There is no common consensus on the physiological role of insulin-like peptide 5 (INSL5) and its cognate receptor, relaxin family peptide receptor 4 (RXFP4). The experimental data for INSL5-RXFP4 expression and function point to a potential role of the peptide hormone and receptor pair in linking energy availability, homeostasis, and inflammation. In this review, we summarize studies on the INSL5-RXFP4 system and propose that the current findings from diverse experimental settings point broadly to a role as a protective energy sensor (PES). Specifically, we review the evidence that (1) INSL5-RXFP4 could regulate immune response by decreasing the production of proinflammatory cytokines and may be involved in the stress response via the HPA axis; (2) INSL5-RXFP4 may signal through sensory neurons on the vagus nerve, transmitting signals to the CNS; and (3) INSL5-RXFP4 could have local autocrine/paracrine roles within the intestinal tract and immune cells. Further investigation and clarification of these proposed roles of INSL5-RXFP4 may prove a greater physiological relevance for the pair and add to existing evidence of INSL5-RXFP4 role as a PES.
Keywords: INSL5; L-cells; RXFP4; energy homeostasis; gastrointestinal tract; gut microbiome; immunometabolism; inflammation; protective energy sensor.