MB ChB Year 1: Nutrition and Energy

Lecture 24: Mobilisation of food reserves [2] - growth hormone, ACTH & steroid hormones.

Dr John Illingworth

Click here to download the printed handout sheet for this lecture

In addition to their effects on protein kinase activities, many hormones work alone or in combination to control the pattern of gene expression, on a tissue-specific basis.

More on PEPCK

Phosphoenolpyruvate carboxykinase (PEPCK) has attracted considerable attention because it forms the gateway from the Krebs cycle into gluconeogenesis, it is regulated purely by control of gene expression, and it integrates the action of five major hormones: adrenalin, cortisol, insulin, glucagon and probably thyroid hormone. For most practical purposes it is active only in liver cells, which raises the interesting question of how the various hormones turn it on and off in just one tissue, without affecting gene expression in any of the others.

Adrenalin and glucagon were initially thought to act solely through a cyclic AMP reponse element (CRE) which is a palindromic DNA sequence TGACGTCA near the start of mRNA transcription. There is a CRE binding protein CREB, which is a substrate for cyclic AMP dependent protein kinase. After phosphorylation it binds to the CRE and assists the formation of an initiation complex with RNA polymerase 2 (Pol II).

The simple account above cannot explain the tissue specificity of gene expression, or the potentiation by corticosteroids and the inhibition by insulin. Current theories envisage an extended array of regulatory elements and DNA binding proteins covering several hundred base pairs before the start of gene transcription, which act together in a combinatorial fashion to determine the polymerase initiation frequency.

The following cartoon showing the assembly of an active transcription complex at thestart of the PEPCK gene is taken from Duong et al (2002) J Biol Chem 277(35), 3223432242. CBP = CREB binding protein, DEX = dexamethasone (a synthetic corticosteroid), GR = glucocorticoid receptor and INS = insulin.

Changes in gene expression are generally much slower than protein kinase effects (hours or days rather than seconds or minutes).

The slow response from genes limits their usefulness in responding to rapid changes in the environment. There may also be delays waiting for mRNA to be degraded and for existing proteins to turn over and be removed from the cell. Where there is selection pressure for greater speed, additional controls may be introduced, such as the regulation of mRNA and protein stability. Messenger RNAs are much more than passive tape recordings of the corresponding genes, but recognisable macromolecules in their own right, with distinct 3D structures, and maybe catalytic activity. We have already encountered proteolytic digestion used to regulate enzyme activity in relation to lanosterol regulation of HMG-CoA reductase in lecture 21.

Changes in gene expression usually affect enzymes within the cytosolic compartment, rather than those sequestered within the mitochondria or other subcellular organelles. Nevertheless, enzymes within organelles are expressed in tissue-specific patterns.

This almost certainly reflects the difficulties and delays associated with importing proteins manufactured on cytoslic ribosomes across the organelle membranes. Subcellular organelles may also lack the rapid protein degradative machinery needed to terminate the response. This does not apply to steady state gene expression, which is tissue specific, and affects all parts of the cell. For example, human liver mitochondria contain a constant internal PEPCK activity which is probably used when recycling lactate into glucose. This avoids the need to move reduced coenzyme between cell compartments, and the requirement changes little from day to day.

Major blocks of metabolism are regulated as coherent units in response to environmental or internal events.

Compare and contrast feeding and starvation

Please do not try to learn this table as a mass of isolated facts. Look instead for the overall patterns, and the way that groups of genes and enzymes are regulated together. We will not quiz you about the individual details, but we expect you to recognise the larger theme.


