MB ChB Year 1: Nutrition and Energy

Lecture 26: Regulation of body weight.

Dr John Illingworth

Click here to download the printed handout sheet for this lecture

The "metabolic syndrome" characterised by abdominal obesity, insulin resistance, dislipidaemia, low-grade inflammation, hypertension and cardiovascular disease is a common, serious medical problem throughout the developed world that merits particular attention.

Session content

Session objectives:

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Obesity is often defined in terms of the body mass index (BMI):

BMI = weight (kg) / height (m)2

A BMI of 25-30 is overweight, above 30 is obese. This is useful as a guide, but BMI does not adequately distinguish fat from lean muscle mass. Separate norms should be used for men, women, children and for different races, but this is rarely done. Skinfold measurements with callipers are better, but require skilled observers and repeated tests. The definitive method is based on dual wavelength X-ray absorption, but this is too complex for routine use. Weighing people under water and measurements of electrical impedance have also been employed. Ordinary waist measurements may be the best guide to abdominal fat deposition, which seems to carry a greater risk of disease than peripheral, subcutaneous fat.

Obesity is an increasingly serious medical problem throughout the developed world. This reflects in part previous selection pressure for "thrifty" genes that could protect individuals against frequent famines. There is, however, a markedly reduced life expectancy from all causes in overweight individuals, that is sufficiently obvious to affect their life assurance premiums. About 20% of North American adults are now clinically obese, and obesity is growing in children including those under four years old. Europe, North America and Japan are following similar paths.

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Serious diseases are associated with obesity.

The data below is taken from Willet et al. (1999) Guidelines for Healthy Weight NEJM 341, 427 - 433.

The most serious links are those between obesity, type 2 diabetes, hypertension and cardiovascular diseases (principally heart attacks and stroke) since these conditions are major causes of death in the general population. The pathogenic mechanisms in diabetes seem to involve the non-enzymic glycation of connective tissue proteins, leading to microangiopathy followed by kidney, retinal and neurological problems. Diabetics also have an adverse blood lipid profile that is associated with atherosclerosis and large vessel disease. The key to successful therapy is good glycaemic control.

The pathogenic mechanisms in hypertension are still disputed, however they most probably involve damage to the vascular endothelium (which increases the risk of clot formation) coupled with an increased myocardial oxygen demand because the heart has more work to do.

Obesity, hypertension and diabetes are not the only risk factors for the development of cardiovascular disease. A complete list of cardiovascular risk factors would also include:

Numerous other conditions are allegedly associated with obesity, including: asthma; cancers (breast, colon, ovary, prostate, rectum, uterus and biliary tract); Cushing's syndrome; dyslipidaemias; dyspnoea (breathlessness); gallstones; gastro-oesophageal reflux disease; hiatus hernia; hyperlipidaemia; osteoarthritis or degenerative joint diseases (knees, hips or spine); psychological problems; renal disease; reproductive problems; snoring and sleep apnoea (not breathing); varicose veins. These associations do not necessarily imply causality, and some of them are disputed, especially the asthma and cancer risks.

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The metabolic syndrome.

The metabolic syndrome is increasingly recognised as an inflammatory process, involving reactive oxygen species (ROS) and pro-inflammatory cytokines such as TNF-α and IL-1. Blood glucose homeostasis Œ and inflammatory mechanisms  share a common regulator in the pituitary-adrenal axis. Despite this cross-talk, these two systems normally coexist without serious problems. The inflammatory systems contain positive feedback loops Ž but these amplifying mechanisms normally self-terminate once the cause of the inflammation has been removed. Obese, hyperglycaemic individuals  can enter a persistent inflammatory state, where hyperglycaemia activates the inflammatory response via RAGE, then the inflammatory cytokines TNF-α and IL-1 exacerbate the insulin resistance and make the problem worse.

NFκB – nuclear factor kappa B – regulates inflammatory genes
RAGE – receptor for advanced glycation end products
ROS – reactive oxygen species

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Weight regulation is normally very precise.

