Appetite Flashcards
Control of thirst caused by
Body Fluid Osmolality (increasing increases thirst) - change of 2/3% to induce thirst
-Blood volume (reduction increases thirst) - change of 10-15% to induce thirst
-Blood pressure (reduction increases thirst) - change of 10-15% to induce thirst
Regulation of osmolality
ADH- acts on kidneys
Low ADH= large volume of urine, water diuresis
High ADH= low diuresis
Released and stored from posterior pituitary
Osmoreceptors
Measure osmolality
Found in hypothalamus:
- Organum Vasculosum of the Lamina Terminalis (OVLT)
- Subfornical Organ (SFO)
Cells shrink when plasma is more concentrated
Proportion of action channel increase and membrane depolarizes
Sends signals to ADH producing cells to increase ADH
Fluid retention involves drinking
Sensation of thirst
- Thirst is decreased by drinking even before there is sufficient water absorption in the GI tract to correct the plasma osmolality
- This is because there are receptors in the mouth, pharynx and oesophagus
- Thirst is only fully satisfied once plasma osmolality has decreased or blood volume / pressure are corrected
Renin-angiotensin-aldosterone system
- Blood pressure falling leads to excretion of renin from juxtaglomerular cells of renal afferent arteriole
- Angiotensinogen converted to angiotensin I by renin
- ACE from lungs cleaves angiotensin I into angiotensin II
- Angiotensin II increases ADH secretion, increases thirst
- Angiotensin II also causes influx of potassium and efflux of sodium from the zona glomerulosa of the adrenal cortex, resulting in aldosterone release, which then promotes systemic H2O retention due to Na+ and Cl- absorption, alongside K+ excretion
Angiotensin II also causes vasoconstriction and increases sympathetic activity
Homeostasis
- Neuman 1902 - noticed maintaining body weight didn’t need active input
- Passmore 1971 - noticed most adults maintain stable weight
- Reduction in fat mass increases food intake and reduces energy expenditure
- Adipose tissue expansion reduces food intake and increases energy expenditure
System underpinning rapid weight loss is well understood, but there is no knowledge of what prevents rapid weight gain
##
Melanocortin system
POMC > a-MSH stimulates MC4R in the paraventricular Nucleus
POMC and MC4R mutations associated with human obesity
Amygdala, latera hypothalamus, vagus nerve all transmit signals about hunger
What does the body do if fat mass reduces
Try to gain weight by:
- Sympathetic NS energy activity decreases
- Energy expenditure decreases
- Hunger/food intake increases
- Thyroid activity decreased
- What does the body do if fat mass is increased?
- Increasing sympathetic nervous system activity
- Increasing energy expenditure
- Decreasing hunger/food intake
What body system defends against rapid expansion of fat mass?
Not discovered yet
Where does appetite regulation occur
Hypothalamus
What peripheral stimuli are there that are involved in appetite regulation?
- Ghrelin, PYY and other gut hormones- communicate through vagus nerve to brainstem which communicates with hypothalamus which then communicated with higher CNS regions like amygdala
- Neural input from the periphery and other brain regions
- Leptin (via leptin control system)
How does the hypothalamus sensitise a response
By increasing or decreasing energy expenditure and food intake
What is the arcuate nucleus responsible for?
- It’s an aggregation of neurones in the medial basal part of the hypothalamus and is adjacent to the 3rd ventricle
- It has:
- orexigenic (appetite stimulating/increasing) neurones
- anorectic (appetite suppressive) neurones
Stimulatory-NPY/AGRP
inhibitory-POMC
When does the arcuate nucleus decrease food intake?
When its pro-opiomelanocortin (POMC) neurones activate
What does the paraventricular nucleus do?
- Lays adjacent to 3rd ventricle
- Contains neurones that project to posterior pituitary and secrete oxytocin and ADH, to regulate osmoregulation, appetite and stress reaction of the body
What does the lateral hypothalamus do?
Produces only orexigenic peptides
(Feeding centre)
What does the ventromedial hypothalamus do?
- Associated with satiety
- Lesions in this region in rats leads to severe obesity
Is an appetite suppressant
What other hypothalamic factors are implicated in appetite regulation? (3)
- Endocannabinoids
- AMP (activated protein kinase)
- Protein tyrosine phosphatase
Arcutae nucleus
- Brain area involved in regulation of food intake
- Integrates peripheral and central feeding signals
Has an incomplete BBB to allow access to peripheral hormones
What 2 neuronal populations does the arcuate nucleus have
Stimulatory and inhibitory
Stimulatory neurones in arcuate nucleus
- neuropeptide Y (NPY)
- Agouti-related peptide (Agrp)
- Increasing neuropeptide Y signalling
- Reducing melanocortin signalling via release of Agrp (an endogenous melanocortin receptor antagonist)
Inhibitory neurones in arcuate nucleus make
POMC
What receptors for other hormones does arcuate nucleus have
For leptin and insulin, and are activated by a decrease or increase of leptin or insulin signalling
- what leads to increased food intaks
- Fasting
- Uncontrolled diabetes
- General leptin deficiency
What do circulating factors do when they reach the hypothalamus in the blood?
- Cross incomplete BBB and penetrate arcuate nucleus
- Either POMC neurones or NPY/Agrp neurones are activated which both go to the paraventricular nucleus
- Fertility regulation
- Cardiovascular regulation
Besides feeding, what other 2 important things is the arcuate nucleus involved in?
- Fertility regulation
- Cardiovascular regulation
How does the melanocortin system work?
