
• Obesity is linked to serious disease. Per the Canadian Liver Foundation (2007), obesity has overtaken alcohol as the number one cause of liver disease in Canada. Over 1.4 million Canadians have non-alcoholic fatty liver disease (NAFLD) and 15% of obese children have NAFLD. The progression is NAFLD to non-alcoholic steatohepatitis (NASH) to cirrhosis to death. Grossly, a fatty liver is pale and enlarged compared with a darker, smaller normal liver.

Why obesity is not simple: the competing hypotheses

Obesity can seem simple as an energy balance:

$E_{stored}=E_{intake}-E_{expended}$
$E_{expended}=\text{basal metabolism}+\text{activities}$

In practice it is complex, with many hypotheses involving genetics, endocrine regulation, diet and metabolic adaptation.

Genetic hypothesis

The FTO gene has long been linked to obesity. Mice lacking FTO did not become obese and had less fat tissue overall because they burned off more calories, even though they moved less and ate more. In humans, people with two copies of the “obese” version of the gene weigh on average nearly 7 lb (3 kg) more and are about 70% more likely to be obese than those with other versions. People and mice are similar genetically.

Endocrinological hypothesis

The claim is that an imbalance involving insulin and/or other related hormones underlies obesity.

Regulation of NPY in the hypothalamic arcuate nucleus (Tisdale 2002):

1. Glucocorticoids stimulate hypothalamic production of neuropeptide Y (NPY).
2. Increased NPY increases food intake and reduces energy expenditure.
3. Leptin, produced by adipose tissue, crosses the blood-brain barrier and blocks NPY production; insulin, produced by the pancreas, does the same.
4. Increased NPY in turn decreases leptin and insulin production.

Evidence that leptin matters: the leptin-deficient mouse eats too much and is severely obese, and in leptin-deficient patients leptin treatment converts marked childhood obesity to a normal body habitus.

The fuller arcuate circuit (Schwartz and Morton):

• Ghrelin from the stomach stimulates the NPY/AgRP neuron, acting at the ghrelin receptor.
• PYY3-36 from the colon inhibits the NPY/AgRP neuron, acting at the Y2R receptor.
• Leptin from fat tissue and insulin from the pancreas act at leptin and insulin receptors to inhibit the NPY/AgRP neuron and to stimulate the melanocortin neuron.
• The NPY/AgRP neuron inhibits the downstream (second-order) neuron, with AgRP blocking MC4R, and NPY acting at Y1R.
• The melanocortin neuron stimulates the downstream neuron via MC4R and MC3R.
• The net output of that downstream neuron balances food intake against energy expenditure.

Diet hypothesis

Certain foods in the diet are said to help cause diabetes and obesity: sugary drinks, diet drinks, saturated fat, too many carbohydrates, not enough carbohydrates, the wrong kind of carbohydrates. Even dieting itself has been blamed, as the “yo-yo” hypothesis. The results here are very unclear, but in some people adaptation plays a big role.

Metabolic adaptation hypothesis

Working from the same energy balance equations, the claim is that expenditure itself shifts. The six-year follow-up of “The Biggest Loser” contestants (Fothergill et al., Obesity) found:

• Contestants continued to exercise and diet.
• Basal metabolic rate was sharply lowered during the competition and remained sharply lowered even 6 years after leaving the show.
• Predicted metabolic rates from metabolic charts were no longer accurate, with energy expended dramatically lower, by 20 to 30%, than expected.
• For at least 6 years it did not change back.

State of the evidence

Gary Taubes’ BMJ analysis essay (BMJ 2013;346:f1050) argues the history of obesity research is a history of two competing hypotheses, that the wrong hypothesis won out, and that this plus substandard science has exacerbated the obesity crisis and related chronic diseases. The take-home is that in 2026 we still need more, higher quality research to understand metabolism better.

The core metabolic map

Warning

The IUBMB-Nicholson metabolic wall chart (http://www.iubmb-nicholson.org/chart.html) is shown purely for visual effect, to illustrate that metabolism can seem intimidating. The transcript flags it as too dense to read reliably, so no specific pathway content is taken from it.