glycolysis / lipogenesis

lipolysis / gluconeogenesis

principal source

dietary carbohydrates

body fat and muscle

principal product

triglyceride stores

blood glucose and ketones

dominant hormone


glucagon, adrenalin, cortisol

35 cyclic AMP



sugar phosphates



acetyl-CoA, NADH



mitochondrial export


malate and / or aspartate




glucose 6 phosphatase



glycogen synthase



glycogen phosphorylase






fructose bisphosphatase



pyruvate kinase






pyruvate dehydrogenase



ATP:citrate lyase



"malic" enzyme



acetyl-CoA carboxylase



fatty acid synthetase



adipocyte lipase



muscle proteases



"Malic" enzyme has a non-standard name because it was one of the first dehydrogenases to be properly characterised about 60 years ago. It is the decarboxylating malate dehydrogenase in liver cytosol that converts malate plus NADP into pyruvate, carbon dioxide and NADPH, which is mainly used for fatty acid biosynthesis.

International maintained databases such as OMIM and NCBI provide accurate and up-to-date information about human genetic research.

Using databases

The following short exercise shows how to access genetic data from OMIM (On-line Mendelian Inheritance in Man) and link to the human genome project. First, right click and switch off the Google toolbar!

The link below will open TWO windows: one of them is a set of instructions and the other is the database. The instructions will soon be covered by other windows, but you can always make the instructions visible by clicking the relevant icon in the task bar at the bottom of the screen. Please remember to close the instruction window when you have finished.

Click the link to go to OMIM.

The hypothalamus receives information from many sources, it controls the pituitary gland and the autonomic nervous system and it is the principal integrating centre for the overall regulation of physiology and metabolism.

Hypothalamus and pituitary

The hypothalamus contains its own glucose-sensing cells and has receptors for pro-inflammatory cytokines and hormones such as insulin, leptin and corticosteroids. In addition, it receives neural inputs from chemosensors throughout the body, and is best placed to make an informed assessment of the overall metabolic situation. Neurosecretory cells within the hypothalamus deliver a variety of specific releasing factors into the hypophyseal portal system, which act on target cells in the anterior pituitary and cause the release of pituitary hormones.

Anterior pituitary hormone Releasing factor Inhibiting factor

Growth hormone



Thyroid hormone



Adrenocorticotropic hormone



Plus MSH, FSH, LH & prolactin which are covered elsewhere

The hypothalamus manufactures vasopressin and oxytocin which are transported and released by the posterior pituitary. These hormones are discussed in other parts of your course.

The hypothalamus also controls the autonomic nervous system, which provides direct neural regulation of blood distribution, pancreatic islet function and liver metabolism. In addition to managing the long term metabolic effects of the pituitary hormones, the hypothalamus simultaneously manages the short term metabolic changes mediated via the ANS.

Actions of growth hormone:

The major effect of growth hormone is to promote the synthesis of insulin-like growth factors (IGFs) by target tissues, particularly liver, but also skeletal muscle and bone.

Actions of insulin-like growth factors

IGFs increase the rates of amino acid uptake and protein synthesis. They cause cells to grow and multiply. They also have anti-insulin, diabetogenic effects, increasing lipolysis in adipose tissue and glucose output from the liver, and decreasing glucose utilisation by peripheral tissues, except brain.

Production of ACTH

Adrenocorticotropic hormone [ACTH] is a 39 amino acid peptide derived from proopiomelanocortin which is necessary for the growth and normal activity of the adrenal cortex and the production of corticosteroid hormones (both mineralocorticoids and glucocorticoids).

Pro-opiomelanocortin (POMC) is a protein that is cleaved to yield a variety of important signals. It is the precursor of the pitutitary hormones MSH and ACTH, and in addition transmits a variety of messages within the brain.

At least four distinct 7-transmembrane G-protein linked receptors recognise the core heptapeptide sequence of the melanocortins. MC1R controls skin pigmentation, MC2R is the ACTH receptor, while MC3R and MC4R control appetite and energy expenditure.

