Appetite lecture Flashcards
LO:
- Water homeostasis: Summarise the behavioural and hormonal control of hydration
- Appetite regulation: Outline the hypothalmic circuits controlling body weight and relate these to the aetiology, complications and management of obesity and malnutrition
Session plan:
Note obesity used to just be associated with high income countries, but now it is very much associated with low and middle income countries too.
Global eating disorders such as anorexia nervosa or bullimia have also increased in the recent years.
The control of thirst-the body controls thirst through three main triggers:
Q. Which is the most potent stimulus?
- Body fluid osmolality
- Blood volume is reduced
- Blood pressure is reduced
Q. Which is the most potent stimulus?
=•Plasma osmolality increase is the more potent stimulus – change of 2-3% induces strong desire to drink
•Decrease of 10-15% in blood volume or arterial pressure is required to produce the same response ie and drink the same amount of water
Regulation of Osmolality - How does the body regulate osmolarity?
Where is ADH stored in the body?
- Through a hormone= Antidiuretic hormone (ADH) or vasopressin
- Acts on the kidneys to regulate the volume & osmolality of urine
- Collecting duct - Aquaporin 2 channel
- When plasma ADH is low a large volume of urine is excreted (water diuresis)
- When plasma ADH is high a small volume of concentrated urine is excreted (anti diuresis).
Where is ADH stored in the body?
=in the posterior pituitary gland
What is the Physiological action of vasopressin?
- Other name from arginine vasopressin = Anti-Diuretic Hormone (tells you it’s job)
- Diuresis = production of urine, so anti- tells us it stops you producing urine
- Main physiological action = stimulation of water reabsorption in the renal collecting duct
- This concentrates urine (as absorb water into blood)
- Acts through the V2 receptor in the kidney
2 other physiological effects
- Also a vasoconstrictor (via V1 receptor)
- Stimulates ACTH release from anterior pituitary (don’t know why, but biggest stimulus for ACTH release is CRH from hypothalamus)
How does vasopressin concentrate urine?
Red is plasma, yellow is blood
Vasopressin binds to V2 receptors on the cell surface of tubular cells in the collecting ducts of the kidneys. This triggers adenylate cyclase activity to form cyclic-AMP, secondary messenger enables protein kinase A to activate aquaporin-2 genes and increase insertion of aquaporin-2 channels into apical membrane. Water can then pass from the urine into the tubular cell via AQP-2 channels and across the cell and then through aquaporin-3 channels in the basement membrane into the blood
Less water in urine so concentrated, smaller volume
Osmotic stimulation of vasopressin release
Organum vasculosum & subfornical organ
- both nuclei which sit around the 3rd ventricle (‘circumventricular’)
- no blood brain barrier – so neurons can respond to changes in the systemic circulation (without a bb barrier neurons have direct contact with whatever is in systemic circulation)
- highly vascularised
- neurons from these nuclei sitting around the 3rd ventricle project to the supraoptic nucleus - site of vasopressinergic neurons
How do osmoreceptors regulate vasopressin?
Osmoreceptors sensitive to changes in systemic circulation, e.g. senses changes in concentration
Extracellular increase in sodium is sensed by osmoreceptors around 3rd ventricle. The osmoreceptors can detect this increase in concentration since there is a higher sodium concentration extracellularly water flows out of osmoreceptor down osmotic gradient as there is more sodium outside.
This loss of water causes the osmoreceptor to change shape- shrinks which causes increased osmoreceptor firing and therefore lots of action potentials along the neurons which project to hypothalamus where vasopressin is made (supraoptic nuclei) and therefore there is an increase in arginine vasopressin release from hypothalamic neurons
Physiological response to water deprivation
We’d become dehydrated, so taken in less water and plasma conc. (osmolality) goes up, special osmoreceptors in areas around 3rd ventricle directly in contact with systemic circulation are senstive and detect osmolarity increase so they change shape and fire off to neurons which stimulate increase in avp release which flows to collecting duct and bind to V2 receptors stimulates reabsorption so end up producing small volume of concentrated urine so decrease in urine osmolality, since held on to water leading to reduction in plasma osmolariry
Non-osmotic stimulation of vasopressin release
- Atrial stretch receptors detect pressure in the right atrium (when bp is normal they inhibit vasopressin release by telling hyopthalamus no need)
- Inhibit vasopressin release via vagal afferents to hypothalamus
- Reduction in circulating volume eg haemorrhage means less stretch (as less blood in heart) in right atrium of these atrial receptors, so less inhibition of vasopressin, so more is made
How and where does the body measure osmolality?
