Module 3 - Hypothalamus and monogenic obesity Flashcards
role of hypothalamus
body temp sleep/wake cycle cicadian rhythms energy homeostasis - acts through autonomic, endocrine and behavioural responses to maintain homeostasis
monogenic obesity
mongenic = single genes
- hypothalamus
- pathway has no redundancy and highly conserved in euk
2 classes of genes that mutate
- energy balance
- development of hypothalamus
genes involved with energy balance
leptin (LEP)
leptin receptor
melanocortin-4 receptor (MC4R)
POMC
genes involved with development of hypothalamus
single-minded 1 (SIM1)
brain derived neurotrophic factor (BDNF)
etc
arcuate nucleus of hypothalamus
1st order neurons
- POMC (inhibits food intake, increases energy expenditure)
- NPY/AGRP (stimulates food inatake, decreases energy expenditure)
paraventricular nucleus of hypothalamus
2nd order neurons
- MC4R
- SIM
- BDNF
Leptin comes from
adipose tissue
- some in placenta, ovaries, skel muscle, and stomach
leptin role
signal nutrient deficiency
- fasting, weight loss
leptin regulation
at level of gene expression
positive energy balance signals
- insulin, glucocorticoids, glucose, BCAAs
negative energy balance
- catecholamines, tumor necrosis factor alfa (TNF-a)
leptin role other than hunger
haemopoiesis (platelet aggregation)
- high leptin promotes this
- possible link b/w high adipose and CVD
reproduction
- increases fertility
- hypothalamic, pituitary, gonadal, adipose tissue axis
insulin secreation and sensitivity
- leptin resistance during pregnancy increase food intake for developing fetus
leptin association with body weight
high levels in individuals with high body fat %
- suppose to reduce hunger, but receptors become resistant
leptin mutations - clinical characteristics
- little to no serum leptin
- severe early onset obesity
- hyperphagic (drive to eat)
- delayed puberty
- thyroid disfunction
- 50% body fat
congenital leptin deficiency
- type of disorder
- rate of occurrence
- types of mutations
autosomal recessive disorder (both parents)
- 1-5% of patients with extreme obesity
mutations
- frame shift mutation (truncated, unsecreated leptin molecule)
- missense mutation (changes an amino acid, possibly released into blood but dysfunctional)
leptin therapy effect
injections successful with no leptin
- mutation in leptin receptor no effect (leptin receptor B in the brain)
db/db mouse example
LEPRb in brain (6 isoforms exist)
- mutation cause receptor to resemble LEPRb
- leptin cant bind, extreme obesity
leptin effects on first order neurons
POMC = stimulated AgRP/NPY = inhibited
POMC neuron stimulated by?
receptors?
Leptin (LepR b)
Insulin (ISR)
AgRP/NYP neuron stimulated and inhibited by?
receptors?
stim
- Ghrelin (GHR)
Inhibit
- leptin (LEPRb)
- insulin (ISR)
Leptin signaling pathway
- binds to LEPRb dimer
- dimer activates Jak2 (kinase)
- Jak2 phosphorylates (P) LEPRb, which activates STAT3
- STAT3 signalling pathway activated
POMC meaning
- what is it
pro-opiomelanocortin
- prohormone
- activated by PC1 (prohormone convertase)
pituitary - POMC -> ACTH hormone
pancreas - pro-inuslin -> insulin
hypothalamus - POMC -> MSH peptides
POMC mutations - clinical signs
- severe early onset obesity
- hyperphagic
- normal birth weight, rapid gain
- red hair
- cant produce corticotropin hormone (low ACTH - leads to hypocortisolism)
- autosomal recessive
POMC mutation reason for multiple effects
fragments produced from POMC effect expression of diff tissue
- Melanocyte (low causes red hair, pale skin)
- adrenal gland (ACTH production)
- brain (energy production)
- skin (?)
POMC hypothalamic pathway
PC1 (pro-hormone convertase 1)
- chops POMC into pieces
- produces alpha-MSH peptides
- stimulates MC4R receptor (in paraventricular nucleus neuron - 2nd order neuron)
PC1 mutations
- clinical signs
autosomal recessive (very rare, only 3 discovered)
- early onset obesity
- hyperphagic
- mild hypocortisolism (less than POMC mut)
- malabsorption by small bowel dysfunction
- impaired glucose homeostasis -> pro-insulin not converted to insulin*** (unique feature)
MC4R meaning
melanocortin 4 recptor
MC4R mutation
- rate
- clinical signs
- location
autosomal DOMINANT
- most common monogenic obesity
- 6% of severe obese individuals
- 150 mutations found within gene (mostly missense, some frameshift)
clinical signs
- marked obesity, hyperphagic
- no other signs, requires genome sequencing to diagnose
location
- mutations occur everywhere in protein
- some actually lower body weight (field of study for treatment)
5 classes of MC4R mutations
Based on synthesis step
I - null mutations (defective protein)
II - intracellular retention muts. (misfolding in ER - degraded)
III - binding defective mutations (gets through ER, cant interact with MSH)
IV - signalling defective mutations (on intracellular side of protein, scaffold not developing properly)
V - unknown defects
SIM1 mutation
autosomal recessive
- early onset obesity (*link unknown)
- hyperphagic, normal energy expenditure
- mild developmental issues (unique feature
support -> deletions in chromosome 6 where SIM1 gene is located are obese
BDNF meaning
brain derived neurotrpic factor
BDNF mutation (and its receptor)
autosomal recessive
- receptor tropomyosin related kinase B (TRKB)
- severe obesity, hyperphagic, hyperactivity, impaired memory
BDNF role
proliferation, survival and differentiation of neurons during development of the hypothalamus
- role in memory
- decreases food intake
Role of leptin and insulin in hypothalamus signalling
activate POMC/CART neurons
inhibit AgRP/NPY neurons
*leptin/melanocortin signalling pathway
Role of ghrelin (from stomach) in hypothalamus signalling
activate AgRP/NPY neurons to stim food intake
Ghrelin, leptin, and insulin signalling throughout the day
ghrelin - spikes before meals - remains high at night insulin - spikes after meal - low at night leptin - large drop before breakfast - slow steady increase throughout day and night
3 mechanisms for regulating energy balance
- central regulators (alpha, beta, gamma melanocyte stimulating hormone MSH)
2 . acute signals (ghrelin) - long term signals (leptin, insulin)
orexigenic signal
- how it works
hunger signal (ghrelin)
- increases with weight loss, fasting amd hypoglycemia
- ghrelin activates GHSR on AgRP/NPY neurons
GHSR meaning
growth hormone secretagogue receptor
anoerxigenic signal
satiety signal (insulin) - insulin receptors on both POMC/CART and AgRP/CART neurons
AgRP meaning
agoutti receptor protein
MC4R effects of signals from 1st order (arcuate) neurons
MC4R signals satiety (paraventricular neuron, 2nd order neuron)
- a-MSH stimulates
- AgRP inhibits
marijuanna
- significance of research
stimulates hunger
- endocannabinoid system (ECS)
- stimulated by cannabinoids to increase hunger
2 receptors
- CB1 and CB2 (g-protein coupled receptors)
- CB1 in metabolic tissues, hypothalamus, liver, muscle
- can knockout to reduce hunger
omega fats and ECS
higher omega 6 fat in diet
- increases endocannabinoid synthesis
- 2-AG and AEA
- impairs satiety, possible reason for increase obesity