Ignoring short term fluctuations (which are mostly gain and loss of water) our body weight stays remarkably constant. A person who gains 20kg over 10 years has ingested about 590MJ above their energy requirements, but this represents only about 1.3% excess in their total energy consumption of about 44GJ over the same period. Weight regulation is achieved through precise and effective negative feedback loops, making it very difficult to lose weight by dieting. We will now examine the reasons for this:

There are two components to this regulation:.

  1. Hunger varies inversely with body weight

  2. Metabolism varies directly with body weight

In other words, if you lose weight the desire to eat more food becomes very powerful, while at the same time your basal metabolic rate declines to conserve the limited fat stores that remain. [Several of the following figures have been adapted from Schwartz et al (2000) Central nervous system control of food intake Nature 404(6778), 661 - 671.]

There is a direct calorific effect of eating, which represents the energy needed for digestion, interconversion and storage of newly ingested food. This immediate increase in respiration accounts for about 10% of the total energy consumed. In addition, there are slower changes in physical activity and metabolism that are mediated by a variety of hormonal control mechanisms described below. Finally, there is a calorific effect from the stored fat, because moving around with 20kg excess baggage is like doing permanent weight training, and this effects our fuel requirements.

As a result, the overall muscle mass, food consumption and metabolism of an extremely fat person may differ only slightly from somebody who is very thin. In humans there is a huge genetic contribution to differences in body build: search the OMIM website with the keyword "obesity" for details.

Short term changes in energy expenditure have relatively little effect upon the size of the immediately following meal. Over the next few days, however, total food consumption will gradually change to largely compensate for sustained alterations in fuel demand. The brain is able to monitor the total reserves of fat and the state of the short term fuel supplies, and the gut provides a fairly accurate estimate of how many calories have been eaten in the latest meal. There is a vast literature on feeding behaviour in humans, but if you want to read one fairly recent and entertaining paper, we recommend Yeomans et al (2001) Physiology and Behaviour 73, 533-540. Leeds students can read this on line via Elsevier Science Direct.

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Local control by the enteric nervous system

Almost all multicellular animals possess basic feeding reflexes, whereby food is recognised by taste and smell at the start of the alimentary tract, and swallowed provided that the gut is not already full. For much of the time the gut functions semi-autonomously: peristalsis, secretion and absorption are coordinated by the enteric nervous system. Peristalsis is mainly controlled by the myenteric plexus (Auerbach's plexus) between the circular and longitudinal muscles in the gut wall, and secretion mainly by the submucous plexus (Meissner's plexus) which is closer to the lumen of the gut. The gastrointestinal tract has several distinct modes of operation: in one of these coordinated patterns of electrical and muscular activity known as migrating motility complexes originate from the stomach and propagate through the small intestine, gently massaging the contents along the gut. The stomach releases partially digested food (called "chyme") through the pyloric sphincter in small squirts that are adjusted to match the processing capacity of the duodenum. Consumption of fresh food stimulates a gastrocolic reflex that moves previous meals through the hindgut. These are ancient survival mechanisms that have been in use for over 600 million years. They are deeply integrated within the genome, hardwired into the nervous system, and they are impossible to resist.

The basic survival strategy is similar in many species: a distensible stomach allows opportunistic feeding when food is available, and eating also denies access to competitors. However there are limits to the amount of food that can be stored, and the rate at which it can be processed. It takes time to hydrolyse food and absorb the products. Unless the nutrients are absorbed quickly there is a risk that unwanted bacteria will proliferate within the gut, and a significant osmotic problem will be created by the hydrolysis of macromolecules into smaller fragments.

Digestion works because the luminal water and sodium ions that drive solute uptake are recycled many times. It is essential to conserve water by re-assembling the digested foodstuffs back into fat globules or glycogen as rapidly as possible. The insolubility or high molecular weight of these storage materials generates very little osmotic pressure. It is also desirable to keep the solute concentrations within the intestinal lumen as low as possible to discourage bacterial growth. Local hormones from the mid-gut stimulate the production of digestive juices by the liver and pancreas and restrain the stomach from releasing food too quickly. Sensory cells in the gut walls also warn the downstream processing systems in the pancreas, liver and adipocytes of the imminent arrival of osmotically active sugars and calorigenic fats. The insulin response to oral glucose with all these sensory cues intact is more accurate and better timed than the response to the same amount of intravenous glucose. The gut hormones that signal this information are known as incretins.