Q. Which regions are these receptors found in the hypothalamus?
This is done through osmoreceptors
- Osmoreceptors are sensory receptors
- Osmoregulation
- Found in the hypothalamus
ADH is secreted in neurones in the hypothalamus. These neurones express these osmoreceptors, that are very responsive to blood osmolality and responsive to the smallest, tiniest of changes of osmolality resulting in secretion or reduction of ADH.
Q. Which regions are these receptors found in the hypothalamus?
- Organum vasculosum of the lamina terminalis (OVLT)-more important one!
- Subfornical Organ (SFO)
Osmoreceptors – ADH release
Under resting conditions as you can see in the left hand side of the picture, the proportion of cation channels is active, and there is a hypertonic situation that leads to cell shrinkage, and increases the proportion of active cation channels. Thus increasing positive charge influx depolarises the membrane, which then increases neurone action potential firing frequency and sends signals to the ADH producing cells which then increase ADH. ADH leads to fluid retention and involves drinking.
Under hypotonic conditions, this works the other way around and the channels are inhibited and the loss of cation influx causes hyperpolarisation and inhibits firing.
Sensation of thirst
Thirst=desire to drink
- Thirst is decreased by drinking even before sufficient water has been absorbed by the GI tract to correct plasma osmolality
- Receptors in mouth, pharynx, oesophagus are involved
- Relief of thirst sensation via these receptors is short lived.
- Thirst is only completely satisfied once plasma osmolality is decreased or blood volume or arterial pressure corrected.
The reason for drinking may not always be physiological. Sometimes it’s prompted by habit, rituals, or indeed cravings such as alcohol, caffeine or other drugs, and even the desire to consume fluid that will give a warming or cooling sensation can trigger thirst.
There is a delay in the absorption of water in the GI tract, and the correction of plasma osmolality. It takes time while water is being absorbed and circulates around the body. Hence there must be a mechanism in place to stop humans from overdrinking. Excessive fluid intake is something that the kidneys potentially can deal with. Fluid overload is a medical condition, but could occur in any human, and if the kidneys work, they normally just get rid of the excess water. But this comes with a wastage of energy, and also can interfer with nutrient absorption, which has got a strong depence.
Changes in blood pressure/volume - The renin-angiotensin-aldosterone system controls this
(remember this is the less effective way of regulating thirst)
When the blood pressure drops, the juxtaglomerular cells of the afferent arteriole secrete the enzyme renin.
(Random:
Renin Release
The first stage of the RAAS is the release of the enzyme renin. Renin released from granular cells of the renal juxtaglomerular apparatus(JGA) in response to one of three factors:
Reduced sodium delivery to the distal convoluted tubule detected by macula densa cells.
Reduced perfusion pressure in the kidney detected by baroreceptorsin the afferent arteriole.
Sympathetic stimulation of the JGA via β1 adrenoreceptors.
The release of renin is inhibited by atrial natriuretic peptide (ANP), which is released by stretched atria in response to increases in blood pressure.)
Renin is also known as angiotensinogenase. Renin activates the angiotensin system by cleaving angiotensinogen, which is secreted by the liver. So angiotensinogen becomes angiotensin 1. Angiotensinogen is a precursor protein.
Angiotensin 1 is converted to angiotensin 2 primarily through ACE within the lung (but also present in endothelial cells, kidney epithelial cells, and the brain).
Effects of angiotensin 2
-it induces thirst
It increases thirst sensation, it leads to ADH secretion, and activates the sympathetic nervous system leading to vasoconstriction.