Central interconversions (Voet, Voet and Pratt, Figure 21-1):

• Protein ⇌ amino acids (amino acid synthesis and amino acid degradation).
• Glycogen ⇌ glucose-6-phosphate/glucose (glycogen synthesis and glycogen degradation).
• Glucose-6-phosphate ⇌ pyruvate (glycolysis forward, using ATP; gluconeogenesis in reverse, using ATP).
• Triacylglycerol ⇌ fatty acids (fatty acid synthesis, using ATP; β-oxidation in reverse).
• Amino acids, pyruvate and fatty acids all converge on acetyl-CoA.
• Pyruvate ⇌ oxaloacetate.
• Acetyl-CoA plus oxaloacetate enter the citric acid cycle, generating ATP by oxidative phosphorylation, and acetyl-CoA can also form ketone bodies.
• Amino acid degradation also produces urea, via the oxaloacetate/pyruvate route, as nitrogen disposal.

The liver cell diagram adds the sugar entry points and the hepatic detail:

• Galactose → Gal-1-P → G1P.
• G1P ⇌ glycogen via UDPG (glycogen synthesis and glycogen mobilisation).
• G1P ⇌ G6P ⇌ glucose; G6P ⇌ F6P ⇌ F1,6-bisphosphate.
• Fructose → F1P; glyceraldehyde → triose-P; glycerol → glycerol-P → triose-P. These three converge into triose-P.
• Triose-P ⇌ phosphoenolpyruvate ⇌ pyruvate, glycolysis in the downward direction and gluconeogenesis upward.
• Pyruvate ⇌ oxaloacetate, pyruvate ⇌ lactate, pyruvate ⇌ alanine.
• Pyruvate and fatty acids (the latter by β-oxidation) → acetyl-CoA, which goes to ketone bodies (ketogenesis) or into the citric acid cycle to CO2.

Anabolic and catabolic pathways: substrates and products

Utilization and storage of metabolic fuels (Baynes and Dominiczak, Table 20-1).

Anabolic

• Gluconeogenesis: lactate, alanine, glycerol → glucose.
• Glycogen synthesis: G-1-P → glycogen.
• Protein synthesis: amino acids → proteins.
• Lipogenesis: acetyl-CoA, glycerol → fatty acids, triglycerides.

Catabolic

• Glycolysis: glucose → pyruvate, ATP.
• Tricarboxylic acid cycle: pyruvate, acetyl-CoA → NADH+H+, FADH2, CO2, H2O, ATP.
• Glycogenolysis: glycogen → G-1-P, glucose.
• Lipolysis: triglycerides → glycerol, fatty acids.
• Proteolysis: proteins → amino acids, which go on to glucose or to ketones.

Metabolites such as pyruvate and acetyl-CoA are what link the different pathways.

Fuel stores and energy homeostasis

Fuel stores in a 70 kg individual:

Fuel	Site	Mass	Energy
Glycogen	Liver	70 g	1176 kJ
Glycogen	Muscle	120 g	2016 kJ
Free glucose	Body fluids	20 g	336 kJ
Triacylglycerol	Adipose	15,000 g	567,000 kJ
Protein	Muscle	6000 g	100,800 kJ

The aims of energy homeostasis are:

• Maintenance of blood glucose within relatively narrow limits.
• Storage of excess fuel.
• Provision for the special fuel needs of each tissue.
• Making available alternative fuels.
• Maintenance of structural body proteins.

Resting energy expenditure by organ, and share of daily energy expenditure:

Tissue	kJ/kg organ/day	% of daily energy expenditure
Liver	840	21%
Brain	900	20%
Heart	1,800	9%
Muscle	55	22%
Adipose	20	4%

Note the dissociation between rate and total: heart has by far the highest rate per kg but a small share of the total, while muscle has the lowest rate per kg yet the largest single share because of its mass.

