Insulin-like peptide 5 is an orexigenic gastrointestinal hormone

Abstract

The gut endocrine system is emerging as a central player in the control of appetite and glucose homeostasis, and as a rich source of peptides with therapeutic potential in the field of diabetes and obesity. In this study we have explored the physiology of insulin-like peptide 5 (Insl5), which we identified as a product of colonic enteroendocrine L-cells, better known for their secretion of glucagon-like peptide-1 and peptideYY. i.p. Insl5 increased food intake in wild-type mice but not mice lacking the cognate receptor Rxfp4. Plasma Insl5 levels were elevated by fasting or prolonged calorie restriction, and declined with feeding. We conclude that Insl5 is an orexigenic hormone released from colonic L-cells, which promotes appetite during conditions of energy deprivation.

A causal role for hyperinsulinemia in obesity

“…These mammalian peptides appear to be derived from a shared ancestral gene and have structural similarities, although the known biological functions of the majority of these peptides appear largely distinct from those of insulin and IGF1 (Shabanpoor et al 2009). However, a recent study showed that insulin-like peptide 5 produced by enteroendocrine cells acts as an orexigenic hormone with circulating levels that change in response to feeding status, which suggests that this peptide also plays a role in coordinating energy homeostasis (Grosse et al 2014).…”

Gut chemosensing mechanisms

“…However, a recent study identified insulin-like 5 (INSL5) as an additional orexigenic gut peptide, produced by colonic L cells in response to caloric restriction. INSL5 is thought to increase food intake by acting on the relaxin family peptide receptor (RXFP4) (20).…”

“…Subsets of enteric neurons are also thought to express CCK1 and GLP2 receptors (142,143) and have additionally been found to contain Rxfp4, potentially mediating responses to the orexigenic gut hormone INSL5 (20). Whether these receptors are located in the same or in different individual neurons remains to be established.…”

International Union of Basic and Clinical Pharmacology. XCV. Recent Advances in the Understanding of the Pharmacology and Biological Roles of Relaxin Family Peptide Receptors 1–4, the Receptors for Relaxin Family Peptides

“…INSL5 is widely distributed with high expression in the gastrointestinal tract (Conklin et al, 1999) particularly in L cells isolated from mouse colon/rectum but also in ascending, transverse, and descending colon and proximal rectum, with lower levels in the cecum and distal rectum (Grosse et al, 2014). Low levels of Insl5 mRNA were found in the pancreas, thymus, and eye (Grosse et al, 2014).…”

“…Low levels of Insl5 mRNA were found in the pancreas, thymus, and eye (Grosse et al, 2014). INSL5 knockout mice display dysfunctional glucose homeostasis (Burnicka-Turek et al, 2012).…”