-Most important effect is increasing aldosterone. Aldosterone has a major role in sodium conservation. It influences the absorption of sodium, and excretion of potassium and water retension. Aldosterone has a central role in the homeostatic regulation of blood pressure, plasma sodium and plasma potassium.
Angiotensin 2 is the major biproduct of the renin-angiotensin system. It binds onto receptors on the intraglomerular mesangial cells, causing these cells to contract, along with the blood vessels surrounding them, which then leads to release of aldosterone in the zona glomerulosa of the adrenal cortex.
Important clinical relevance of the renin-angiotensin-aldosterone system:
-There are 2 main drugs that affect this pathway. Most well known are the ACE inhibitors, but can also find direct renin inhibitors. These medications are used to treat high blood pressure.
Random: Aldosterone increases hydrogen secretion, by increasing Hydrogen ATPases in the apical membrane of the intercalated cells and by increasing the sodium hydrogen exchanger in the apical membrane of the principal cells.
Body weight homeostasis
- Neuman 1902 – observed his weight was stable for a long time despite no conscious effort to balance out intake and expenditure
- Further studies by Passmore 1971 – most individual adults maintain a relatively stable weight over long periods
- A reduction in fat mass increases food intake and reduces energy expenditure
- Adipose tissue expansion reduces food intake and increases energy expenditure
Dysfunction of weight homeostasis
After Passmore, in modern medicine it is not clear that humans regulate their body mass in a way that changes the adipose activate responses that favour the return to the previous/original weight.
If fat mass reduces, it activates systems that reduces energy expenditure, hence decreasing the sympathetic activity, energy expenditure, increases hunger and food intake, and turns down the thyroid gland so it becomes underactive, and hopefully subject will gain weight.
Conversely, overfeeding, or rapid adipose tissue expansion, reduces food intake, activates sympathetic NS, increases energy expenditure, reduces hunger and intake leading to weight loss.
- We now know that the central circuit defends against reduction of body fat. And there is an important hormone in the middle of it called leptin.
- What system defend against rapid expansion?
=Yet to be discovered
Appetite regulation
Appetite is mostly regulated by the hypothalamus. This provides a link between higher brain circuits, and peripheral stimuli. Peripheral, neural or hormonal stimuli arrive through the vagus nerve.
There are 2 gut hormones: ghrelin and PYY that are involved in peripheral signalling. As mentioned, this travels through the vagus which connects to the brainstem. The brainstem then communicates with the hypothalamus. The hypothalamus further communicates with higher CNS regions such as the amygdala. There’s also very important long term hormonal effects on appetite regulation-the leptin control system.
Because the hypothalamus receives all these triggers, it sensitises a response to them by increasing or decreasing energy expenditure and regulating food intake.
Hypothalamus
The arcuate nucleus of the hypothalamus is an aggregation of neurones in the medial, basal part. This is adjacent to the third ventricle and produces both appetite increasing (orexigenic) or appetite suppressing (anorectic) peptides. One of the terminal feeds of these orexigenic or anorecigenic neurones is the paraventricular nucleus. The paraventricular nucleus of the hypothalamus lays again adjacent to the third ventricle and contains neurones that project into the posterior pituitary gland. These projecting neurones secrete oxytocin, and ADH which then affects osmoregulation, appetite, and stress reaction of the body.
The lateral hypothalamus only produces orexigenic peptides (think LO). The ventromedial hypothalamus is associated with satiety. Lesions in this region in rats leads to severe obesity. There is a debate to what effect it is important to humans, however the most studies suggested that melanocortins in the ventromedial hypothalamus, regulate feeding behaviour. Food intake decreases when the arcuate nucelus pro-opiomelanocortin (POMC) neurones activate.
Other hypothalamic factors have recently been implicated in appetite regulations including the endocannabinoids, A and B activated protein kinase and protein tyrosine phosphatase.
Arcuate Nucleus
•Brain area involved in the regulation of food intake
This is the most important site in the hypothalamic integration of energy balance.
- Incomplete blood brain barrier around the arcuate nucleus, allows access to peripheral hormones circulating in plasma.