Which tissue uses which fuel

Tissue	Fuel store	Preferred fuel	Fuels exported
Brain	none	glucose, ketone bodies (during fasting)	none
Skeletal muscle (resting)	glycogen	fatty acids	none
Skeletal muscle (exercise)	none	glucose, fatty acids, branched-chain amino acids	lactate, alanine
Heart muscle (exercise)	none	fatty acids	none
Adipose tissue	triacylglycerols	fatty acids	fatty acids, glycerol
Liver	glycogen	amino acids, glucose, fatty acids	triacylglycerols (VLDL), glucose, ketone bodies

Interorgan fuel exchange

The whole-body map (Voet, Voet and Pratt, Figure 22-2) links brain, adipose tissue, liver, kidney and muscle:

• Brain takes up ketone bodies and glucose, releasing CO2 and H2O.
• Adipose tissue interconverts triacylglycerols with fatty acids plus glycerol and releases fatty acids and glycerol into the circulation.
• Liver is the central hub, interconverting ketone bodies, acetyl-CoA, fatty acids, triacylglycerols, glucose, glycogen, pyruvate and lactate. It takes up amino acids and protein-derived carbon from muscle and produces urea; it exports ketone bodies, glucose and urea.
• Kidney handles α-ketoglutarate and glutamine to NH3, and also makes glucose.
• Muscle takes up ketone bodies and fatty acids and oxidises them to CO2 and H2O, interconverts glycogen ⇌ glucose ⇌ pyruvate ⇌ lactate, and converts proteins to amino acids and then alanine and glutamine for export to liver and kidney.
• Overall this depicts fasting and exercise fuel exchange: lactate and alanine cycling to the liver, ketone body and glucose supply to brain and muscle, and urea disposal via the kidney.

The three nutritional states

After a meal

Blood glucose rises to 8 to 9 mM within an hour and glucose is taken up by all tissues. Some is converted to glycogen for storage in muscle and to some extent in the liver, and some is oxidised as an immediate energy source. Most circulating fatty acid is in the form of triacylglycerols absorbed from the gut and en route to adipose tissue for storage. Some triacylglycerol is produced in the liver, which, recognising the caloric excess, converts glucose to fat and exports it to adipose tissue. The liver meets its own energy needs from oxidation of amino acids in excess of those required for protein synthesis, and to some extent from oxidation of glucose. Muscle oxidises both glucose and fatty acids, and the brain uses only glucose. Muscle and liver exchange lactate bidirectionally; adipose tissue takes up glucose and dietary triacylglycerols and forms glycerol-P plus fatty acids to make storage triacylglycerols.

Between meals

Circulating glucose would drop rapidly if it were not maintained by the liver. Glucose is provided initially from liver glycogen reserves, but also through gluconeogenesis, using glycerol from adipose tissue and lactate from muscle and erythrocytes. By several hours after a meal the liver derives its own energy requirement from oxidation of fatty acids. Muscles use their own glycogen plus fatty acids released from adipose tissue, and export lactate back to the liver. The energy needs of the brain are still met entirely by glucose.

Starving

Most circulating fat is free fatty acids released from adipose tissue. The gluconeogenic substrates are glycerol from adipose tissue and amino acids from muscle protein. After several days the circulating concentration of ketone bodies increases, reflecting the imbalance in the liver between carbohydrate and fatty acids. Muscle oxidises both ketone bodies and fatty acids, and exports to the liver glycogenic substrates derived from degradation of structural proteins. As blood glucose drops to the hypoglycaemic level of about 2 mM, the brain adapts to using increasing amounts of ketone bodies while also consuming almost all the glucose the liver can produce.

Important

The brain is the constraint that shapes the whole fasting response: it has no fuel store, and in the fed and between-meal states its energy needs are met entirely by glucose. Only after several days of starvation does it shift substantially onto ketone bodies.

Fed versus fasted summary

• Fed state, fuel storage: glycogen synthesis, lipogenesis, storage of fatty acids as triacylglycerols (TAGs).
• Fasted state, fuel mobilisation: glycogenolysis, gluconeogenesis, ketogenesis, lipolysis.