Taste buds and entero-endocrine cells share numerous signaling systems, and probably have a common evolutionary and embryonic origin.

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Supervision by the autonomic nervous system

The brain uses the autonomic nervous system to supervise the operation of the local gut hormones and the enteric nervous system. There are several levels to this control: the hindbrain adds a layer of anticipation and tactical planning to the digestive processes, while the hypothalamus modulates these responses to reflect longer term strategic needs and the size of the energy reserves. The forebrain can only interfere to a limited extent: we can control our mouth and our anus (more or less!) but we have little conscious control over the processes in between. It may be difficult to reconcile subjective feelings of hunger or satiety derived from the visceral nervous system with the objective evidence from our bathroom scales. Food preferences show considerable personal, cultural and temporal variations. Novelty-seeking behaviour may increase food intake while helping to ensure a varied diet. Flavour and presentation plainly influence our immediate food choices, but it is not clear whether they change overall consumption in the longer term.

hindbrain hypothalamus forebrain mouth salivary glands stomach small intestine large intestine anus liver gall bladder exocrine pancreas islet tissue pylorus vagus sympathetic chain cholecystokinin blood glucose local gut hormones peristalsis stretch taste smell vision insulin brain pathways autonomic autonomic autonomic autonomic autonomic

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Basic integration by the hindbrain

In humans, and in all other vertebrates, information about smell, taste and gastric fullness is conveyed by the cranial nerves. Numerous types of smell receptor transmit information via the olfactory nerve (I) which is really a specialised brain tract. The taste buds are mainly innervated by the facial nerve (VII) and the glossopharyngeal (IX) while the liver, stomach and duodenum are served by the vagus nerve (X). This system does not merely detect that the gut is full, but can also monitor what kinds of food have been eaten, their digestibility and their likely calorific yield. The flow of information is a two-way process, and the brain is able to modulate the volume and composition of the digestive juices, the rate of passage through the pylorus and the total residence time within the gut. Fundamental feeding assessments ranging from "unbearable hunger" to "stuffed to capacity" are made by the hindbrain, in the nucleus of the solitary tract or possibly in the parabrachial nucleus nearby. The corresponding emotional and physical sensations are communicated to the higher centres and influence our conscious behaviour.

solitary tract solitary tract fourth ventricle inferior olive inferior olive pyramid pyramid medulla solitary tract solitary tract cerebellar peduncle cerebellar peduncle caudate nucleus caudate nucleus third ventricle pineal body habenular trigone habenular trigone dorsal thalamus dorsal thalamus midbrain pons medulla

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Strategic modulation by the hypothalamus

A second tier of control systems in the hypothalamus modulate the basic meal feeding reflexes according to the body's fat stores and blood sugar levels. The hypothalamus is a small volume of nervous tissue surrounding the third ventricle, with important neural connections to the hindbrain, and also to the pituitary gland. Some of this tissue lies outside the blood - brain barrier, and is able to respond directly to circulating hormones, and sense the glucose concentration in the blood. It is uniquely placed to control both energy inputs and outputs.

cerebellum hypothalamus pituitary Optic tract medulla oblongata pons pineal gland midbrain corpus callosum fornix

To locate your own hypothalamus, put your fingers in your ears, then move upwards about 20mm and forwards about 20mm. The line joining your fingertips now passes through your hypothalamus, in the middle of your skull. The total volume of human hypothalamic tissue is only about 4ml but it contains at least a dozen distinguishable nuclei which collectively regulate blood pressure, osmolarity and thirst, temperature, diurnal rhythms, sexual activity and emotional responses in addition to food intake and metabolic activity. The "wiring diagram" for this tiny area is extremely complex, and in addition it contains major nerve tracts connecting the midbrain and hindbrain to the higher centres. The areas concerned with feeding are coloured green on the diagrams below. Point at the figure with your mouse for additional information.

anterior pituitary posterior pituitary Optic tract arcuate nucleus paraventricular nucleus pons supraoptic nucleus Optic tract supraoptic nucleus Optic tract supraoptic nucleus arcuate nucleus lateral hypothalamic area lateral hypothalamic area paraventricular nucleus paraventricular nucleus third ventricle

The hypothalamic controls preserve the natural feeding cycle, but if food is available meals become progressively larger and more frequent when signals indicate that fuel reserves are running low. At first hungry animals search assiduously for food, but there is a second stage during longer term starvation when activity declines and metabolism closes down to preserve the remaining fuel stocks, in the hope that things might improve. Conversely, a generous food supply stimulates metabolism and provides an ideal opportunity to breed. There are important links between the fuel gauges and the reproductive system.

