MB ChB Year 1: Nutrition and Energy

Lecture 25: Cytokines, thyroid hormones, thermoregulation and basal metabolic rate.

Dr John Illingworth

Click here to download the printed handout sheet for this lecture

Anorexia, bulimia and cachexia:

Anorexia nervosa and bulimia nervosa are related conditions, which are both very much more common in younger women than in older women or in men. Anorexia nervosa is failure to eat, in the absence of any physical cause. It may become life-threatening. Body image may be altered, so the emaciated patient considers herself normal or even fat. Bulimia is binge eating, which may be associated with self-induced vomiting and purgative abuse. It is hypothesised that both conditions result from inappropriate emotional input from the limbic system to the hypothalamus. These are common conditions, but they are much less common than simple obesity.

Cachexia (pronounced ca-hexia) is the weakness and emaciation commonly associated with serious illness, such as AIDS, burns, cancer, major surgery, trauma or tuberculosis. It is mediated by pro-inflammatory cytokines, such as TNF-α (tumour necrosis factor alpha, originally known as cachexin) and interleukin 1 (IL-1). Interleukin 6 (IL-6) was previously included in this pro-inflammatory group, but this may be over-simplified (see below).

Kotler (2000) Cachexia Annals of Internal Medicine 133(8), 622-634.

Effects of the pro-inflammatory cytokines


Altered sleep pattern
Altered level of consciousness


Increased body temperature
Increased resting energy expenditure
Stress hormone response (cortisol, epinephrine, glucagon)
Skeletal muscle wasting
Increased hepatic acute-phase response
Trace mineral sequestration
Decreased gastric emptying, intestinal transit
Bone marrow suppression


Weight loss
Negative nitrogen balance
Hypocholesterolemia, low levels of high-density lipoprotein (LDL) cholesterol

Nutritional Alterations in Starvation and Cachexia*


Body weight

-- --

Body cell mass

- ---

Body fat

--- --

Caloric intake

--- ---

Total energy expenditure

-- -

Resting energy expenditure

--- ++

Protein synthesis

--- +/-

Protein degradation

--- +++

Serum insulin

--- +++

Serum cortisol

+ ++

* Minus sign = decrease; plus sign = increase; +/- = little change.

There is scope for confusion between gross rates and net rates of metabolism. Well-fed, healthy people may have high gross rates of fat and protein turnover, but no net loss. Starving people, and those with cachexia, are in negative nitrogen and energy balance. They experience net losses of fat and muscle mass. Well adapted starving people have low gross rates of fat and protein degradation - they have minimised their heat losses and their physical activity and they are carefully husbanding their remaining resources, hoping that things will improve. It is simply that their income has fallen below their expenditure. As far as possible, famine victims conserve their protein and live off their fat. In contrast to this, cachectic patients squander their resources, burning off first proteins then fats as though there is no tomorrow, which frequently proves to be the case.

There is some resemblance between the unwanted processes in cachexia and the "cytokine storm" which may be a terminal event in serious diseases such as Marburg and Ebola viruses, Dengue haemorrhagic fever, or H5N1 bird flu infections. All involve an exaggerated immune response, but the time course for cachexia is probably longer than the catastrophic viral infections.

Drug treatment

In some circumstances, cachexia might be an adaptive response. As death approaches, after infection or major injuries, the best option may be to commit all the remaining reserves to a last ditch attempt to retrieve the situation. Those responsible for the care of seriously ill patients have tried hard to prevent these changes, so far with very little success. Some experimental treatments have proved more beneficial to invasive cancers than they are to the patient. The numerous investigational drugs include cannabinoids, and the notorious thalidomide, which caused developmental abnormalities, but also acts to destabilise TNF-α mRNA.

Recent experimental work in rats suggests a central role for neuronal AMP-activated protein kinase in cancer cachexia, and showed some benefit from metformin treatment in tumour-bearing animals. However, a recent international clinical trial showed that aggressive control of the hyperglycaemia commonly observed in ICU patients resulted in worse outcomes than conventional treament.

Low grade inflammation

It is now believed that many common but intractable diseases, including rheumatoid arthritis, atherosclerosis, heart failure, hypertension and type 2 diabetes are associated with chronic low-grade inflammation, and that this results from cytokines such as TNF-α produced by over-filled adipocytes. If true, this could explain the generally beneficial effects from increased exercise (which has an anti-inflammatory action) and losing weight. As might be expected, this is an area of intense medical and scientific research.

Interleukin 6

IL-6 is anomalous. It was previously associated with the acute phase response to trauma and infection, when the liver produces increased amounts of "acute phase proteins" which help to deal with bacterial infections, including C-reactive protein, mannan-binding lectin, fibrinogen, haptoglobin, ferritin, ceruloplasmin, alpha1-antitrypsin and alpha1-acid glycoprotein.

Recent work has shown that IL-6 is produced by exercising muscle, when it appears to have anti-inflammatory actions. It may be that IL-6 is involved in the adaptive response to pro-inflammatory signals, and that it may antagonise TNF-α rather than acting in a similar way. This could explain the generally beneficial effects of increased exercise on chronic inflammatory conditions.

