Chemerin Receptor Structures Disclose New Mechanism of Lipid Metabolism

By Liu Jia

Edited by Lisa Lock, Reviewed by Robert Egan

Published on November 21, 2025

Introduction

Chemerin is an important adipokine that plays a critical role in regulating lipid metabolism and insulin sensitivity, implicating it in various metabolic disorders such as obesity and diabetes. Moreover, it functions as a chemoattractant, guiding immune cell trafficking to sites of inflammation. Recent research has explored the structural mechanisms through which chemerin acts via its two primary receptors: CMKLR1 and GPR1.

The Role of GPR1 and CMKLR1

CMKLR1 is recognized as a canonical G protein-coupled receptor (GPCR) that recruits G proteins and enhances β-arrestin recruitment. In contrast, GPR1, identified as an atypical GPCR, is characterized by its weak G protein signaling and its dependency on β-arrestin for internalization. A recent study published in Science has provided insights into the interaction between these two receptors and how they collaboratively mediate chemerin's actions.

Key Findings

• The researchers determined the structures of GPR1 when bound to chemerin and either β-arrestin 1 or β-arrestin 2, along with the GPR1–β-arrestin 1 complex in the absence of chemerin.
• The study reveals distinct binding modes between GPR1 and β-arrestin 1, demonstrating a transition from a "pre-coupled" state to a fully "engaged" state.
• Cholesterol was identified as essential for β-arrestin-2 engagement with GPR1, indicating a unique interaction platform compared to β-arrestin-1.

Mechanistic Insights into Arrestin-Dependent Modulation

This work builds on existing understandings of GPCR signaling by exploring the non-canonical signaling mechanisms that emerge from the engagement of arrestins with GPR1. Observations indicated that:

• β-arrestin 1 and β-arrestin 2 both interact with GPR1 but follow different signaling patterns.
• β-arrestin 2 predominantly engages with GPR1 in a single binding configuration that promotes receptor internalization.
• Endogenous fatty acids such as palmitoleic acid and palmitic acid enhance GPR1's binding to β-arrestin 1, aiding constitutive internalization.

Implications for Metabolic Diseases

Through their findings, the researchers emphasize the role of GPR1 as a scavenger receptor that fine-tunes chemerin signaling. This study suggests that the intricate relationship between lipid molecules and receptor dynamics could open up new avenues for therapeutic strategies aimed at treating obesity and associated inflammatory conditions. The unique binding patterns of β-arrestins with GPR1 posit new hypotheses about the physiological roles of these interactions in metabolic diseases.

“This work provides the first molecular characterization of GPR1 as a scavenger receptor, highlighting the complexity of GPCR signaling and the potential for targeted drug development.” – Heng Cai, Lead Researcher.

Conclusion

Overall, this research underscores the importance of understanding the structural and functional nuances of GPCRs like GPR1 and their interactions with arrestins. Further studies are needed to elucidate the therapeutic implications of these findings and their potential to mitigate metabolic disorders.

Sources

[1] Heng Cai et al, Noncanonical agonist-dependent and -independent arrestin recruitment of GPR1, Science, 2025.

[2] Medical Xpress. Retrieved from here.

For additional exploration of this topic, consider examining related articles on GPCR signaling and metabolic disease pathways.