Self-test

1. State the overarching goal of the Metabolism and Nutrition module.
2. List the three broad ways metabolism connects to disease, with an example of each.
3. Give the New Zealand figures for adult obesity prevalence, its annual health care cost, and the share of total health care costs that represents.
4. Describe the progression from obesity to death via liver disease, naming each stage.
5. Write the two energy balance equations used in the lecture and explain why they make obesity look simpler than it is.
6. Explain what the FTO knockout mouse experiment showed, and why the result was counterintuitive given the animals’ behaviour.
7. Describe the regulation of NPY production in the hypothalamic arcuate nucleus, including the effect of increased NPY on food intake and energy expenditure.
8. In the arcuate circuit, distinguish the actions of ghrelin and PYY3-36 on the NPY/AgRP neuron, naming the receptor involved in each case.
9. Explain how leptin and insulin produce a coordinated anorexigenic signal through two different neuronal populations.
10. Predict what happens to body weight if AgRP signalling at MC4R is increased, and explain why.
11. State the metabolic adaptation hypothesis and give the specific findings of the six-year “Biggest Loser” follow-up that support it.
12. Describe the steps by which glucose-6-phosphate carbon reaches the citric acid cycle, naming the pathways involved.
13. List the four anabolic pathways from the fuel utilization table, with the substrates and product of each.
14. List the five catabolic pathways from the same table, with the substrates and products of each.
15. Rank the body’s fuel stores in a 70 kg person by energy content, and state roughly how much larger the largest is than liver glycogen.
16. List the five aims of energy homeostasis.
17. Muscle and heart sit at opposite ends of the resting energy expenditure table. Explain how muscle can account for a larger share of daily energy expenditure than heart despite a far lower rate per kg.
18. Distinguish the preferred fuel and exported fuels of resting skeletal muscle from those of exercising skeletal muscle.
19. Describe what happens to glucose, fat and amino acids in the liver in the hour after a meal.
20. Describe the sources of blood glucose between meals, and state which organ’s needs are still met entirely by glucose at that point.
21. A patient has been starving for several days. Describe the fuels being mobilised, the gluconeogenic substrates available, the approximate blood glucose concentration, and how the brain adapts.
22. Integrate the fed and fasted states: name the storage processes of the fed state and the mobilisation processes of the fasted state, and identify the metabolites that link the pathways.