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Input signals to the CNS

Many local peptide hormones conveying information in the gut are also detected in the brain, where they act as neurotransmitters. Although there is some similarity between the signals conveyed at these two locations, both systems have evolved independently for about 500 million years. There is now great diversity of function and we should not expect an exact match. Neural pathways within the brain have been traced by dissection, and more recently by following axonal transport of peroxidase and virus particles. Activation of nerve cells leads to transiently increased expression of the fos gene, which can be detected immunologically. This has greatly assisted the identification of the neural pathways involved in appetite regulation. Gene knockout on the other hand has been less useful. These systems have considerable redundancy, and knocking out individual genes often has only minor effects on the animal's behaviour. Some of these genes are imprinted, and disruption of the maternal and paternal copies produces opposite effects.

Blood glucose monitors: There are at least five independent sensors that monitor blood glucose concentration and contribute to the overall regulation of food intake.

  1. Pancreatic b cells

  2. Portal vein glucose sensor - found in rodents, not sure about humans

  3. Nucleus of the solitary tract

  4. Hypothalamus

  5. Carotid bodies

These sensors differ in their cross-sensitivities to other metabolites, but they appear to have some features in common, including low-affinity GLUT2 transporters mediating glucose entry to the cells and the low-affinity glucokinase enzyme. This makes their intracellular ATP supply exquisitely sensistive to glucose availability, and forms the basis for their signalling systems. Low blood glucose (hypoglycaemia) triggers a massive response from the sympathetic nervous system, and is associated with a pounding heart, trembling, anxiety, sweating and hunger. The effects of hyperglycaemia on feeding and satiation are much less obvious, and it may even lead to a paradoxical increase in food intake.

There is an excellent brief review by Korner & Leibel (2003) To Eat or Not to Eat — How the Gut Talks to the Brain New England Journal of Medicine 349, 926-928 which includes a very useful diagram. You are strongly recommended to read this article, and the associated report on Peptide YY in the same issue of this journal.

There is a more recent review by Valassi et al (2008) Neuroendocrine control of food intake. Nutrition, Metabolism & Cardiovascular Diseases 18, 158-168 which covers much of the material in this lecture. It may be helpful to review this material from a slightly different point of view.

There is two-way exchange of information between the hypothalamus and the nucleus of the solitary tract. Recent research on the ascending sensory pathways has been reviewed by Rinaman (2007) Visceral sensory inputs to the endocrine hypothalamus. Frontiers in Neuroendocrinology 28(1), 50-60 but this research paper is MUCH too detailed for the present course. The intricate connections are shown in Figure 1, but just be aware that these pathways exist.

Adiponectin is a mixture of anti-inflammatory peptide hormones secreted by adipocytes that also regulate energy homeostasis and the metabolism of glucose and lipids. Adiponectin stimulates the phosphorylation and activation of 5'-AMP-activated protein kinase (AMPK) in skeletal muscle and liver. As a result, adiponectin stimulates phosphorylation of acetyl coenzyme A carboxylase (ACC), fatty-acid oxidation, glucose uptake and lactate production in myocytes, and phosphorylation of ACC and reduction of molecules involved in gluconeogenesis in the liver. By increasing glucose catabolism, adiponectin achieves a reduction of glucose levels in vivo. Adiponectin increases insulin sensitivity in target tissues, but also stimulates fatty acid oxidation and blocks the differentiation of new adipocytes in bone marrow. Paradoxically, obese patients often have lower adiponectin levels than thin people, suggesting that other factors modulate adiponectin release.

Leptin, a cytokine released by fat cells acts on the arcuate nucleus within the hypothalamus to suppress eating behaviour and also increases energy expenditure. Leptin production rises with increasing fat cell mass. Mice that are homozygous for the ob mutation fail to make leptin and are grotesquely obese, as are db/db mice that lack the leptin receptor.

