Paradigm shift: the primary function of the \u201cAdiponectin Receptors\u201d is to regulate cell membrane composition

Marc Pilon

doi:10.1186/s12944-021-01468-y

Abstract

The ADIPOR1 and ADIPOR2 proteins (ADIPORs) are generally considered as adiponectin receptors with anti-diabetic properties. However, studies on the yeast and C. elegans homologs of the mammalian ADIPORs, and of the ADIPORs themselves in various mammalian cell models, support an updated/different view. Based on findings in these experimental models, the ADIPORs are now emerging as evolutionarily conserved regulators of membrane homeostasis that do not require adiponectin to act as membrane fluidity sensors and regulate phospholipid composition. More specifically, membrane rigidification activates ADIPOR signaling to promote fatty acid desaturation and incorporation of polyunsaturated fatty acids into membrane phospholipids until fluidity is restored. The present review summarizes the evidence supporting this new view of the ADIPORs, and briefly examines physiological consequences.

Highlights

The ADIPOR1 and ADIPOR2 proteins (ADIPORs) have been the subject of several high-profile articles suggesting that they are adiponectin receptors with anti-diabetic properties [1–5]
The crystal structure of the ADIPORs has been solved and consists of a barrel-shaped conformation open towards the cytoplasm with a cavity capable of accommodating fatty acids (FAs), or FAlike substrates, and a zinc-coordination site that may either stabilize the structure and/or participate in a hydrolytic reaction, such as the proposed ceramidase activity first suggested by studies of the yeast homologs and consistent with observations with the mammalian proteins [5, 13, 14]
A forward genetics screen led to the identification of the protein IGLR-2 as an obligate partner for Progestin and adipoQ receptor (PAQR)-2 function: both proteins must be present in the same cell for systemic maintenance of membrane fluidity when worms are challenged with either cold temperatures or SFArich diets [28, 35]

Summary

Introduction

The ADIPOR1 and ADIPOR2 proteins (ADIPORs) have been the subject of several high-profile articles suggesting that they are adiponectin receptors with anti-diabetic properties [1–5]. The yeast homologs of the ADIPORs regulate membrane composition (structural lipids), are up-regulated by membrane rigidification (e.g. excess SFAs), are inhibited by the presence of membrane-fluidizing UFAs, carry a ceramidase activity, signal via sphingoid bases and can be functionally replaced, at least partially, by the human ADIPORs. Lessons from C. elegans There are 5 PAQR proteins encoded by the C. elegans genome, two of which are clear ADIPOR homologs and are named PAQR-1 and PAQR-2 (there are no adiponectin homologs in C. elegans) [25].

Results

Conclusion