Calcitonin-Receptor-Like Receptor Signaling Governs Intestinal Lymphatic Innervation and Lipid Uptake

Area of Science:

• Gastroenterology
• Endocrinology
• Molecular Biology

Background:

• Dietary fat absorption relies on neuroendocrine control of chylomicron transport.
• Calcitonin-receptor-like receptor (Calcrl) interacts with adrenomedullin/RAMP2 or CGRP/RAMP1.
• Calcrl's role in lipid absorption and enteric innervation is not fully understood.

Purpose of the Study:

• To investigate the function of Calcrl in regulating dietary fat absorption and lymphatic function.
• To determine the impact of Calcrl deletion in lymphatic endothelial cells on lipid absorption.
• To elucidate Calcrl's role in the neurolymphocrine axis controlling lipid homeostasis.

Main Methods:

• Conditional and inducible genetic deletion of Calcrl in lymphatic endothelial cells (Calcrlflox/Prox1-CreER mice).
• High-fat diet administration to assess lipid absorption and weight gain.
• Analysis of lymphatic endothelial junctions, enterocyte chylomicron processing, and gut innervation.

Main Results:

• Calcrl deletion in lymphatics led to inefficient dietary fat absorption and excessive lipid accumulation.
• Altered lymphatic endothelial junctions and abnormal enterocyte chylomicron processing were observed.
• Calcrl-deficient mice exhibited reduced and disorganized mucosal and submucosal innervation, linked to CGRP signaling.

Conclusions:

• Calcrl is essential for normal dietary fat absorption and lymphatic function.
• Calcrl regulates lipid absorption through distinct functions in lymphatic endothelial cells and enteric neurons.
• Calcrl acts as a critical regulator in the neurolymphocrine axis, integrating lymphatic and neural signaling for lipid homeostasis.