Answers

Reveal answers

1. Given a patient’s history, clinical signs and symptoms, physical exam and the results of biochemical analysis of blood and/or urine or specialised metabolic tests, discern whether aspects of metabolism might have a role in the patient’s condition, identify what these aspects might be, explain what is occurring in the patient, and suggest further investigations or treatment.
2. Genetically inherited disorders, from absence or abnormal function of enzymes or regulatory proteins caused by mutations; problems involving regulation, such as hypermetabolic states (thyroid), trauma, cancer cachexia, metabolic syndrome, diabetes, hypercholesterolaemia, hypertriglyceridaemia and gout; and problems involving ischaemia, meaning insufficient fuels and oxygen, such as heart attack, stroke and peripheral vascular disease.
3. 1 in 3 adults, 34.3%, are obese; attributable health care costs are $686 million per year; that is 4.5% of total yearly health care costs.
4. Obesity leads to non-alcoholic fatty liver disease (NAFLD), which can progress to non-alcoholic steatohepatitis (NASH), which can progress to cirrhosis, which can progress to death. Obesity has overtaken alcohol as the number one cause of liver disease in Canada, with over 1.4 million Canadians affected by NAFLD and 15% of obese children having NAFLD.
5. $E_{stored}=E_{intake}-E_{expended}$ and $E_{expended}=\text{basal metabolism}+\text{activities}$. They present obesity as simple arithmetic, but in reality it is complex, with hypotheses involving genetics, endocrine regulation, diet and metabolic adaptation.
6. Mice without the FTO gene did not become obese and had less fat tissue overall because they burned off more calories, even though they moved less and ate more. In humans, two copies of the “obese” version of FTO is associated with weighing nearly 7 lb (3 kg) more and being about 70% more likely to be obese.
7. Glucocorticoids stimulate hypothalamic production of NPY. Increased NPY increases food intake and reduces energy expenditure. Leptin from adipose tissue and insulin from the pancreas cross the blood-brain barrier and block NPY production. Increased NPY in turn decreases leptin and insulin production.
8. Ghrelin comes from the stomach and stimulates the NPY/AgRP neuron via the ghrelin receptor. PYY3-36 comes from the colon and inhibits the NPY/AgRP neuron via the Y2R receptor.
9. Leptin from fat tissue and insulin from the pancreas both act at their receptors to inhibit the NPY/AgRP neuron and to stimulate the melanocortin neuron. Since NPY/AgRP inhibits the downstream neuron and the melanocortin neuron stimulates it, both arms push the downstream neuron’s output in the same direction, shifting the balance away from food intake and towards energy expenditure.
10. Body weight would increase. AgRP blocks MC4R on the downstream neuron, so more AgRP action removes the melanocortin-driven stimulation of that neuron, shifting its output towards increased food intake and reduced energy expenditure.
11. The hypothesis is that energy expenditure itself adapts, working from $E_{stored}=E_{intake}-E_{expended}$ with $E_{expended}=\text{basal metabolism}+\text{activities}$. In the six-year follow-up of “The Biggest Loser” contestants, basal metabolic rate was sharply lowered during the competition and remained sharply lowered 6 years afterwards despite continued exercise and dieting; predicted metabolic rates were no longer accurate and energy expended was 20 to 30% lower than metabolic charts predicted; for at least 6 years it did not revert.
12. Glucose-6-phosphate goes to pyruvate by glycolysis, using ATP. Pyruvate is converted to acetyl-CoA and can also interconvert with oxaloacetate. Acetyl-CoA combines with oxaloacetate to enter the citric acid cycle, which yields ATP through oxidative phosphorylation. Amino acids and fatty acids also converge on acetyl-CoA, and acetyl-CoA can alternatively be diverted to ketone bodies.
13. Gluconeogenesis: lactate, alanine and glycerol to glucose. Glycogen synthesis: G-1-P to glycogen. Protein synthesis: amino acids to proteins. Lipogenesis: acetyl-CoA and glycerol to fatty acids and triglycerides.
14. Glycolysis: glucose to pyruvate and ATP. Tricarboxylic acid cycle: pyruvate and acetyl-CoA to NADH+H+, FADH2, CO2, H2O and ATP. Glycogenolysis: glycogen to G-1-P and glucose. Lipolysis: triglycerides to glycerol and fatty acids. Proteolysis: proteins to amino acids, which then go to glucose or to ketones.
15. Adipose triacylglycerol 567,000 kJ (15,000 g), muscle protein 100,800 kJ (6000 g), muscle glycogen 2016 kJ (120 g), liver glycogen 1176 kJ (70 g), free glucose in body fluids 336 kJ (20 g). Adipose triacylglycerol holds roughly 480 times the energy of liver glycogen.
16. Maintenance of blood glucose within relatively narrow limits; storage of excess fuel; provision for the special fuel needs of each tissue; making available alternative fuels; maintenance of structural body proteins.
17. Muscle uses only 55 kJ/kg/day against the heart’s 1,800 kJ/kg/day, but muscle accounts for 22% of daily energy expenditure versus the heart’s 9%, because the total depends on organ mass as well as rate and skeletal muscle mass is far greater.
18. Resting skeletal muscle stores glycogen, prefers fatty acids and exports no fuels. Exercising skeletal muscle has no listed store, uses glucose, fatty acids and branched-chain amino acids, and exports lactate and alanine.
19. Blood glucose rises to 8 to 9 mM within an hour. The liver takes up glucose and stores some as glycogen; recognising the caloric excess it converts glucose to fat, making triacylglycerols that it exports to adipose tissue; it also receives dietary triacylglycerols. The liver meets its own energy needs mainly from oxidation of amino acids in excess of those required for protein synthesis, and to some extent from oxidation of glucose.
20. Glucose comes initially from liver glycogen reserves and also from gluconeogenesis, using glycerol from adipose tissue and lactate from muscle and erythrocytes. The brain’s energy needs are still met entirely by glucose.
21. Adipose tissue releases free fatty acids, which make up most of the circulating fat, plus glycerol. Gluconeogenic substrates are glycerol from adipose tissue and amino acids from muscle protein, with muscle exporting glycogenic substrates from degradation of structural proteins. After several days ketone bodies rise, reflecting the hepatic imbalance between carbohydrate and fatty acids. Blood glucose falls to the hypoglycaemic level of about 2 mM, and the brain adapts by using increasing amounts of ketone bodies while still consuming almost all the glucose the liver can produce.
22. Fed state means fuel storage: glycogen synthesis, lipogenesis and storage of fatty acids as triacylglycerols. Fasted state means fuel mobilisation: glycogenolysis, gluconeogenesis, ketogenesis and lipolysis. Metabolites such as pyruvate and acetyl-CoA link the different pathways, allowing carbon to move between carbohydrate, fat and protein routes as the state changes.