Leptin has at least two signalling pathways: JAK/STAT via nuclear gene expression, and an effect on ATP-sensitive potassium channels in glucose-responsive neurones. This affects the neuronal firing rate. [The same K channel is involved in islet cells and cardiac muscle.] Leptin also has major effects on reproductive behaviour. Sexual maturation is delayed by lack of food. Starving women, female athletes and anorexics with low fat stores experience secondary amenorrhea. Leptin signalling defects lead to gross obesity, but these are very rare in humans. Other factors must be responsible for obesity in the general population.

Resistin is a newly discovered peptide hormone produced by adipocytes and probably by other tissues. Polymorphism of the resistin gene is associated with obesity. Resistin has an anti-insulin action, and is itself suppressed by insulin and the pro-inflammatory cytokines. Output is increased by thyroid hormone T4 but the physiological function is not yet understood.

Pro-inflammatory cytokines: (TNFa IL-6 & IL-1) act on the hypothalamus to reduce appetite and raise body temperature in response to infection, and many other serious illnesses. They were first identified as products of the immune system, especially macrophages, but it is now realised that many other tissues (including adipocytes) can secrete these compounds. There is a major negative feedback loop involving the hypothalamus, corticotropin releasing hormone, corticotropin (=ACTH) secreted by the pituitary, and corticosteroids from the adrenal cortex which damp down pro-inflammatory cytokine production. This loop normally acts to stabilise immune system activity, but it also has spill-over effects on appetite and weight regulation.

Cholecystokinin (CCK) is the best known member of a group of hormones secreted by the duodenum in response to the partially digested output from the stomach, which is called chyme. Fatty meals are particularly effective. CCK delays gastric emptying, stimulates pancreatic enzyme production, causes the gall bladder to contract, promotes insulin release by the pancreas and produces a sensation of fullness or satiation. CCK signals to the brain via the vagus nerve. Other incretins in the same group are gastric inhibitory peptide (GIP), glucagon-like peptide 1 and glucagon-like peptide 2. All have been identified as drug development targets.

Ghrelin is a 28-residue peptide secreted by endocrine cells within the gastric sub-mucosa. It acts on the hypothalamus to stimulate growth hormone release by the pituitary. Ghrelin is also produced locally by neurons within the hypothalamus, and in other parts of the intestine. It antagonises leptin, increases metabolic efficiency and stimulates eating behaviour, resulting in weight gain. "When your stomach’s growling its making ghrelin." The control of gastric ghrelin production is complex. The hormone normally indicates hunger and is released by the empty stomach, but paradoxically it may also be released in response to high-protein meals. It is thought that the effective weight loss achieved by gastric surgery may reflect a fall in ghrelin output.

Insulin: In addition to its role in blood glucose homeostasis, insulin reduces food intake and plays a major part in appetite regulation. Gene knockout experiments have confirmed that lack of either brain insulin receptors or insulin receptor substrate 2 (IRS2) results in hyperphagia, obesity and female infertility. It is believed that insulin promotes phosphorylation of leptin receptors and JAK2, which enhances the phosphorylation of STAT3 in the presence of leptin. Insulin levels are often raised in type 2 diabetes which is associated with insulin resistance and obesity.

Amylin: Pancreatic b cells co-release a second polypeptide hormone called amylin at the same time as they release insulin. Amylin binds to receptors in the area postrema (in the hindbrain) and produces a feeling of satiation. This assists in the regulation of food intake.

Apolipoprotein A-IV is a glycoprotein synthesised by enterocytes in response to long chain dietary fat. Short chain fats are ineffective. It is a component of chylomicrons, which are microscopic globules of fat and proteins secreted by the cells lining the small intestine into the lymph draining from the gut. Apolipoprotein A-IV may be regulated by PYY (see below). It is thought to regulate food intake, possibly by stimulating CCK production. It may be effective in its own right because it is also present in the brain.