- Integrates peripheral and central feeding signals
- Two neuronal populations:
- Stimulatory peptides (NPY (neuropeptide Y) /Agrp (agouti related protein) neuron)
- Inhibitory (POMC neuron)
Two neuronal populations in the Arcuate nucleus
Picture on the right demonstrates a fluoresent microscope image of POMC and NPY neurones. The NPY, AgRP neurones are found only in the hypothalamic arcuate nucleus. These neurones make peptides that potentially stimulate food intake by increasing neuropeptide Y signalling, and reducing melanocortin signalling (MC4R) by the release of AGRP and melanocortin receptor antagonists.
These neurones also express receptors for leptin and insulin, as they are activated by a decrease in leptin or insulin signalling. Fasting, uncontrolled diabetes and genetic leptin deficiency, are examples of conditions in which food intake increases via this mechanism.
Controls appetite and energy expenditure
As mentioned, circulating factors enter through the incomplete blood brain barrier can penetrate the arcuate nucleus. And the neurones in the arcuate nucelus are also responsible for integrating the information, and providing inputs to other nuclei.
So as you can see, when these factors arrive, they activate POMC, which then decreases feeding. Or they can activate NPY or Agrp neurones, which then increases feeding. Both of these go through the paraventricular nucleus.
The function of the arcuate nucleus lies in its diversity of nerves, and its central role in homeostasis. The arcuate nucleus, besides feeding, is involved in fertility and cardiovascular regulations.
The melanocortin system
The central melanocortin system is a collection of the previously discussed central nervous circuits such as the Neuropeptide Y or the agouti related protein and the POMC.
Melanocortins are products of the POMC gene. Alpha MSH is a classic example. The system is a central regulator of the energy balance in both feeding relationships and energy expenditure.
Melanocortin 4 receptors are expressed in the paraventricular nucleus. These receptors are stimulated by melotonin, which leads to reduction of appetite and weight and decreased food intake.
Human CNS mutations affecting appetite
- No NPY or Agrp mutations associated with appetite discovered in humans.
- POMC deficiency and MC4-R (melanocortin 4 receptor) mutations cause morbid obesity.
- In the population, mutations not responsible for the prevalence of obesity - but useful to explain signaling.
Signals from other brain regions
- Higher centres such as the Amygdala, play an important role in controlling reward related motivation pathways, which has a strong effect on appetite.
- Amygdala- emotion, memory.
- Other parts of the hypothalamus, e.g. lateral hypothalamus which produces appetite stimulant peptides or the ventromedial hypothalamus, which is associated with satiety.
Neural infomation from the digestive tract is carried to the brainstem via the vagus nerve. The brainstem is linked with the hypothalamus, which is then linked with the amygdala, the 3 higher centres. The hypothalamus being in the middle and the most important, and the brainstem, working together to regulate appetite.
•Vagus to brain stem to hypothalamus.
Adipostat mechanism often referred to as the body’s thermostat
When we talk about energy expenditure, what we really talk about is thermal regulation, or increasing body temperature, hence increasing energy expenditure. So this thermostat is keeping an individual’s fat mass within a very very narrow range, despite changes to diet or daily activity. There are 2 neural pathways in the hypothalamus involved in that.
The sense of this mechanism is that
- Circulating hormones are produced by adipose tissue. The more adipose tissue you have, the more hormones are being produced.
- Hypothalamus senses the concentration of hormone.
- Hypothalamus then alters neuropeptides to increase or decrease food intake.
- Perhaps a problem with the regulation of the adipostat mechanism leads to obesity ?
The ob/ob mouse
By chance, in the Jackston laboratory they discovered the ob/ob or obese mouse.
On the right is an ob/ob mouse which is unable to poduce the hormone leptin, which leads to severe obesity. The ob/ob mouse is a mutant mouse and eats excessively, leading to severe obesity.
The identification of the gene mutated in the Ob lead to the discovery of the hormone leptin, which is a very important factor in the control of appetite. the ob/ob mouse develops high blood sugar, pancreatic islet cells enlargement, and increased levels of insulin.
Leptin
•Meaning - thin
Hormone made by the adipose cells and enterocytes in the small intestine.