Thyroid hormones

Thyroid hormones are essential for the development of the central nervous system, and a deficiency leads to cretinism. They are also essential for normal body growth, and they regulate the gene for growth hormone. They are necessary for cold adaptation. Thyroid hormones regulate the basal metabolic rate and their most obvious effects are on heat production.

For animals eating a mixed diet, it is unlikely that all their various nutritional requirements will be exactly satisfied at the same time. It may be necessary to consume more than the minimum energy intake in order to guarantee an adequate supply of trace nutrients. This requires mechanisms to dispose of any surplus energy. Changes in physical activity and basal metabolic rate are part of this adaptive system.

Synthesis of thyroid hormones

The thyroid hormones thyroxine (T4) and T3 are formed within the thyroid gland by the non-enzymic iodination and coupling together of tyrosine residues within the protein thyroglobulin. The elemental iodine required for this reaction is produced by action of peroxidase on iodide ions and the reaction takes place within the lumen of the thyroid follicles. The active hormone is released after hydrolysis of the protein.

The follicular cells actively accumulate iodide ions from the blood. In mountainous areas remote from the sea, where there may be a local deficiency of iodide in the environment, iodine intake and hormone production may be inadequate. This leads to compensatory over-production of thyroid stimulating hormone by the pituitary, so the thyroid gland increases markedly in size, leading to the development of goitre. Nowadays goitre is almost unknown, as a result of the use of iodised table salt.

Control of thyroid secretion

Hormone secretion shows diurnal variations, and is regulated by a typical pituitary feedback loop. TSH signals in the thyroid via cAMP, with a major effect on iodine uptake. Most of the hormone in the bloodstream is bound by thyroxine binding globulin. T4 is produced in the greatest amounts, but T3 is much more potent. T4 is converted into T3 in the tissues, especially in the liver, and this process may be an additional site for regulation. Further loss of iodine, deamination or glucuronidation leads to inactivation.

The most potent stimulus for TRH and TSH production is cold. However, thyroid hormones also respond to food intake, and thyroid hormone activity and metabolic rate fall during starvation. This may involve a direct effect on the hypothalamus, but hepatic conversion of T4 into T3 may also be important.


Animals have several strategies for keeping warm. They can seek out warm places, fluff up their fur or feathers, reduce skin blood flow, fidget, shiver or indulge in non-shivering thermogenesis by increasing their resting metabolic rate. The first three methods are counterproductive if the main objective is to burn off surplus fuel without raising body temperature. Such behaviour might confer a selective advantage if animals were obliged to eat an unbalanced diet, where essential nutrients are diluted in a sea of calories.

In many species, and in particularly in new-born babies, brown adipose tissue is an important site of heat production. This tissue is coloured brown because it is rich in mitochondria, which can be temporarily uncoupled under the control of the sympathetic nervous system. This superficially futile dissipation of mitochondrial chemiosmotic gradients produces heat rather than ATP. Heat production has an absolute requirement for thyroid hormone. It was previously believed that there is very little brown adipose tissue in adult humans, but an important group of three papers in April 2009 has overturned this misconception. Brown adipose tissue is now recognised as an important source of heat in human adults as well as babies.

Five uncoupling proteins (UCP1, UCP2, UCP3, BMCP1 and UCP4) have been characterised in mammals. The first three have apparently evolved from the adenine nucleotide carrier. UCP1 or thermogenin is found in brown adipose tissue and requires oxidised CoQ as a cofactor. Expression of the UCP1 gene is stimulated by catecholamines. Catecholamines also activate the UCP1 protein, through a mechanism involving cyclic AMP, hormone sensitive lipase, and free fatty acids.

UCP2 is widely expressed in many tissues but mRNA levels are unexpectedly increased by fasting. It seems to have little connection with thermogenesis, but it is apparently associated with fat oxidation. It may form part of a mechanism that minimises the unwanted generation of reactive oxygen species (ROS) during fat oxidation. UCP2 reduces ATP levels in pancreatic islet cells, and may mediate the anti-insulin actions of free fatty acids. There is an excellent short account of this by Dominique Langin (2001) New England Journal of Medicine 345(12), 1772-1774 which you are recommended to read. The University Library have password details.

UCP3 is found mainly in skeletal muscle and mRNA levels are increased by thyroid hormone and fasting. Transgenic mice that over-express human UCP3 are thin and hyperphagic, have lower fasting plasma glucose and insulin levels and an increased glucose clearance rate. However, gene knockout mice are apparently normal, and the function of this protein remains a mystery.

Auto-immune thyroid disease. Hashimoto's disease. Graves disease.

Thyroid disorders are the second most common endocrine disease after diabetes. They very frequently have an immune pathology, and most thyroid conditions are much more common in women than in men. It is hypothesised that this results from the immunisation of mothers by foetal cells during pregnancy, although this is not yet generally accepted. Other autoimmune conditions, such as pernicious anaemia may co-exist with the thyroid problem.

