Appetite Flashcards
How many people die everywhere as a result of being overweight or obese?
2.8 million people
What are the 3 triggers for regulation of thirst?
Which is the most potent for triggering thirst?
Body fluid (plasma) osmolality - most potent
Reduction in blood volume
Reduction in blood pressure
Why is body fluid (plasma) osmolaltiy the most potent?
A change (increase) of 2-3% in plasma osmolality induces strong desire to drink
A change (decrease) in 10-15% in blood volume or arterial pressure is required to produce the same response
How does ADH regulate osmolality?
Antidiuretic hormone (ADH) or vasopressin
ADH acts on the kidneys affecting the Aquaporin-2 channels in the collecting duct = regulation of the volume & osmolality of urine
When plasma ADH is low, a large volume of urine is excreted (water diuresis)
When plasma ADH is high a small and concentrated volume of urine is excreted (anti diuresis)
How does the body measure / detect osmolality?
Via osmoreceptors found in the hypothalamus
These are sensory receptors responsible for osmoregulation
Where is ADH secreted?
Where is ADH stored?
ADH secreted by the neurons in the hypothalamus that express osmoreceptors (v. responsive to blood osmolality) - osmoreceptors control the increase or decrease in secretion of ADH
ADH stored in the posterior pituitary
Which anatomical regions are the osmoreceptors found in the hypothalamus?
Organum vasculosum of the lamina terminalis (OVLT) - more important
Subfornical Organ (SFO)
What is the mechanism by which osmoreceptors cause ADH release?
At rest, a specific proportion of the cation channels on the osmoreceptors is active
Hypertonic stimulation = cells shrinkage due to more concentrated plasma
This then increases the proportion of cation channels that are active – results in a positive charge influx within the osmoreceptor
The membrane therefore depolarizes
This increases action potential neuron firing frequency
This sends signals to the ADH producing cells to increase ADH production
What are the effects of ADH?
Fluid retention
Invokes drinking
What is the mechanism by which osmoreceptors decrease ADH release?
Vice versa mechanism for hypotonic solution
Decrease in proportion of active cation channels - channels are inhibited
Lesser frequency of neurons firing due to hyperpolarisation of membrane
Less signals to ADH producing cells to secrete ADH
What is thirst?
Is it always physiological?
Thirst = desire to drink
Not always physiological - can also drink due to habit, routines, cravings (alcohol, caffeine etc.)
What is thirst decreased by?
Thirst is decreased by drinking, even before sufficient water has been absorbed by the GI tract to correct plasma osmolality
Why is it important not to wait until water is absorbed by the GI tract to correct plasmaosmolality?
There is a delay between drinking, and having it absorbed in the GI tract - so if it takes that long to decrease the feeling of thirst, humans would overdrink
Although a functioning kidney is equipped to excrete excess water - overdrinking is a waste of energy and can interfere with nutrients absorption (due to Na+ dependence)
What receptors are involved in thirst?
Receptors in mouth, pharynx, oesophagus are involved
Relief of thirst sensation via these receptors is short lived
When is thirst completely satisfied?
Thirst is only completely satisfied once plasma osmolality is decreased, or blood volume or arterial pressure corrected
How do changes in pressure regulate thirst?
Renin-angiotensin-aldosterone system (RAAS)
Less effective pathway
What is the renin-angiotensin-aldosterone system (RAAS)?
BP drops
Juxtaglomerular apparatus secretes renin
Renin AKA angiotensinogenase = protein and enzyme secreted by the kidneys
Renin activates the renin-angiotensin system by cleaving angiotensinogen (secreted by the liver) to produce angiotensin I
Angiotensin 1 is then converted into angiotensin II by ACE in the lungs
What are the effects of angiotensin II?
Induces thirst - leads to ADH secretion
Activates sympathetic NS = vasoconstriction
Also is a major bioproduct of RAAS - it binds onto receptors on the intraglomerular messenger cells
Causes the cells and blood vessels surrounding them to contract
Leads to release of aldosterone in the zona glomerulosa of the adrenal cortex
What is the function of aldosterone?
