Gut derived hormones

Gut derived hormones

Enteroendocrine cells throughout the GI tract are able to express a broad spectrum of peptide hormone precursors. The number and secretory profile of these enteroendocrine cells can also be modified.

L-cell secretion

These cells secrete PYY, GLP-1 and OXM in response to neural, hormonal and nutrient factors.

  • Ghrelin has been shown to ‘prime’ the cells
  • Nutrients in the gut, acting directly on the cells, prolong the secretory phase
  • Vagus nerve stimulation mediates the early response

A recent finding is that melanocortin-4 receptors (MC4Rs) on the cell cell suface act to regulate secretion of PYY and GLP-1.

Peptide YY

  • Cells expressing PYY are present throughout small and large bowel
  • Circulating PYY are low and progressively fall in the fasted state
  • They increase proportionally to caloric load of intake and dependent on macronutrient composition
  • Peripheral PYY administration reduces calorific intake in rodents and humans
  • It works on the Y2R receptor and agonists cause anorectic effects
  • Low-PYY state = fasted state = changes in hypothalamus to cause food intake
  • High-PYY state = fed state = neural activity in orbitofrontal cortex, implicated in reward processing.

GLP-1

  • GLP-1 has a well-established role in regulating glucose homeostasis, increasing insulin in response to glucose (an incretin hormone) and increases insulin-sensitivity of a- and b-cells
  • GLP-1 also delays nutrient absorption and delays gastric emptying and intestinal motility
  • Peripheral GLP-1 reduces caloric intake in rodents, humans and type 2 diabetics.
  • It has a short half-life
  • Good evidence that GLP-1 also acts directly on the brain to affect feeding behaviour

Oxyntomodulin

  • An amino acid peptide that activates the GLP-1Rs and glucagon receptors.
  • Peripheral administration reduces caloric intake in rodents, lean and obese individuals
  • Given over 4 weeks, it causes a weight loss of around 2.3kg.
  • Though to involve vagal and direct CNS action
  • Increases energy expenditure through the GCGR (glucagon receptors)

Ghrelin

  • Peptide hormone released from P/D1 cells (located in the gastric mucosa, small bowel and particularly duodenum)
  • The majority of gastric cells are not in contact with lumen but the ones in the duodenum and jejunum ARE.
  • Circulating levels increase before meals and decrease rapidly after.
  • Proportion correlates with caloric load
  • In humans, circulating ghrelin levels are inversely associated with adiposity and increase with weight loss due to exercise, low calory diet and cachexia
  • Ghrelin seems more involved with the reward based, hedonic feeding

In obesity

  • Progressive reduction of PYY, active GLP-1 and ghrelin

Effect from diet

  • A very low calory diet adversely changes these hormones: hunger is increased, fasted and nutrient-stimulated PYY levels are reduced, ghrelin levels are inceased.
  • These changes persist upto a year after the diet!