13-Food intake

Question 1

Hypothalamic Arcuate Nucleus

Answer 1

Two main neuron populations:
POMC (αMSH) – anorexigenic.
AgRP/NPY/GABA – orexigenic.
POMC neurons release αMSH, decreasing appetite.
AgRP/NPY neurons release AgRP and NPY, enhancing appetite.
AgRP/NPY neurons also release GABA, inhibiting POMC neurons.
Arc neurons project to anorectic neurons in the PVH.
PVH neurons project to brainstem, sympathetic nervous system, higher brain regions, and thyroid axis.

Question 2

POMC Processing

Answer 2

POMC is cleaved by Prohormone Convertases (PC).
POMC ➔ αMSH via PC1/3 and PC2

Question 3

Melanocortin Signaling

Answer 3

αMSH is an agonist of MC4R.
AgRP is an inverse agonist of MC4R.
MC4R is a Gs-coupled GPCR expressed on anorectic PVH neurons.
Activation of MC4R reduces food intake.
PVH neurons project to other brain regions, brainstem, sympathetic nervous system, and thyroid axis.

Question 4

POMC Mutation and Obesity

Answer 4

Defects in POMC, PC1, or MC4R are monogenic causes of obesity.
In humans, POMC and PC1 mutations are recessive and rare, while MC4R gene defects are dominant.
Setmelanotide (αMSH analogue) is prescribed for patients with LepR, POMC, or PC1 deficiency but inefficacious for MC4R mutations

Question 5

Brainstem Dorsal Vagal Complex

Answer 5

Comprising Area Postrema, Nucleus of the Solitary Tract, and Dorsal Motor Nucleus of the Vagus Nerve.
Area Postrema exposed to blood-borne signals.
NTS receives input from vagus nerve afferent fibers.
DMV contains cell bodies of vagal efferents, part of parasympathetic innervation.
DVC contains anorectic neuronal populations.
PrRP (Prolactin Releasing Peptide) is an anorectic neuropeptide expressed in the NTS

Question 6

Mechanosensation of Distension

Answer 6

Stretch of stomach or intestines activates mechanoreceptors.
Activated mechanoreceptors lead to vagal activation.
Serotonin release also triggers vagal activation

Question 7

Chemosensation of Nutrients

Answer 7

Fats, simple sugars (e.g., glucose), and peptides/amino acids detected locally in the gut.
Nutrients transported in the blood and detected in the brain.
Hormone release occurs in response to nutrients

Question 8

Long-term Control of Food Intake

Answer 8

Adipose tissue produces leptin:
Leptin reports adipose tissue size.
Adiposity increase ➔ circulating leptin increase.
Adiposity decrease ➔ circulating leptin decrease.
Leptin is an anorexigenic hormone:
Activates POMC (αMSH) neurons.
Inhibits AgRP/NPY neurons.
Decreases food intake and increases energy expenditure

Question 9

Obesity

Answer 9

Multi-factorial genes x environment interaction causes most forms of obesity.
Global factors include increased intake of energy-dense foods and physical inactivity.
High circulating levels of leptin and leptin resistance are associated with increased adiposity.
Monogenic forms of obesity exist, with more than 30 known syndromes, involving gene mutations for leptin, leptin receptor, melanocortin-4 receptor (MC4R), and proopiomelanocortin (POMC), leading to hyperphagia and obesity