Module 3 - Hypothalamus and monogenic obesity

Question 1

role of hypothalamus

Answer 1

body temp
sleep/wake cycle
cicadian rhythms 
energy homeostasis
- acts through autonomic, endocrine and behavioural responses to maintain homeostasis

Question 2

monogenic obesity

Answer 2

mongenic = single genes

• hypothalamus
• pathway has no redundancy and highly conserved in euk

2 classes of genes that mutate

• energy balance
• development of hypothalamus

Question 3

genes involved with energy balance

Answer 3

leptin (LEP)
leptin receptor
melanocortin-4 receptor (MC4R)
POMC

Question 4

genes involved with development of hypothalamus

Answer 4

single-minded 1 (SIM1)
brain derived neurotrophic factor (BDNF)
etc

Question 5

arcuate nucleus of hypothalamus

Answer 5

1st order neurons

• POMC (inhibits food intake, increases energy expenditure)
• NPY/AGRP (stimulates food inatake, decreases energy expenditure)

Question 6

paraventricular nucleus of hypothalamus

Answer 6

2nd order neurons

• MC4R
• SIM
• BDNF

Question 7

Leptin comes from

Answer 7

adipose tissue

- some in placenta, ovaries, skel muscle, and stomach

Question 8

leptin role

Answer 8

signal nutrient deficiency

- fasting, weight loss

Question 9

leptin regulation

Answer 9

at level of gene expression

positive energy balance signals
- insulin, glucocorticoids, glucose, BCAAs

negative energy balance
- catecholamines, tumor necrosis factor alfa (TNF-a)

Question 10

leptin role other than hunger

Answer 10

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

Question 11

leptin association with body weight

Answer 11

high levels in individuals with high body fat %

- suppose to reduce hunger, but receptors become resistant

Question 12

leptin mutations - clinical characteristics

Answer 12

• little to no serum leptin
• severe early onset obesity
• hyperphagic (drive to eat)
• delayed puberty
• thyroid disfunction
• 50% body fat

Question 13

congenital leptin deficiency

• type of disorder
• rate of occurrence
• types of mutations

Answer 13

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)

Question 14

leptin therapy effect

Answer 14

injections successful with no leptin

- mutation in leptin receptor no effect (leptin receptor B in the brain)

Question 15

db/db mouse example

Answer 15

LEPRb in brain (6 isoforms exist)

• mutation cause receptor to resemble LEPRb
• leptin cant bind, extreme obesity

Question 16

leptin effects on first order neurons

Answer 16

POMC = stimulated
AgRP/NPY = inhibited

Question 17

POMC neuron stimulated by?

receptors?

Answer 17

Leptin (LepR b)

Insulin (ISR)

Question 18

AgRP/NYP neuron stimulated and inhibited by?

receptors?

Answer 18

stim
- Ghrelin (GHR)

Inhibit

• leptin (LEPRb)
• insulin (ISR)

Question 19

Leptin signaling pathway

Answer 19

• binds to LEPRb dimer
• dimer activates Jak2 (kinase)
• Jak2 phosphorylates (P) LEPRb, which activates STAT3
• STAT3 signalling pathway activated

Question 20

POMC meaning

- what is it

Answer 20

pro-opiomelanocortin

• prohormone
• activated by PC1 (prohormone convertase)

pituitary - POMC -> ACTH hormone
pancreas - pro-inuslin -> insulin
hypothalamus - POMC -> MSH peptides

Question 21

POMC mutations - clinical signs

Answer 21

• severe early onset obesity
• hyperphagic
• normal birth weight, rapid gain
• red hair
• cant produce corticotropin hormone (low ACTH - leads to hypocortisolism)
• autosomal recessive

Question 22

POMC mutation reason for multiple effects

Answer 22

fragments produced from POMC effect expression of diff tissue

• Melanocyte (low causes red hair, pale skin)
• adrenal gland (ACTH production)
• brain (energy production)
• skin (?)

Question 23

POMC hypothalamic pathway

Answer 23

PC1 (pro-hormone convertase 1)

• chops POMC into pieces
• produces alpha-MSH peptides
• stimulates MC4R receptor (in paraventricular nucleus neuron - 2nd order neuron)

Question 24

PC1 mutations

- clinical signs

Answer 24

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)

Question 25

MC4R meaning

Answer 25

melanocortin 4 recptor

Question 26

MC4R mutation - rate - clinical signs - location

Answer 26

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)

Question 27

5 classes of MC4R mutations

Answer 27

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

Question 28

SIM1 mutation

Answer 28

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

Question 29

BDNF meaning

Answer 29

brain derived neurotrpic factor

Question 30

BDNF mutation (and its receptor)

Answer 30

autosomal recessive - receptor tropomyosin related kinase B (TRKB) - severe obesity, hyperphagic, hyperactivity, impaired memory

Question 31

BDNF role

Answer 31

proliferation, survival and differentiation of neurons during development of the hypothalamus - role in memory - decreases food intake

Question 32

Role of leptin and insulin in hypothalamus signalling

Answer 32

activate POMC/CART neurons inhibit AgRP/NPY neurons *leptin/melanocortin signalling pathway

Question 33

Role of ghrelin (from stomach) in hypothalamus signalling

Answer 33

activate AgRP/NPY neurons to stim food intake

Question 34

Ghrelin, leptin, and insulin signalling throughout the day

Answer 34

``` 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 ```

Question 35

3 mechanisms for regulating energy balance

Answer 35

1. central regulators (alpha, beta, gamma melanocyte stimulating hormone MSH) 2 . acute signals (ghrelin) 3. long term signals (leptin, insulin)

Question 36

orexigenic signal | - how it works

Answer 36

hunger signal (ghrelin) - increases with weight loss, fasting amd hypoglycemia - ghrelin activates GHSR on AgRP/NPY neurons

Question 37

GHSR meaning

Answer 37

growth hormone secretagogue receptor

Question 38

anoerxigenic signal

Answer 38

``` satiety signal (insulin) - insulin receptors on both POMC/CART and AgRP/CART neurons ```

Question 39

AgRP meaning

Answer 39

agoutti receptor protein

Question 40

MC4R effects of signals from 1st order (arcuate) neurons

Answer 40

MC4R signals satiety (paraventricular neuron, 2nd order neuron) - a-MSH stimulates - AgRP inhibits

Question 41

marijuanna | - significance of research

Answer 41

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

Question 42

omega fats and ECS

Answer 42

higher omega 6 fat in diet - increases endocannabinoid synthesis - 2-AG and AEA - impairs satiety, possible reason for increase obesity