Anti-thyroid antibodies may be directed against a variety of cellular constituents, including the TSH receptor, and consequently may either stimulate or suppress thyroxin secretion. It is quite common for the pattern to change as the disease progresses, so a patient might undergo a partial thyroidectomy, or radioiodine treatment to relieve hyperthyroidism, only to become hypothyroid a few months later.

Graves' disease is hyperthyroidism. The famous eye symptoms are not an obligatory finding, and apparently arise from a separate immune reaction to orbital tissues. Hashimoto's disease is hypothyroidism in which a partial regeneration leads to a firm rubbery goitre.

TSH levels will be raised in hypothyroid patients if the gland is unresponsive to pituitary stimulation. TSH measurement may be more informative than total T3 or T4 because thyroid binding globulin obscures the true position. Conversely TSH will be low in hyperthyroid patients if the pituitary is working normally.

signs / symptoms




heat intolerant, fever (rare), warm vasodilated peripheries, raised basal metabolic rate

cold intolerant, hypothermia, lowered basal metabolic rate

body weight



GI tract

increased appetite but sometimes anorectic, diarrhoea, vomiting,

decreased appetite, constipation, large tongue


breathlessness, tachycardia, atrial fibrillation, palpitations, systolic hypertension (high output with low peripheral resistance), angina, heart failure

bradycardia, pericardial effusion, oedema, hypertension (low output with high peripheral resistance), heart failure, hypercholesterolaemia

mental and behavioural

hyperkinesis, tremor, irritability, restlessness, psychosis

tiredness, poor memory, dementia, slow reflexes, depression, psychosis

bones, muscles

proximal myopathy, wasting

arthralgia (joint pain), myalgia (muscle pain)

hair and skin

pretibial myxoedema (NOT the same as ordinary myxoedema) in Graves disease

thin dry umanageable hair, coarse dry skin, myxoedema (mucopolysaccharides under skin)

eyes and ears

exophthalmos, lid lag

"puffy" eyes, deafness


amenorrhea / oligomenorrhea, loss of libido, gynaecomastia

menorrhagia / oligomenorrhea, loss of libido


diffuse goitre, high flow bruit

goitre, deep voice

Hyperthyroidism may be treated with drugs (carbimazole), surgery or radioiodine. Patient compliance may be poor. Hypothyroidism is treated with lifetime replacement T4, but care is needed in cases of ischaemic heart disease.

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Summary of Hormonal Regulation

cytokine / hormonefactors promoting releasefactors inhibiting releaseeffects

high glucose, amino acids, fatty acids (short term), glucagon, gastrin, CCK, GIP, GH, ACTH, acetylcholine

somatostatin, catecholamines, fatty acids (long term)

glycolysis, store glycogen, fats and proteins


low blood glucose, amino acids, acetylcholine, catecholamines

fatty acids, somatostatin, insulin

gluconeogenesis, mobilise all stores


low blood glucose, injury, anger, fear, pain, cold, excitement, exercise (all via ANS)


gluconeogenesis, mobilise all stores

growth hormone

sleep, low blood glucose, stress, exercise, dietary protein

hypothalamic feedback, ageing (much more released in childhood)

gluconeogenesis, store protein and glycogen, mobilise fats


inflammation, low blood glucose, injury, pain, cold, stress (all via ACTH)

hypothalamic feedback, "comfort"

immunosuppression, gluconeogenesis, mobilise proteins, redistribute fat and glycogen reserves


cold, high energy diets

hypothalamic feedback, warmth, starvation

increase BMR


injury, infection


mobilise all stores, increase BMR

There are strongly pulsatile patterns of insulin, growth hormone, ACTH & catecholamine release.


In practice, some of these situations might occur at the same time. There is competition between metabolic pathways for access to the respiratory chain. Usually fat oxidation wins out over all the others, and if fats are available most tissues (except brain and red blood cells) prefer free fatty acids over the other substrates. At high rates of fat delivery, liver produces ketone bodies from surplus fat, which can be used by other tissues.


Cephalic controls normally ensure a smooth and well coordinated insulin response to food. The immediate insulin effect is on glucose entry into cells, glycogen deposition and glycolysis. Slower (24 hour) induction of lipogenic enzymes.

Foods differ in their digestibility and "glycaemic index". Contrast pasta with white bread. Less insulin is required for slowly digested foods: better for diabetics and probably for everybody else.


Immediate short term effects of catecholamines, glucagon on lipolysis and recycling of lactate & glycerol into glucose. Longer term effects (24 hours) mediated via growth hormone. Exercise enhances glucose uptake by muscle cells and has an anti-diabetic effect.


Immediate response (seconds) to a fall in blood glucose via catecholamines and glucagon. Liver glycogen breakdown is the first line of defence, but the store is limited. Gluconeogenesis from muscle protein requires several hours to establish.

"Profligate" period over the first few days of fasting, associated with very high unsustainable rates of protein catabolism and ureogenesis.

"Adapted" fasting response after about 1 week, protein degradation is reduced, ketone body production increases, brain starts to use ketones effectively in place of glucose.

Final rapid protein degradation phase after the exhaustion of triglyceride stores, then death.




























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