Peptide YY: (PYY) is a 36-residue peptide secreted by endocrine cells within the lower small intestine, pancreas and colon. It slows down digestion and reduces the consumption of food. PYY inhibits gastric acid secretion, gastric emptying, pancreatic enzyme secretion and gut motility. It acts on the arcuate nucleus in the hypothalamus to suppress appetite and reduce food intake. There has recently been great interest in PYY after it was found to reduce food intake by 33% in obese subjects, who are normally leptin resistant. PYY shows sequence homology to orexigenic NPY described below and to pancreatic polypeptide (PPY) from F cells in the pancreatic islets. PPY inhibits the secretion of pancreatic enzymes and bicarbonate.

The time sequence for gut hormone production reflects the location of the secreting cells: ghrelin generates sensations of hunger and is produced before the meal, while CCK generates a feeling of satiation and helps to terminate the meal. PYY is produced later when chyme reaches the lower gut. It generates a feeling of satiety and delays the start of the next meal.

In addition to the chemical information about the meal contents, the body also measures gastric distension, and the metabolic situation in the liver. Although the details remain to be elucidated, it is clear that this system can judge what you have eaten, and arrive at a fairly accurate estimate of its likely energy yield. It matches the output of the foregut to the digestive capacity of the midgut, controls the duodenal pH and osmolarity, and warns the downstream processors of exactly what to expect. It is not so easily fooled, and it can tell a low-calorie slimming product from a normal meal.

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Signalling within the brain

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. Gene knockout experiments show that both MC3R and MC4R transduce anorexic (appetite reducing) signals, but double knockouts are significantly heavier than single knockouts, showing that MC3R and MC4R have distinct roles. MC3R appears to control the conversion of dietary fuel into fat whereas MC4R regulates food intake and possibly energy expenditure.

Cocaine and amphetamine regulated transcript (CART) is a neuropeptide precursor protein that is abundant in the hypothalamus. It is upregulated after cocaine or amphetamine administration. CART-derived peptides reduce food intake when injected into the third cerebral ventricle, and probably have several other functions within the central nervous system.

Neuropeptide Y (NPY) is a 36-residue, highly conserved peptide that is widely distributed throughout the vertebrate nervous system. NPY has multiple neurosecretory and cardiovascular functions. There are at least five classes of NPY receptor distributed over a wide range of tissues. NPY delivers a powerful orexigenic (appetite-promoting) signal within the hypothalamus, which activates a neural pathway leading to the nucleus of the solitary tract. NPY is over-produced in leptin-deficient mice, but double knockout mice show less severe symptoms, suggesting that NPY mediates the overfeeding observed in leptin-deficient animals.

Agouti-related protein (AGRP) is named after a related gene controlling hair colour in rodents. It is a powerful antagonist of the MC3R and MC4R melanocortin receptors in the hypothalamus. Obese patients have elevated plasma levels of AGRP, and over-expression of AGRP in animal models leads to obesity.

Orexins A & B This important pair of neurotransmitters (otherwise known as hypocretins 1 & 2) are derived from a common precursor and were discovered in 1998 together with their G-protein linked receptors OX1-Rs and OX2-Rs. They have a major role in arousal and food seeking behaviour. Damage to the orexin signalling system leads to narcolepsy.

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Output signals from the hypothalamus

The hypothalamus is able to control energy input and expenditure through a variety of output routes.

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Metabolic pituitary hormones

In addition to the neural outputs modulating feeding reflexes in the hindbrain, the hypothalamus controls energy expenditure via the anterior pituitary and the sympathetic nervous system. A important output signal to the pituitary is thyrotropin releasing hormone (TRH) a small peptide secreted into the hypophyseal portal system which causes the anterior pituitary to release thyroid stimulating hormone (TSH). Thyroid hormone acts on peripheral tissues, increasing alertness, heat production and basal metabolic rate. Conversely, the temperature regulating system interacts with energy homeostasis, and low ambient temperatures induce a powerful urge to eat. In addition, there is interaction between energy homeostasis and the reproductive systems. Sexual maturation is delayed, and sexual activity generally diminishes when food supplies are inadequate.