How does it achieve this?
Sodium conservation, which then leads to water retention
Important for homeostatic regulation of BP, plasma Na+, and plasma K+
Induces reabsorption of Na+, excretion of K+, and so H2O reabsorption via diffusion gradient
What are the 2 drugs that affect the RAAS pathway?
ACE inhibitors
Renin inhibitors
Used to treat hypertension (high BP)
How is body weight homeostasis achieved?
A reduction in fat mass increases food intake and reduces energy expenditure
Adipose tissue expansion reduces food intake and increases energy expenditure
What occurs in a weight reduced - underfed state?
Decreased sympathetic nervous activity Decreased energy expenditure Increased hunger and food intake Decreased thyroid activity Weight gain
What occurs in a weight augmented - overfed state?
Increased sympathetic nervous activity
Increased energy expenditure
Decreased hunger and food intake
Weight loss
What circuit defends against reduction of body fat?
What circuit defends against rapid expansion of body fat?
Central circuit - leptin hormone
Still unknown
Where is appetite regulated?
What nerve and hormones connect the appetite regulation between the CNS and PNS?
Mainly in the hypothalamus
Vagus nerve and gut hormones ghrelin and leptin provide a link between higher brain circuits and peripheral stimuli
Ghrelin and leptin travel through vagus nerve to the brainstem –> brainstem communicates with hypothalamus –> hypothalamus communicates with higher CNS regions e.g. amygdala
What does the hypothalamus do to regulate appetite?
Arcuate nucleus is an aggregation of neurons in the medial basal part - adjacent to third ventricle
Produces appetite increasing (orexigenic) and appetite decreasing (anorectic) peptides - which terminate at the paraventricular nucleus of the hypothalamus (contains neurons that project to the posterior pituitary)
These projecting neurons secrete oxytocin and ADH - affects osmoregulation, appetite and stress regulation of body
Lateral hypothalamus only produces orexigenic
Ventrolmedial hypothalamus - associated with satiety
What does a lesion in the ventrolmedial hypothalamus lead to?
Severe obesity - never feeling satiated = constantly eating
What causes food intake to decrease?
Arcuate nucleus pro-opiomelanocortin (POMC) neurons activate
What are other hypothalmic factors implicated in appetite regulation?
Endocannabinoids
AMP activated protein kinase
Protein thyrosine phosphatase
What are the main features of the arcuate nucleus?
Brain area involved in the regulation of food intake - most important site in hypothalamus for energy balance
Incomplete blood brain barrier, allows access to peripheral hormones.
Integrates peripheral and central feeding signals
What are the two neuronal populations in the arcuate nucleus?
Two neuronal populations:
Stimulatory: neuropeptide Y (NYP) and agouti-related peptide (AGRP) = increase in food intake
Inhibitory: pro-opiomelanocortin (POMC) = decrease in food intake
What receptors do the neurons in the arcuate nucleus express?
How can they lead to a food intake increase?
Leptin and insulin receptors
These are activated by a decrease of leptin or insulin signalling - e.g. fasting, uncontrolled diabetes, genetic leptin deficiency = food intake increase via this mechanism
How do circulating factors in the blood affect food intake?
Factors circulate in blood and penetrate into arcuate nucleus via incomplete blood brain barrier (BBB)
Can either activate POMC = decreased feeding
Or activate NYP / AGRP = increased feeding
What else is the arcuate region important for?
Fertility
CV (cardiovascular) regulation
How does the melanocortin system (MCS) work?
Central melanocortin system = collection of CNS circuits e.g. NYP, AGRP, POMC
Melanocortins (MC) are products of the POMC gene
Regulates energy balance in feeding behaviours and energy expenditures
MC4R receptors are expressed in the paraventricular system and are stimulated by serotonin
Leads to reduction in appetite and weight
Mutations in which of these peptides or receptors can affect appetite?