- Discovered in 1994.
- Missing in the ob/ob mouse.
- Made by adipocytes in white adipose tissue.
- Circulates in plasma.
- Acts upon the hypothalamus regulating appetite (intake) and thermogenesis (expenditure).
As previously discussed leptin acts on cell receptors in the arcuate and ventromedial nuceli which both lie in the hypothalamus, and through this they mediate feeding and thermogenesis (energy expenditure)
Besides the primary function of regulation of adipose tissue pass, leptin plays a role in the development of atherosclerosis through the innate immune system, a huge part of that is the complement system.
Low levels of leptin were also discovered in Alzeheimer’s disease, and people with depression.
Congenital leptin deficiency
- In these children leptin has been effective in reducing body weight.
- Only few people known to have this defect. (incredibly rare condition)
First subjects discovered in 1997, there were 2 children carrying the mutation and they were related. Both children were severely obese.
Congenital leptin deficiency is a condition which causes obesity very early in life. Subjects carrying the mutation are born with normal weight, but they are constantly hungry and because they are constantly eating, they quickly gain weight.
These obese children have very low serum leptin levels, despite them being obese and having markedly elevated fatness.
Leptin in obesity
The same concentration of leptin was measured in 136 normal weight subjects and 139 obese subjects.
Serum leptin was significantly higher for obese subjects. Furthermore serum leptin concentrations are correlated with the percentage of body fat, suggesting that most obese people are insensitive to leptin.
The results of this study are displayed
Leptin – mechanism of action
There are 3 main mechanisms:
Number 1 is the easiest. There might be insufficient production
Number 2-the receptor signalling or the regulatory signalling can be defective and reduce leptin levels despite high adipose tissue mass
Number 3-there could also be a decreased sensitivity to leptin, similar to insulin resistance in type 2 diabetes, which results in inability to detect satiety despite high energy stores and high levels.
Short term hormonal regulation of appetite – GUT hormones
Why do we feel less hungry after a meal?
-Is it because stomach is distended?
If drink lots of water with no sugar generally we may feel full for a little bit but generally no, we still feel hungry.
-Nutrients in circulation?
To an extent yes, but not really
The answer= hormone signals from your gut
These hormones or hormonal signals arriving at the gut aka gastrointestinal hormones or gut hormones.
The gastrointestinal hormones
- Secreted by enteroendocrine cells in the stomach, pancreas & Small bowel, colon
- Control various function of digestive organs-motility, appetite, satiety etc.
- Appetite regulation by :
- Ghrelin
- Stimulates appetite, increases gastric emptying
- Peptid YY
- Inhibits food intake
Concentration of Ghrelin in humans over 24 hour period
Ghrelin concentration levels were measured at multiple time points as shown.
This was done by a radioimmunoassay
=a technique for determining antibody levels by introducing an antigen labelled with a radioisotope and measuring the subsequent radioactivity of the antibody component.
These are the cumulative results of 30-38 healthy subjects. As we can see plasma ghrelin levels are increasing almost immediately before each meal time and levels fall an hour or so after eating. Displays diurnal rhythm, rising throughout the day, and then falling over night and reaching the lowest level at around 9am???
Circulating ghrelin doesn’t just correlate with the time of day, but also correlates positively with age. The clear preprandial rise and postprandial fall in ghrelin levels suggested that ghrelin plays a physiological role in meal initiations in humans, as we discussed through gastric motility and gastric acid secretion.
Effect of Ghrelin on feeding in rats
Furthermore, ghrelin also stimulates food intake.
Here investigated the lowest systematically effective or exogenic dose of ghrelin in rats and in humans in a different study.
After chronic systemic or intracerebral ventricular administration of ghrelin for 7 days, cumulative food intake was increased and this was associated with excess weight gain and adiposity.
Effects on feeding in humans
Same scientists did similar experiment in humans by administering saline and ghrelin intravenously. The study subjects were put into a huge free buffet, so they could eat as much as they wanted. And there was a clear cut in energy consumed by every individual from the ghrelin group compared to those that just had saline infusion.