Thyroid hormone production and a "normal" level of alertness and physical activity require adequate food intake. Thyroxin output falls during prolonged starvation when metabolism and physical activity are severely restricted to conserve fuel stocks. The strategy is a sensible one: if you don't find food fairly quickly, the best option is to slow down and hope for the best, instead of squandering precious resources on a fruitless search. Two other pituitary hormones are associated with fasting and gluconeogenesis: corticosteroids (which participate in a feedback loop involving pro-inflammatory cytokines) and growth hormone, which defends the body's protein and glycogen reserves, and promotes the breakdown of fat.

The pituitary also produces ACTH and growth hormone, which have significant metabolic effects.

Autonomic outputs: Hypoglycaemia and hypothermia both lead to sustained sympathetic responses. Subjects feel hungry and eat if possible, but they refine their other actions to suit the circumstances. Hypoglycaemia requires hepatic glycogenolysis and gluconeogenesis, while hypothermia requires increased heat production and a redistribution of blood flow. Sympathetic activity is controlled by the hypothalamus, which instructs the adrenal medulla to secrete adrenalin. This is a rather blunt instrument, and localised sympathetic responses (such as blood flow regulation) are mediated by individual nerves. Parasympathetic activity can also respond to the hypothalamus, which controls the nucleus of the solitary tract.

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Recommended lifestyle changes

There is no question that weight loss is beneficial for patients suffering from the metabolic syndrome.

Highly motivated pathologically obese individuals have achieved some spectacular results, but it is very difficult for most people to achieve a weight loss greater than 10% for an extended period. Even this modest reduction is considered to be worthwhile.

To achieve a sustained weight loss for medical or cosmetic reasons it is normally recommended that people should eat a low-fat, physically bulky diet, rich in fresh fruit, green vegetables and unrefined carbohydrates, and that their total energy consumption should be slightly less than before. The diet should have a low glycaemic index, reducing the need for insulin. In practice most of the energy will come from starch. This diet should be supplemented by an exercise program to increase energy demand, leading to a gradual weight loss over several months. Crash diets should be avoided because they chiefly affect body water content, rather than fat. They may also promote muscle catabolism for gluconeogenesis. The altered lifestyle must be maintained indefinitely: if the person ceases to control their food intake then most of the missing fat will be rapidly replaced.

Download the dietary advice published in 2001 by the American Heart Association. This is the "conventional wisdom".

High fat "Atkins" diets also produce effective weight loss without causing unbearable hunger, because they induce rapid satiation. They are not widely recommended by nutritionists although the evidence against them is largely speculative and anecdotal. The "not invented here syndrome" possibly applies. A recent small but well-controlled prospective study placed high-fat and "mediterranean" (salads plus olive oil) diets well ahead of conventional low carbohydrate diets for effective and sustained weight loss. The great advantage of high fat diets is that they do not leave the patients feeling permanently hungry. Nevertheless, this particular study had a higher than normal drop-out rate. The predicted dislipidaemia and cardiovascular problems have so far failed to materialise.

Although fat people tend to suffer from various medical problems, it does not necessarily follow that unsuccessful dieting will make them any healthier. Weight loss brings obvious benefits to obese people suffering from type 2 diabetes, dyslipidaemias and related forms of metabolic disease, but it has been much more difficult to prove that attempted weight loss in otherwise healthy individuals leads to increased life expectancy. "If it ain't bust, don't fix it" is one possible conclusion from the clinical trials. There is an interesting but long-winded review article on obesity that challenges some of the conventional wisdom by Lev-Ran (2001) Human obesity: an evolutionary approach to understanding our bulging waistline Diabetes - Metabolism Research & Reviews 17(5), 347-362. Click the links near the top of the abstract to read HTML & PDF full text versions.

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Medical and surgical treatment

The best recent review is Eckel (2008) Nonsurgical Management of Obesity in Adults. NEJM 358, 1941-50.

