GLP-1 and GLP-2 Peptide Receptors Play Distinct Roles in How the Gut Adapts to Cold Stress | Research

The takeaway

The GLP-2 receptor is required for intestinal villi expansion during cold stress in mice, while GLP-1 receptor signaling supports body weight gain independently of gut structural changes.

GLP-2R required for villi expansion
Mice lacking the GLP-2 receptor failed to expand their intestinal absorptive surface during cold stress despite elevated GLP-1 levels, revealing non-redundant peptide receptor functions

What the researchers found

Over five weeks at 6°C, all mice ate significantly more food. Wild-type and GLP-1R/GIPR double knockout mice showed increased jejunal circumference, villi length, and crypt depth — but mice lacking both GLP-1R and GLP-2R did not show these gut adaptations. This pinpoints the GLP-2 receptor as essential for cold-induced intestinal expansion. Despite elevated plasma active GLP-1 levels, villi lengthening did not occur without GLP-2R. However, GLP-1R signaling was sufficient for body weight gain even when gut structural adaptation failed.

Why it matters

Understanding how GLP-1 and GLP-2 peptides control intestinal adaptation has direct implications for patients on GLP-1-based drugs (semaglutide, liraglutide) and GLP-2 therapies (teduglutide for short bowel syndrome). This study shows these peptide systems have non-overlapping functions — blocking one doesn't compensate for the other — which is important for predicting side effects and designing combination therapies.

How the study worked

Male and female wild-type, double incretin receptor knockout (DIRKO: Glp1r-/-Gipr-/-), and GLP double receptor knockout (GLPDRKO: Glp1r-/-Glp2r-/-) mice were housed at either 6°C (cold) or 27°C (thermoneutral) for five weeks. Researchers measured food intake, body weight, jejunal circumference, villi length, crypt depth, and plasma GLP-1 levels.

What this study cannot tell us

This is a mouse study using extreme cold stress (6°C for 5 weeks), which does not directly model any common human condition. The genetic knockout approach eliminates receptors from birth, so compensatory developmental changes may occur that wouldn't apply to pharmacological receptor blockade in adults. The study did not examine long-term outcomes beyond five weeks or assess nutrient absorption directly.

How to read the evidence

This is a well-designed preclinical study using genetic knockout models in both male and female mice with appropriate controls. The evidence is strong for the mechanistic conclusions in mice but requires validation in human physiology.

When this study was published

Published in 2025 in Communications Biology (Nature portfolio), this represents current research in incretin peptide biology and is directly relevant to understanding the growing class of GLP-1-based therapeutics.

The bigger picture

As GLP-1 receptor agonists become ubiquitous for diabetes and obesity treatment, understanding what happens when this signaling pathway is modulated is critical. This study reveals that GLP-1 and GLP-2 have distinct roles in gut adaptation — a fundamental biological process. The findings also have implications for patients with short bowel syndrome on GLP-2 therapy and raise questions about whether long-term GLP-1RA use might affect intestinal adaptive capacity in situations of metabolic stress.

Questions still open

Could chronic GLP-1 receptor agonist use impair the gut's ability to adapt to increased metabolic demands in humans?
Would combining GLP-1 and GLP-2 receptor-targeted therapies have synergistic effects on intestinal health?
Does the elevated plasma GLP-1 seen in cold-stressed GLPDRKO mice have metabolic consequences beyond the gut?

Common questions

What are GLP-1 and GLP-2 and how are they different?

GLP-1 (glucagon-like peptide-1) and GLP-2 are both produced by gut cells after eating. GLP-1 primarily helps regulate blood sugar by stimulating insulin release — it's the target of drugs like Ozempic. GLP-2 promotes intestinal growth and nutrient absorption — it's the basis for teduglutide (Gattex), used to treat short bowel syndrome. This study shows they have distinct, non-interchangeable roles.

Could taking GLP-1 drugs affect how my gut adapts?

This mouse study suggests that GLP-1 and GLP-2 receptor signaling have separate roles in gut adaptation. While GLP-1 drugs used in humans activate (rather than block) the receptor, understanding how these peptide systems interact is important for predicting long-term effects. More research in humans is needed to determine any practical implications.

Read the original research

Intestinal adaptation to cold-induced metabolic demand and feeding requires GLP-1R and GLP-2R signalling.

Communications biology, 9(1), 25

View on PubMed ↗Publisher’s paper ↗

Citation

Morrow, Nadya M; Hanson, Antonio A; Fong-McMaster, Claire; Livingston, Dawson B H; Osman, Hoda; Hamilton, Lauren; Trzaskalski, Natasha A; Locatelli, Cassandra A A; Bellefleur, Mélodie N; Messika-Zeitoun, Ethel; Cino, Sebastian M; Pulente, Serena M; Abramchuk, Iryna; Zhao, Xiaoling; Lorenzen-Schmidt, Ilka; Morissette, Arianne; Power, Krista A; Harper, Mary-Ellen; Mulvihill, Erin E. (2025). Intestinal adaptation to cold-induced metabolic demand and feeding requires GLP-1R and GLP-2R signalling.. Communications biology, 9(1), 25. https://doi.org/10.1038/s42003-025-09281-4