- Melanocortin 4 receptors are expressed on paraventricular nucleus
- Agrp neurones release Agrp which act on MC4R as antagonists
- POMC neurones produce melanocortins, classic example is alpha-MSH, which act on MC4R as agonists → leads to decrease in appetite and weight along with food intake
What do NPY or Agrp mutations do to appetite?
No NPY or Agrp mutations are associated with appetite in humans
What can POMC deficiency cause?
Morbid obesity
What can MC4R mutations cause?
Morbid obesity
What signals from other brain regions are involved in controlling appetite?
- Higher centres e.g. amygdala- responsible for emotion and memory and controlling reward related motivation pathways which has strong effect on appetite
- Lateral hypothalamus and ventromedial hypothalamus
- Vagus communication from digestive tract to brain stem then hypothalamus then amygdala (these 3 centres work together to regulate appetite)
What is the adipostat mechanism?
The body’s thermostat i.e. control of energy expenditure through thermoregulation (controlling body temp) which keeps individual’s fat mass within narrow range despite changes to diet or daily activity
How does adipose tissue interact with hypothalamus for it to regulate food intake?
- Circulating hormones are produced by adipose tissue- the more adipose tissue, the more hormones being produced
- Hypothalamus senses conc of hormones then alters neuropeptides to increase or decrease food intake
Describe the ob/ob mouse experiment
- A mouse with a mutation that means it can’t produce the hormone leptin
- This leads to severe obesity in the mouse as it eats excessively
- It develops high blood sugar, pancreatic islet cell enlargement and increased insulin levels
What is leptin?
- A hormone made by white adipose tissue and gastric mucosaintestines
- Circulates in plasma
- Regulates appetite (intake) and thermogenesis (expenditure
Acts in cells in arcuate and ventromedial nuclei
What role does letpin have in disease development
- Development of atherosclerosis through innate immune system, esp through complement system
- Low levels discovered in Alzheimer’s disease
- Depression associated with low levels of leptin
What is congenital leptin deficiency?
- Incredibly rare genetic condition that causes severe obesity very early in life as they have low levels of serum leptin
- Those with it are born with a normal weight but are always hungry and constantly eat so gain weight quickly
- Only few people known to have defect
What are leptin levels like in obese patients?
- Serum leptin is significantly higher in obese subjects than normal weight people
- Serum leptin is correlated with percentage of body fat of subjects
Obese people beck,e resistant to leptin production
Describe the overall systemic effects of leptin
- It’s low when there’s low body fat
- It’s high when there’s high body fat
- Replacement of leptin in ob/ob mouse decreases weight
- It’s a hormone that decreases food intake and increases thermogenesis
What are the 3 main mechanisms through which the physiological effect of leptin may not work?
- There is insufficient production of leptin
- There is a defect in the regulatory signalling and reduced leptin levels despite high adipose tissue mass
- There is a decreased sensitivity to leptin (similar to insulin resistance in T2DM)- this results in inability to detect satiety despite high energy stores and leptin levels
How effective is leptin as a weight control drug?
Not effective
What secreted GI hormones
Enteroendocrine cells which control motility appetite salivation etc
What are the 2 important hormones appetite regulation-wise (and what do they do)?
- Ghrelin → stimulates appetite, increases gastric emptying
- Peptide YY (PYY) and GLP-1→ inhibits food intake
When are blood ghrelin levels highest and why?
Before meals to help prep for food intake by increasing gastric motility and acid secretion
Returns to lower levels after meal times
What is ghrelin known as
Hunger hormone as infeases food intake
Its name derived from role of growth hormone releasing peptide
How does ghrelin work in arcuate nucleus
Directly modulates neurones in the arcuate nucleus
- Stimulates NPY/Agrp neurones
- Inhibits POMC neurones
Thus increases appetite and regulates reward taste sensation memory and circadian rhythm
Ghrelin throughout day
- Plasma ghrelin levels increased nearly 2x immediately before each meal time
- Fell to a trough around 1 after meal time
- Intermeal ghrelin levels have a diurnal rhythm- rise throughout day to zenith at 1am then falling overnight to a nadir at 9am
Also correlates with age
PYY
Short peptide (36 amino acids) released in terminal ileum and colon in response to feeding
Reduces appetite can be digested or injected iv
How does PYY act on hypothalamus
- Inhibits NPY release
- Stimulates POMC neurones
Release caused by food arrival in terminal ileum and colon
What food types increase PYY release?
- Dietary fibres
- wholegrains
- enzymatic breakdown of crude fish proteins
Effect of PYY on mice and humans
It decreases food intake
The degree of PYY release is proportional (postprandially) to the calorie intake
- How about in humans?
- PYY infusions resulted in dose-dependent reduction in food and calorie intake with maximal inhibition of 35% compared to saline administration
- Fluid ingestion also reduced
What comorbidities is obesity associated with
- Depression- stat1/3 of people with BMI >35 have depression
- Stroke
- Myocardial infarction
- Hypertension
- Diabetes
- Peripheral vascular disease
- Gout
- Osteoarthritis- how?Obese subjects’ joints need to carry more weight
- Bowel cancer and maybe breast cancer
- Sleep apnoea- how?
- Swollen airways lead to sleep apnoea
- This causes tiredness which affects reward mechanism and increases people’s food intake
GLP 1
short peptide released in gut in relosnse to feeding (30 amino acids)
Reduces appetite can be
Incretin increases insulin release in response to glucose
The genetics
Mknogenic obesity rare
Genetic factors explain 40% of variance in obesity
Around 250 genes associated with obesity
Thrifty genes protect us from starvation allowing us to store energy
BMI categories
underweight <18.5
healthy is 18.5-25
overweight is 25-30
obesity
class-30-45
class 2-35-40
class 3-40+
