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Lifestyle Genomics nutr 3360 > Module 3 - Hypothalamus and monogenic obesity > Flashcards

Module 3 - Hypothalamus and monogenic obesity Flashcards

1
Q

role of hypothalamus

A 
body temp
sleep/wake cycle
cicadian rhythms 
energy homeostasis
- acts through autonomic, endocrine and behavioural responses to maintain homeostasis
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2
Q

monogenic obesity

A

mongenic = single genes

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

2 classes of genes that mutate

  • energy balance
  • development of hypothalamus
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3
Q

genes involved with energy balance

A

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

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4
Q

genes involved with development of hypothalamus

A

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

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5
Q

arcuate nucleus of hypothalamus

A

1st order neurons

  • POMC (inhibits food intake, increases energy expenditure)
  • NPY/AGRP (stimulates food inatake, decreases energy expenditure)
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6
Q

paraventricular nucleus of hypothalamus

A

2nd order neurons

  • MC4R
  • SIM
  • BDNF
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7
Q

Leptin comes from

A

adipose tissue

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

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8
Q

leptin role

A

signal nutrient deficiency

- fasting, weight loss

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9
Q

leptin regulation

A

at level of gene expression

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

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

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10
Q

leptin role other than hunger

A

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

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11
Q

leptin association with body weight

A

high levels in individuals with high body fat %

- suppose to reduce hunger, but receptors become resistant

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12
Q

leptin mutations - clinical characteristics

A
  • little to no serum leptin
  • severe early onset obesity
  • hyperphagic (drive to eat)
  • delayed puberty
  • thyroid disfunction
  • 50% body fat
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13
Q

congenital leptin deficiency

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

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)

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14
Q

leptin therapy effect

A

injections successful with no leptin

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

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15
Q

db/db mouse example

A

LEPRb in brain (6 isoforms exist)

  • mutation cause receptor to resemble LEPRb
  • leptin cant bind, extreme obesity
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16
Q

leptin effects on first order neurons

A 
POMC = stimulated
AgRP/NPY = inhibited
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17
Q

POMC neuron stimulated by?

receptors?

A

Leptin (LepR b)

Insulin (ISR)

18
Q

AgRP/NYP neuron stimulated and inhibited by?

receptors?

A

stim
- Ghrelin (GHR)

Inhibit

  • leptin (LEPRb)
  • insulin (ISR)
19
Q

Leptin signaling pathway

A
  • binds to LEPRb dimer
  • dimer activates Jak2 (kinase)
  • Jak2 phosphorylates (P) LEPRb, which activates STAT3
  • STAT3 signalling pathway activated
20
Q

POMC meaning

- what is it

A

pro-opiomelanocortin

  • prohormone
  • activated by PC1 (prohormone convertase)

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

21
Q

POMC mutations - clinical signs

A
  • severe early onset obesity
  • hyperphagic
  • normal birth weight, rapid gain
  • red hair
  • cant produce corticotropin hormone (low ACTH - leads to hypocortisolism)
  • autosomal recessive
22
Q

POMC mutation reason for multiple effects

A

fragments produced from POMC effect expression of diff tissue

  • Melanocyte (low causes red hair, pale skin)
  • adrenal gland (ACTH production)
  • brain (energy production)
  • skin (?)
23
Q

POMC hypothalamic pathway

A

PC1 (pro-hormone convertase 1)

  • chops POMC into pieces
  • produces alpha-MSH peptides
  • stimulates MC4R receptor (in paraventricular nucleus neuron - 2nd order neuron)
24
Q

PC1 mutations

- clinical signs

A

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)
25
Q

MC4R meaning

A

melanocortin 4 recptor

26
Q

MC4R mutation

  • rate
  • clinical signs
  • location
A

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)
27
Q

5 classes of MC4R mutations

A

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

28
Q

SIM1 mutation

A

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

29
Q

BDNF meaning

A

brain derived neurotrpic factor

30
Q

BDNF mutation (and its receptor)

A

autosomal recessive

  • receptor tropomyosin related kinase B (TRKB)
  • severe obesity, hyperphagic, hyperactivity, impaired memory
31
Q

BDNF role

A

proliferation, survival and differentiation of neurons during development of the hypothalamus

  • role in memory
  • decreases food intake
32
Q

Role of leptin and insulin in hypothalamus signalling

A

activate POMC/CART neurons
inhibit AgRP/NPY neurons

*leptin/melanocortin signalling pathway

33
Q

Role of ghrelin (from stomach) in hypothalamus signalling

A

activate AgRP/NPY neurons to stim food intake

34
Q

Ghrelin, leptin, and insulin signalling throughout the day

A 
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
35
Q

3 mechanisms for regulating energy balance

A
  1. central regulators (alpha, beta, gamma melanocyte stimulating hormone MSH)
    2 . acute signals (ghrelin)
  2. long term signals (leptin, insulin)
36
Q

orexigenic signal

- how it works

A

hunger signal (ghrelin)

  • increases with weight loss, fasting amd hypoglycemia
  • ghrelin activates GHSR on AgRP/NPY neurons
37
Q

GHSR meaning

A

growth hormone secretagogue receptor

38
Q

anoerxigenic signal

A 
satiety signal (insulin)
- insulin receptors on both POMC/CART and AgRP/CART neurons
39
Q

AgRP meaning

A

agoutti receptor protein

40
Q

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

A

MC4R signals satiety (paraventricular neuron, 2nd order neuron)

  • a-MSH stimulates
  • AgRP inhibits
41
Q

marijuanna

- significance of research

A

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
42
Q

omega fats and ECS

A

higher omega 6 fat in diet

  • increases endocannabinoid synthesis
  • 2-AG and AEA
  • impairs satiety, possible reason for increase obesity

Lifestyle Genomics nutr 3360 (4 decks)

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