14-Gut hormones

Question 1

Cholecystokinin (CCK)

Answer 1

Released from duodenal I-cells post-prandially.
Stimulated by fat and protein in the intestinal lumen.
Functions: Pancreatic enzyme secretion, gallbladder contraction, sphincter relaxation.
Mechanism for reducing food intake: Binds to CCK1 receptors on vagal afferents, slows gastric motility, decreases gastric emptying, induces profound satiety

Question 2

Glucose-dependent Insulinotropic Polypeptide (GIP)

Answer 2

Released from duodenal K-cells post-prandially.
Stimulated by sugar and fat in the intestinal lumen.
Function: Enhances glucose-dependent insulin secretion (incretin effect).
Mechanism for reducing food intake: Indirect effect via insulin regulation

Question 3

Glucagon Like Peptide-1 (GLP-1)

Answer 3

Released from ileum + jejunum L-cells.
Cephalic phase stimulated by neural inputs; post-prandial phase by sugar in the distal intestine.
Functions: Incretin hormone (↑ insulin, ↓ glucagon), ileal brake (inhibits gastric emptying).
Mechanism for reducing food intake: Hybrid signal (endocrine + neural), activates GLP-1R in target tissues, induces satiety.

Question 4

Peptide Therapies for Obesity

Answer 4

Native gut hormones have short half-lives.
GIP half-life = 5–7 minutes, GLP-1 half-life = 2 minutes.
Gliptins (DPP-4 inhibitors) increase circulating GLP-1.
Exendins (GLP-1 analogs) resistant to DPP-4 degradation.
Dual-agonists, e.g., Tirzepitide (GLP-1R + GIPR agonist), used to treat obesity, initially developed for T2DM treatment.

Question 5

Leptin Receptor (LepR) and Signaling

Answer 5

Five isoforms of LepR located peripherally and centrally.
Hybrid signal (endocrine + neural).
Activates LepR in target tissues (e.g., brain) through endocrine signaling.
Activates LepR on vagal afferent neurons through neural signaling.
Dimmer switch effect: Attenuates orexigenic signals, potentiates anorexigenic signals, induces satiety, promotes negative energy balance.
Inhibits AgRP/NPY neurons, stimulates POMC neurons, leading to decreased food intake and increased energy expenditure.

Question 6

Leptin Resistance and Obesity

Answer 6

Reflects adiposity; most obese humans have high leptin levels (hyperleptinemia) and are leptin resistant.
No validated means of preventing leptin resistance.
Leptin deficiency is a rare cause of obesity due to congenital defects in the leptin gene.
Leptin receptor defects are a rare cause of early-onset severe obesity with hyperphagia.
Administration of leptin can reverse morbid obesity in cases of deficiency or receptor defects.

Question 7

Primary Functions of Ghrelin

Answer 7

Released from stomach P/D1 cells, enteroendocrine X/A-cells, and islets of Langerhans epsilon (ε) cells.
Ghrelin release is stimulated pre-prandially, mainly by an empty stomach
Acts as the only “hunger” hormone, a potent appetite stimulant.
Increases gastric motility and gastric acid secretion.
Major circulating factor increasing appetite

Question 8

Mechanism of Stimulating Food Intake

Answer 8

Hybrid signal (endocrine + neural).
Binds to the Growth Hormone Secretagogue Receptor (GHSR).
Acts on vagal/sympathetic afferent neurons to increase gastric motility and gastric acid secretion (neural).
Stimulates appetite in target tissues, such as the brain (endocrine).
Activates GHSR in the arcuate nucleus:
Stimulates AgRP/NPY neurons.
Inhibits POMC neurons.
Results in increased food intake and decreased energy expenditure.