Actions of ACTH on the adrenal cortex

Production of adrenal glucocorticoids and androgens from the zona fasciculata and reticularis is regulated by ACTH, which also contributes to the short-term secretion of mineralocorticoids from the zona glomerulosa. ACTH acts via a seven-transmembrane domain receptor belonging to the G protein coupled receptor superfamily leading to activation of the adenylate cyclase pathway and consecutive activation of protein kinase A. ACTH may also activate other signal transduction cascades such as the protein kinase C and the lipo-oxygenase pathway. ACTH slowly increases the output of adrenal fasciculata cells by increasing the expression of several key steroidogenic enzymes. Additionally, ACTH is crucial for the development of the adrenal cortex and may be involved in adrenal hypertrophy.

Mineralocorticoids such as aldosterone are produced by the outermost layer of the adrenal cortex (zona glomerulosa) and are mainly regulated by the renin angiotensin system.

Glucocorticoids such as cortisol are produced by the middle layer of the adrenal cortex (zona fasiculata) and are mainly regulated by ACTH.

The innermost layer of the adrenal cortex (zona reticularis) makes sex steroid precursors. It is immediately adjacent to the adrenal medulla, which secretes adrenaline (epinephrine).

Actions of corticosteroids on the rest of the body

Glucocorticoids act slowly on the cell nucleus, changing the patterns of gene expression, and leading to increased protein breakdown, increased lipolysis and increased gluconeogenesis. They have an overall anti-insulin, diabetogenic effect and they also have some mineralocorticoid actions, promoting sodium retention and potassium loss.

Glucocorticoids have immunosuppressive and anti-inflammatory effects. They reduce the ability to fight infections but increase the body's tolerance to stress. Osteoporosis and muscle wasting are their most serious long-term side effects.

At present it is practically impossible to separate the metabolic effects of the glucocorticoids from their effects on the immune system.


  insulin glucagon / adrenalin growth hormone cortisol





















Negative feedback on pituitary hormone release

There are important negative feedback loops controlling the release of the pituitary hormones. The delays inherent in this feedback system lead to a pulsatile pattern of hormone release.

There are marked circadian variations in hormone output, so blood samples for hormone measurements should be timed and ideally taken at a consistent time of day.

Growth hormone production is maximal during the early phase of sleep. Output is very high in children but declines in later life.

ACTH and cortisol production is greatest in the early morning, shortly after waking, and is lowest around midnight.

When high-dose corticosteroids are administered to patients for an extended period (for example in the treatment of inflammatory bowel disease) this will suppress the patient's own ACTH and steroid production. Treatment must be tapered gradually, since a sudden withdrawl might precepitate acute adrenal insufficiency.

Cushing's syndrome (glucocorticoid excess)

Cushing's disease is rare, and results from pituitary tumours that secrete ACTH. Cushing's syndrome commonly results from the medical administration of immunosuppressive or anti-inflammatory doses of corticosteroid hormones, or from ectopic hormone production by neoplastic tissue elsewhere in the body. It may be possible to establish the source of endogenously produced ACTH with a dexamethasone test.

Dexamethasone is a synthetic glucocorticoid that binds to hypothalamic and pituitary receptors but does not interfere with the cortisol assay. Most ACTH-secreting pituitary tumours retain their sensitivity to steroids, and hormone output falls when the dexamethasone dose is increased. Ectopic sources of ACTH lack this sensitivity and steroid output continues unabated.

NIDDK patient leaflet

A case report [based on Colleran et al (1997) Gynecologic Oncology 65, 526-529.]

    A 59-year-old non-smoking female patient complained of postcoital bleeding. Biopsy and various laboratory tests showed stage 1 anaplastic [i.e. de-differentiated] small cell carcinoma (SCC) of the vagina. This was treated with radiotherapy, etoposide and cis-platinum.

  1. What are small cell carcinomas and how are they often treated?

  2. She was disease-free by clinical, laboratory, and CT scan eight months after radiotherapy. Sixteen months later, she developed fatigue, muscle weakness and cramping, peripheral oedema, increased abdominal girth, increased thirst, and polyuria. Fasting blood glucose was 8.5-12.5 mmol/L but glycosylated haemoglobin was only 6.5% (normal 4.8-7.8%).

