INSL5-Deficient Mice Display an Alteration in Glucose Homeostasis and an Impaired Fertility

Abstract

Insulin-like factor 5 (INSL5), a member of the insulin superfamily, is expressed in the colorectum and hypothalamus. To facilitate studies into the role of INSL5, we generated Insl5(-/-) mice by gene targeting. Insl5(-/-) mice were born in the expected Mendelian ratio, reached normal body weight, but displayed impaired male and female fertility that are due to marked reduction in sperm motility and irregular length of the estrous cycle. Furthermore, Insl5(-/-) mice showed impairment in glucose homeostasis with characteristic elevation of serum glucose levels at an advanced age. Glucose and insulin tolerance tests revealed that the increased blood glucose in Insl5(-/-) mice was due to glucose intolerance resulting from reduced insulin secretion. Morphometric and immunohistological analyses revealed that the Insl5(-/-) mice had markedly reduced average islets area and β-cell numbers. Furthermore, immunohistochemistry showed the expression of INSL5 in enteroendocrine cells in the colorectal epithelium and the presence of its putative receptor relaxin family peptide receptor 4 in pancreatic islet cells. These results suggest the potential role of INSL5 signaling in the regulation of insulin secretion and β-cell homeostasis.

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 the cognate ligand for RXFP4 (Liu et al, 2005b). INSL5 has many of the characteristics of an incretin being secreted from enteroendocrine L cells and regulating insulin secretion and glucose homeostasis (Burnicka-Turek et al, 2012). Synthesis of human INSL5 represents considerable challenges so that some of the characterization of the peptide has been performed with mouse INSL5 that has 71% homology (Belgi et al, 2011).…”

“…RXFP4 mRNA is present in a variety of human tissues including brain, kidney, testis, thymus, placenta, prostate, salivary gland, thyroid, and colon (Liu et al, 2005b; Burnicka-Turek et al, 2012; Mashima et al, 2013;Thanasupawat et al, 2013). Many of these tissues also express INSL5 (Burnicka-Turek et al, 2012;Mashima et al, 2013;Thanasupawat et al, 2013), and both RXFP4 and Insl5 are pseudogenes in rats and dogs Wilkinson et al, 2005a). INSL5 was shown to be a high-affinity ligand for RXFP4 (Liu et al, 2005b), and thus the receptor-ligand coevolution, pharmacology, and similarities in expression profiles strongly indicate that RXFP4 is the endogenous receptor for INSL5.…”

“…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). INSL5 activates RXFP4, but not RXFP1 or RXFP2, with high potency and is a weak antagonist at RXFP3 (Liu et al, 2005b).…”

Insulin-like peptide 5 is an orexigenic gastrointestinal hormone

“…Although some members of the relaxin family have important roles in reproductive physiology and remodeling of connective tissue, the functions of others, including Insl5, have remained elusive (13). One recent report suggested a role of Insl5 in insulin secretion, based on the initial observation of impaired glucose tolerance in aging Insl5 −/− mice; however, the phenotype was mild and only observed on a 129/Sv, but not on a C57B6, genetic background (14).…”

Regulation of the reproductive cycle and early pregnancy by relaxin family peptides

“…However, the INSL5 knockout mouse displays impaired fertility in both males and females (Burnicka-Turek et al, 2012). In the female there appear to be no significant differences from wild type in regard to numbers of oocytes ovulated, follicle number or number of corpora lutea.…”