No NYP or AGRP mutations associated with appetite
POMC deficiency and MC4-R mutations can cause morbid obesity
What higher brain regions also play a role in appetite?
Higher centres e.g.
Amygdala = reward-related motivation pathway, emotion, memory
Other parts of the hypothalamus, e.g. lateral hypothalamus (produces appetite stimulant peptides) or ventromedial hypothalamus (satiety)
Vagus to brainstem to hypothalamus to amygdala
What is the purpose of the adipostat mechanism?
Often referred to as the body’s thermostat - energy expenditure is linked to thermal regulation (e.g. increasing body temp = increase in energy expenditure) = body fat mass must be kept within a narrow range despite changes in diet and physical activity
What is the adipostat mechanism?
What can a flaw in this mechanism lead to?
Circulating hormones produced by fat (adipose tissue)
More fat = more hormones produced = more hormones in circulation
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
What is the ob/ob mouse?
Obese mouse in Jackson laboratory - mutant mouse that eats excessively
Unable to produce leptin leading to obesity
Identification of the gene in the mouse led to discovery of leptin significance
What does the ob/ob mouse develop?
High blood sugar
Pancreatic cell enlargement
Increased levels of insulin
What are the features of leptin?
Meaning - thin (leptos - Greek)
Discovered in 1994
Completely 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)
Plays a role in atherosclerosis through the innate immune system
Low levels also discovered in Alzheimer;s disease and depression
What is congenital leptin deficiency?
Very rare - very low serum leptin levels despite being obese and having markedly elevated body fat mass
Causes severe obesity early in life
Constant hunger
What are the systemic effects of leptin?
Low leptin when low body fat
High leptin when high body fat
Replacement in the ob/ob mouse decreases weight
Leptin is a hormone that decreases food intake and increases thermogenesis
What are the 3 main mechanisms of the action of leptin that can lead to obesity?
Insufficient production of leptin
Defective receptor signalling - low leptin levels despite high adipose tissue mass
Decreased sensitivity of leptin - inability to detect satiety despite high energy stores
What are the features of leptin resistance and what leads to this?
Leptin circulates in plasma in concentrations proportional to fat mass
Fat humans have high leptin
Obesity due to leptin resistance - hormone is present but doesn’t signal effectively
Leptin is ineffective as a weight control drug due to this
Why do we feel less hungry after a meal?
Hormonal signals from gastrointestinal (GI) hormones secreted by endocrine cells of the stomach, pancreas and small bowel
They control various functions of the digestive organs - motility, appetite, satiety, salivation etc.
What are the two main GI / gut hormones?
Ghrelin
Stimulates appetite, increases gastric emptying
Peptide YY (PYY) Inhibits food intake
When are the blood levels of ghrelin highest?
Blood levels of ghrelin are highest before meals
Helps prepare for food intake by increasing gastric motility and acid secretion
What does ghrelin do?
Directly modulates neurons in the arcuate nucleus
Stimulates NPY / AGRP neurons
Inhibits POMC neurons
What are the effects of ghrelin?
Increases appetite
Regulation of reward, taste sensation, memory, circadian rhythm
What is PYY?
Short peptide (36 Amino acids) released in the terminal ileum (TI) and colon in response to feeding
What are the effects of PYY?
Reduces appetite – can be digested or injected IV
Food arriving to the TI and colon results in PYY release - best pYY response = fibres, wholegrains, breakdown of crude fish protein
Induces satiety
Inhibits NPY release
Stimulates POMC neurons
What is the effect of IV PPY when taken?
Reduced food ingestion
Experience less hunger
Early fullness
Nausea
What are co-morbidities associated with obesity?
Depression Stroke MI Hypertension Diabetes Peripheral vascular disease Gout Osteoarthritis Bowel cancer Sleep apnoea