  3. Is the blood glucose normal and what does the glycosylated haemoglobin result show?

  4. Physical examination showed proximal muscle weakness, elevated blood pressure, and "pitting" lower extremity oedema (dimples fill slowly). Her chest X-ray was normal.

  5. What do you conclude?

  6. Blood tests showed K 2.7 mEq/L (normal 3.5-5.0 mEq/L), bicarbonate 34 mEq/L (normal 22-30 mEq/L), and blood urea 10 mmol/L (normal 2.5 - 6.5 mM). She continued to deteriorate despite vigorous potassium and fluid replacement.

  7. What does all this suggest?

  8. Her morning serum cortisol was 3450 nmol/L (normal 180-700 nmol/l) and ACTH was 129 pmol/L (normal 4-22 mmol/l). [The sampling time is specified because ACTH and cortisol outputs undergo large diurnal variations].

  9. Comment?

  10. Neither low nor high doses of dexamethasone had any effect on serum cortisol measured the following day.

  11. What is dexamethasone and what does this test show?

  12. CT scans of abdomen and pelvis demonstrated multiple hypoechoic [see note] areas in the liver. Her serum enzymes were AST 115 IU/L (normal 5-35 IU/L), ALT 197 IU/L (normal 9-52 IU/L), GGT 299 IU/L (normal 8-78 IU/L), LDH 1822 IU/L (normal 300-600 IU/L) and ALP 100 IU/L (normal 30-150 IU/L).

  13. What do these findings imply?

  14. Over the following month, hyperpigmentation, hirsutism, progressive biliary obstruction, and jaundice became evident.

  15. What is happening here?

  16. The patient died of hepatic coma and fluid overload at home, before therapy could be instituted, one month after the diagnosis was made.

  17. Vaginal SCC is extremely rare. Where is the above pattern much more commonly seen?

Note: the description "hypoechoic" is a direct quote from the original paper, but this term is normally applied to ultrasound rather than CT.

Addisons disease (adrenal insufficiency)

Addisons disease can be a serious, life threatening condition requiring immediate treatment. It is more frequent in women than in men, and commonly results from auto-immune or tubercular destruction of the adrenal cortex. Lack of mineralocorticoids causes a catastrophic loss of sodium and water from the body, while the lack of glucocorticoids leads to hypoglycaemia.

NIDDK patient leaflet

The adrenal glands are essential for life, and their removal is fatal within a few days unless the patient receives lifetime hormonal and mineral support.

Back to the top

Mobilisation the basic essentials.

  1. Many hormones signal via serpentine transmembrane receptors in the plasmalemma.

  2. These receptors link to heterotrimeric G proteins in the plasmalemma which dissociate after binding GTP.

  3. Free α subunits from the G-proteins regulate hormone-sensitive enzymes on the the inner face of the plasmalemma.

  4. Such regulation often involves either 3'5' cyclic AMP or IP3 + DAG, and may be either positive or negative.

  5. Distinguish between the protein kinases PKA, PKB, PKC and PKG.

  6. Distinguish between α1, α2, β1, β2 receptors for catecholamines.

  7. Major control points that respond to adrenalin / 3'5' cyclic AMP / PKA:

  8. Major control points that respond to insulin:

  9. Compare and contrast the coordinated responses:

  10. The hypothalamus controls the release of pituitary hormones.

  11. Know the principal actions of the pituitary hormones:

  12. Understand about negative feedback loops and diurnal patterns of hormone release.

  13. Distinguish between glucocorticoids and mineralocorticoids.

  14. Cannot separate the anti-inflammatory from the glucocorticoid effects.

  15. Cushing's syndrome - glucocorticoid excess.

  16. Addison's disease - adrenal insufficiency.

  17. Dexamethasone test to distinguish between pituitary and ectopic production of ACTH.


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