Effect of PYY3-36 on feeding in mice.
PYY is released from the GI tract, and the degree of release post prandially, is proportional to the calorie intake.
In experiment above, he demonstrated that peripheral injection of PYY in rats inibits food intake and reduces weight gain, when we compare them to subjects who receive saline.
Effect of PYY3-36 on food intake and hunger in humans
So PYY infusion resulted in a dose dependent reduction in food and calorie intake, with a maximal inhibition of 35, 32% compared to saline administration.
Fluid ingestion was also reduced by PYY
PYY side effects: nausea, especially in subjects with higher dose
These subjects also experience less hunger and early fullness in the premeal period during PYY infusions.
Obesity is Associated with Comorbidities
Not just bowel cancer but further cancers suspected such as breast cancer
Affects whole body-swollen airways-sleep apnoea leading to tiredness which affects the reward mechanism and increases food intake
Obesity trend
Obesity in the UK
Can see Northern parts of the country is most affected. Boston the town in Linconshire is most affected.
London is least affected in UK.
Has big burden on NHS
Interaction of Environmental & Genetic Variance in Multifactorial Diseases
Subjects genetically prone to obesity in healthy environment, very few will actually manifest as obese. However in a toxic environment, the genetically prone population will suffer from severe significant obesity. The genetically resistant population will be not very affected by toxic environment.
Session Review
The peripheral stimulus of body homeostasis consists of 2 important hormone groups: leptin and the gut hormones.
Leptin has an important role in longer term energy homeostasis, while the gut hormones Ghrelin and peptide YY play an important role in immediate appetite regulation.
Effects of angiotensin 2
Cardiovascular Effects
Angiotensin 2 acts on AT1 receptors found in the endothelium of arterioles throughout the circulation to achieve vasoconstriction. This signalling occurs via a Gq protein, to activate phospholipase C and subsequently increase intracellular calcium.
The net effect of this is an increase in total peripheral resistance and consequently, blood pressure.
Neural Effects
Angiotensin II acts at the hypothalamus to stimulate the sensation of thirst, resulting in an increase in fluid consumption. This helps to raise the circulating volume and in turn, blood pressure. It also increases the secretion of ADH from the posterior pituitary gland – resulting in the production of more concentrated urine to reduce the loss of fluid from urination. This allows the circulating volume to be better maintained until more fluids can be consumed.
It also stimulates the sympathetic nervous system to increase the release of noradrenaline (NA). This hormone is typically associated with the “fight or flight” response in stressful situations and has a variety of actions that are relevant to the RAAS:
- Increase in cardiac output.
- Vasoconstriction of arterioles.
- Release of renin.
Renal Effects
Angiotensin II acts on the kidneys to produce a variety of effects, including afferent and efferent arteriole constriction and increased Na+ reabsorption in the proximal convoluted tubule. These effects and their mechanisms are summarised in the table below. In the kidney it has a greater affect on the efferent arterioles than on the afferent arterioles so it tends to maintain the GFR despite the decrease in renal blood flow due to constriction of the afferent arteriole.
Angiotensin II is also an important factor in tubuloglomerular feedback,which helps to maintain a stable glomerular filtration rate. The local release of prostaglandins, which results in a preferential vasodilation to the afferent arteriole in the glomerulus, is also vital to this process.
Aldosterone
Finally, angiotensin II acts on the adrenal cortex to stimulate the release of aldosterone. Aldosterone is a mineralocorticoid, a steroid hormone released from the zona glomerulosa of the adrenal cortex.
Aldosterone acts on the principal cells of the collecting ducts in the nephron. It increases the expression of apical epithelial Na+ channels (ENaC) to reabsorb urinary sodium. Furthermore, the activity of the basolateral Na+/K+/ATPase is increased.
This causes the additional sodium reabsorbed through ENaC to be pumped into the blood by the sodium/potassium pump. In exchange, potassium is moved from the blood into the principal cell of the nephron. This potassium then exits the cell into the renal tubule to be excreted into the urine.
As a result, increased levels of aldosterone cause reduced levels of potassium in the blood.
