Physiology

Mechanism of action

Oxyntomodulin combines GLP-1 and glucagon signalling in a single peptide. This dual agonism suppresses appetite while boosting energy expenditure. Below is a breakdown of how both processes unfold.

GLP-1 receptor (GLP-1R)

Activates cAMP/PKA in hypothalamic neurons, slows gastric emptying and enhances glucose-dependent insulin secretion.

  • Arcuate nucleus (POMC/CART)
  • Vagus nerve
  • Pancreatic β-cells

Glucagon receptor (GCGR)

Raises hepatic fatty-acid oxidation, stimulates PGC-1α and drives thermogenesis in brown adipose tissue.

  • Liver: PPARα activation
  • Brown fat: UCP-1 expression
  • Mild gluconeogenesis increase

Central integration

The combined signal reshapes reward circuits, delivering durable satiety without crashing metabolism.

  • Insular cortex
  • Anterior insula
  • Mesolimbic dopaminergic system

Processing & secretion

Oxyntomodulin derives from proglucagon, a 180–amino acid prohormone produced in L cells of the distal ileum and colon. Tissue-specific processing via PC1/3 yields GLP-1, PYY, glicentin and OXM.

Secretion is nutrient-driven, peaking 15–45 minutes after meals at 30–60 pmol/L. The strongest stimuli include:

  • Amino acids such as glutamine, arginine and leucine
  • Short-chain fatty acids from fermented fiber
  • Low-glycemic complex carbohydrates

Native plasma half-life is under 15 minutes due to DPP-4 and hepatic clearance. Therapeutic analogues therefore add structural tweaks:

  • Pegylation
  • Fatty-acid acylation
  • Non-natural amino-acid substitutions
  • Protected N- and C-termini

Key physiological functions

1Appetite suppression

Signals through GLP-1R in the hypothalamus and brainstem to dampen food intake.

  • Activates POMC/CART neurons
  • Inhibits NPY/AgRP neurons
  • Cuts acute caloric intake by ~19%
  • Modulates food-reward pathways

2Energy-expenditure boost

Partial GCGR activation keeps metabolism high.

  • Thermogenesis in brown adipose tissue
  • UCP-1 mitochondrial expression
  • Additional 90–120 kcal/day at rest
  • Greater fatty-acid oxidation

3Glucose control

Acts in a glucose-dependent manner to stabilise glycaemia.

  • Potentiates insulin release when glucose is elevated
  • Improves peripheral insulin sensitivity
  • Moderately lowers glucagon output
  • Minimal hypoglycaemia risk

4Hepatic effects

GCGR signalling in the liver improves lipid handling.

  • Up to −34% intrahepatic triglycerides
  • Higher β-oxidation
  • ALT/AST improvements in NAFLD
  • Lower hepatic inflammation

Clinical relevance and therapeutic takeaways

Native oxyntomodulin is not a drug because of its short half-life, but its biology inspired dual and triple agonists that fuse satiety with higher energy expenditure.

Compared with pure GLP-1 agonists, OXM analogues blunt adaptive thermogenesis, supporting longer weight-loss plateaus and better lean-mass preservation.

Clinical pipeline agonists

Dual GLP-1/GCGR agonists

  • Cotadutide (phase III)
  • BI 456906 (phase III)
  • Pemvidutide (phase II)

Triple GLP-1/GIP/GCGR agonists

  • Tirzepatide (approved)
  • Retatrutide (phase III)
  • Survodutide (phase III)

Why it matters

  • Greater, sustained weight loss
  • Better lean-mass preservation
  • Lower rebound once therapy stops
  • Ancillary liver benefits (NAFLD/NASH)

Clinical data point

Phase II infusion studies documented a 90–120 kcal/day rise in resting energy expenditure (≈7–10% of basal metabolic rate), enough to counteract adaptive thermogenesis during hypocaloric diets.

Sequence of events

  1. L cells release OXM, GLP-1 and PYY shortly after meals.
  2. Signals reach the vagus nerve and the nucleus tractus solitarius.
  3. Hypothalamic POMC neurons fire while NPY/AgRP neurons are inhibited.
  4. GCGR activation in liver and BAT elevates thermogenesis.
  5. Higher expenditure prevents the typical drop in basal metabolism.