There is no entirely satisfactory drug treatment for obesity, and it is normally recommended that moderately overweight patients (BMI < 30) are treated with diet and exercise alone. Several compounds proved to have serious side-effects, and manufacturers are competing to bring an effective product to this lucrative market place. Development is proving difficult because multiple signalling pathways are involved in the regulation of body weight. Some existing drugs are tabulated below:

drug mechanism side effects comments


blocks pancreatic lipase

anal leakage

fatty stools


blocks 5HT uptake / sympathomimetic

dry mouth, headache

FDA approved

glucagon-like peptide 1

delays gastric emptying, more insulin produced

natural product, so probably fairly safe

use in type 2 diabetes


cannabinoid CB1 receptor antagonist

depression, suicide

recently withdrawn


multiple CNS effects, anti-epileptic drug

psychomotor problems unpleasant for patient

poor patient compliance



high abuse potential

not approved



limited duration of action

potentiates fenfluramine

(dex) fenfluramine

blocks 5HT uptake

heart valve defects

dangerous, withdrawn


activates PPARg

liver damage



blocks cholecystokinin breakdown

not properly tested, not yet in clinical use

development continues

None of these drugs are particularly effective, and a 10% weight loss is considered very good. Patients tend to re-accumulate the lost weight when the therapy is stopped. Nevertheless, even a modest weight loss can lead to a marked improvement in cardiovascular risk. There are two recent excellent reviews of anti-obesity drugs and therapeutic targets, by Crowley et al (2002) Nature Review Drug Discovery 1(4), 276-286 and Yanovksy & Yanovsky (2002) NEJM 346(8), 591-602.

Liposuction to remove excess fat is not currently recommended, but gastric surgery is proving surprisingly effective. "Stomach stapling" operations include Roux-en-Y gastric bypass, and a variety of banding procedures. It is also possible to insert a water-filled intragastric balloon, and there are proprietary dietary equivalents using natural hydrophilic gels. Surgery normally produces much larger weight losses than drug therapy, but carries a significant risk. Excellent results have recently been reported using implanted gastric pacemakers. This minor operation has a negligible risk.

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Principal point: the body actively defends a “target” weight, because:

Fat cells produce leptin which reflects total fat stores. b-cells produce insulin which reflects the recent food supply, and the gut signals its current contents via the vagus nerve and the hindbrain. There are sensory pathways from the NTS to the hypothalamus. All these signals are integrated by the hypothalamus to regulate physical activity, thermogenesis and feeding behaviour.

Within the arcuate nucleus of the hypothalamus the various input signals drive an appetite stimulating (orexigenic) system based on NPY / AgRP secreting neurones which is balanced by an appetite suppressing (anorexigenic) system based on POMC / CART secreting neurones.

In addition, the hypothalamus directly monitors blood glucose which is a major driver for the sympathetic nervous system, and it "knows" the state of the immune system via pro-inflammatory cytokines. These help to regulate ACTH and cortisol output.

Principal point: the hypothalamus runs the show because it has access to all the significant sources of information and it controls all the major effector systems.

Principal point: satiation and satiety are very important for controlling food intake.

Satiation is the feeling of “fullness” that terminates the current meal, satiety is the sensation of well being that controls the interval to the next meal. These sensations involve physical distension and chemical messengers.

Peptides such as PYY from the lower GI tract contribute to the sense of fullness and help to terminate meals. Many of these numerous gut peptides are incretin hormones which also stimulate insulin release.

Principal point: ghrelin is the only peptide "hunger hormone" identified to date.

Ghrelin is produced by empty stomachs. Ghrelin stimulates feeding behaviour and growth hormone output from the anterior pituitary gland, but there are GPCR ghrelin receptors in most tissues, including many other parts of the brain. Ghrelin signalling is widely distributed throughout the vertebrate phylum.

The “front end” of the body (eyes, nose, taste buds and forebrain) all tend to increase food consumption, but the “back end” (liver and lower GI tract) which must cope with the ingested food mainly signal satiation and terminate eating behaviour.

Lack of satiation signals such as CCK and PYY makes it very difficult for subjects to resist the powerful orexigenic signals from ghrelin during voluntary food restriction. Gastric distension alone does not abolish hunger.

Endocannabinoids anandamide (orexigenic) and oleoylethanolamide (anorexigenic) may also be important for gastrointestinal function and the regulation of food intake, but this is not yet completely certain. Rimonabant is an inverse agonist for CB1 cannabinoid receptors which was approved in Europe for weight loss therapy, but has recently been withdrawn because of depression and suicide risks.

All the other weight loss drugs (e.g. orlistat, sibutramine, topiramate, amphetamines, phentermine, (dex) fenfluramine, troglitazone, and butabindide) have significant side effects.

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