Module 3: Hypothalamus & Monogenic Obesity

Question 1

Where is leptin synthesized?

Answer 1

Subcutaneous adipose tissue

Question 2

Where is leptin regulated

Answer 2

Regulated at level of gene expression and protein secretion

Question 3

Signals associated with positive energy balance and how do they affect leptin express.

Answer 3

Insulin, glucocorticoids (cortisol), glucose, branched chain A.A
= increase leptin expression

Question 4

Signals associated with “starvation” and how do they affect leptin express.

Answer 4

Catecholamines (epinephrine), tumor necrosis factor (TNF-a)
=decrease leptin expression

Question 5

Association between leptin and body weight

Answer 5

Obesity associated with a leptin RESISTANCE
-blood leptin levels strongly/positively correlated with body fat

Question 6

Leptin loss-of-function mutation in humans symptoms (6)

Answer 6

-little to no serum leptin
-severe early onset obesity
-hyperphagic (increased drive to eat)
-delayed puberty
-thyroid dysfunction
-50% body fat
SEEN IN OB/OB MOUSE

Question 7

Leptin mutation type of disorder

Answer 7

Autosomal RECESSIVE disorder

Question 8

Examples of loss-of-function mutations (leptin) that have been identified

Answer 8

1.frameshift mutation
(leptin stuck in adipose tissue, unsecreted)
2.missense mutation
(changes conformation of leptin protein, prevents interaction w receptor)

Question 9

Affects of leptin therapy in humans (6)

Answer 9

-BMI and % body fat drop
-Blood triglyceride level normalized
-Increased HDL-C
-normalized insulin
-improved thyroid function
-improved immunity

Question 10

POMC/CART neuron

Answer 10

-activated by leptin after binding to leptin receptor
-inhibit food intake, increase energy expenditure

Question 11

NPY/AgRP neuron

Answer 11

-inhibited by leptin after binding to leptin receptor
-stimulate food intake, decrease energy expenditure

Question 12

Leptin receptor (LEPR) mutation characteristics

Answer 12

-severe early onset obesity, continue through adolescence
-no developmental delays
-normal leptin levels

Question 13

How many isoforms of LEPR exist and which is expressed in hypothalmic neurons

Answer 13

-6 isoforms
-LEPRb –> has intracellular domains to activate JAK/SKAT signal pathway (necessary for appetite regulation)

Question 14

Leptin pathway

Answer 14

-leptin binds to LEPRb
-LEPRb activates Jak2 kinase, allows for STAT3 to be activated
–> activates POMC
–> inhibits NPY/AgRP

Question 15

POMC mutation characteristics
(5)

Answer 15

-severe early onset obesity
-hyperphagia (excessive eating)
-normal birth weight, rapid gain
-RED HAIR
-cant produce ACTH (produces cortisol) = adrenal insufficiency = hypocortisolism

Question 16

POMC mutation type

Answer 16

Autosomal RECESSIVE mutation

Question 17

Melanocortin peptide receptors

Answer 17

MC1R = hair pigmentation
MC2R =ACTH production
MC3R & MC4R = energy balance
MC5R = ? (skin)

Question 18

Prohormone convertases (PCs)

Answer 18

Endoproteases (molecular sciessors)
-cleave peptide bonds at end of peptide chain
(inactive precursers –> biologically active peptides)

Question 19

PC1 mutation characteristics (5)

Answer 19

-severe, early onset obesity (associated w improper processing of POMC)
-hyperphagia
-mild hypocortisolism
-malabsorpton by small bowel dysfunction
-impared glucose homeostasis

Question 20

PC1 mutation type

Answer 20

Autosomal RECESSIVE

Question 21

MC4R mutation type

Answer 21

-Autosomal DOMINANT
-most common cause of monogenic obesity

Question 22

MC4R mutation characteristics

Answer 22

-marked obesity, hyperphagic
-no promotor mutations, over 150 within gene

Question 23

Ghrelin in leptin pathway

Answer 23

-activates AgRP/NPY
-AgRP inhibits MC4R
-NPY inhibits POMC/CART

Question 24

A deletion in which chromosome contains genes involved in leptin and insulin signalling?

Answer 24

chromosome 16

Question 25

3 Mechanisms of energy balance regulation

Answer 25

1.central reg
-alpha, beta, gamma MSH
2.acute signals (ghrelin, insulin) - change in response to immediate metabolic environ)
3.long-term signals (leptin) - change in relation to a person’s overall metabolic status

Question 26

Ghrelin

Answer 26

Hunger signal

Question 27

When does ghrelin increase

Answer 27

Weight loss, fasting, hypoglycemia

Question 27

Insulin

Answer 27

Satiety signal