Neuromedin U suppresses insulin secretion by triggering mitochondrial dysfunction and endoplasmic reticulum stress in pancreatic β‐cells

Abstract

Neuromedin U (NMU), a highly conserved peptide in mammals, is involved in a wide variety of physiological processes. NMU, which is synthesized in β‐cells and co‐localizes with insulin, directly acts on β‐cells via NMU receptor 1 (NMUR1) to suppress glucose‐stimulated insulin secretion (GSIS). The mechanism underlying this insulinostatic effect has yet to be elucidated. We observed that NMU caused mitochondrial dysfunction by impairing mitochondrial biogenesis, respiration, and mitochondrial Ca2+ uptake in β‐cell‐derived MIN6‐K8 cells. NMU administration induced the endoplasmic reticulum (ER) stress, as reflected by the activation of ER stress signaling pathways involving ATF6, XBP‐1s, and PERK‐ATF4‐CHOP. Nmu knockdown in MIN6‐K8 cells increased the number of insulin granules and improved mitochondrial biogenesis and function. NMU was upregulated in both the islets of db/db mice and palmitate‐treated MIN6‐K8 cells. Our results highlight the crucial role of NMU in the maintenance of β‐cell function and glucose metabolism through regulation of mitochondria dysfunction and ER stress. In pathological stages that develop into diabetes, upregulation of NMU could suppress the insulin secretion by inducing mitochondrial dysfunction and ER stress, which may contribute to subsequent β‐cell dysfunction.

Neuromedin S Regulates Steroidogenesis through Maintaining Mitochondrial Morphology and Function via NMUR2 in Goat Ovarian Granulosa Cells

“…Moreover, NMS is an isoform of NMU and plays many physiological roles similar to NMU by binding to NMUR1 and NMUR2. As reported, NMU can act directly on β cells through NMUR1 to affect insulin secretion [ 26 , 27 ], and both NMU and NMS can regulate the synthesis and release of LH and FSH from the pituitary through NMUR2 [ 24 , 28 , 29 ]. These results suggest that NMS may regulate different types of hormones through different receptors.…”

Neuromedins NMU and NMS: An Updated Overview of Their Functions

“…A new perspective on the insulinostatic role of NMU is presented by the group of Zhang et al (40,110). These authors highlight the colocalization of NMU and insulin in pancreatic bcells.…”

The association of Neuromedin U levels and non-alcoholic fatty liver disease: A comparative analysis

“…It has been shown that rats have increased insulin sensitivity following NmU injection [ 66 ]. In another clinical study, it has been demonstrated that NmU suppresses glucose-induced insulin secretion through mitochondrial dysfunction and endoplasmic reticulum [ 67 ]. In our study, we observed that the NmU level was significantly lower in patients with NAFLD, but NmU was not identified as an independent risk factor.…”