Y1 receptor deficiency in β-cells leads to increased adiposity and impaired glucose metabolism

Abstract

Insulin secretion from pancreatic β-cells is critical for maintaining glucose homeostasis and deregulation of circulating insulin levels is associated with the development of metabolic diseases. While many factors have been implicated in the stimulation of insulin secretion, the mechanisms that subsequently reduce insulin secretion remain largely unexplored. Here we demonstrate that mice with β-cell specific ablation of the Y1 receptor exhibit significantly upregulated serum insulin levels associated with increased body weight and adiposity. Interestingly, when challenged with a high fat diet these β-cell specific Y1-deficient mice also develop hyperglycaemia and impaired glucose tolerance. This is most likely due to enhanced hepatic lipid synthesis, resulting in an increase of lipid accumulation in the liver. Together, our study demonstrates that Y1 receptor signaling negatively regulates insulin release, and pharmacological inhibition of Y1 receptor signalling for the treatment of non-insulin dependent diabetes should be taken into careful consideration.

Peptide YY (1–36) peptides from phylogenetically ancient fish targeting mammalian neuropeptide Y1 receptors demonstrate potent effects on pancreatic β‐cell function, growth and survival

“…A more exciting area of PYY research in recent times relates to the beneficial effects of PYY (1–36) at the level of the endocrine pancreas . The NPYR1 is abundantly expressed on pancreatic β cells, with local islet synthesis and secretion of PYY (1–36) also noted . Indeed, there is a suggestion that the impressive endocrine pancreatic benefits following Roux‐en‐Y gastric bypass surgery are linked to altered PYY secretion and enhanced NPYR1 activity .…”

PYY, a Therapeutic Option for Type 2 Diabetes?

“…In in vitro experiments, addition of the NPY1R blocker BIBP3226 abolishes the potentiating effect of sitagliptin on insulin release, 28 while activation of NPY1R (and NPY4R, NPY5R) protects mouse and human islets from cytokine-induced apoptosis and restores their glucose responsiveness. 29 In vivo studies have also demonstrated that mice lacking NPY1R either in beta cells 42 or in osteoblasts 43 have impaired glucose tolerance, thus extending the impact of NPY signalling, that could be additionally modulated by NPY and pancreatic polipeptide, on glucose homeostasis beyond pancreatic tissue regulation. On the other hand, injection of lipidated-NPY analogues appears to be able to protect beta cells and reduce hyperglycaemia induced by multiple low doses of streptozotocin 29 thus mimicking the protective effect reported for PYY analogues.…”

Sex differences in behavioral and metabolic effects of gene inactivation: The neuropeptide Y and Y receptors in the brain

“…Comparison between male and female conditional knockout rodent models. Chao et al, 2011;Ste Marie et al, 2005;Baldock et al, 2007;Bertocchi et al, 2011Bertocchi et al, , 2020Statello et al, 2016;Longo et al, 2014Longo et al, , 2015Longo et al, , 2018Loh et al, 2018;Acton et al, 2019;Baldock et al, 2006;Allison et al, 2006;Shi et al, 2010;Tasan et al, 2010;McCall et al, 2013. ARC, hypothalamus arcuate nucleus; DMH, dorsomedial hypothalamus; HFD, high fat diet; nd, not determined; PP, pancreatic polypeptide; VGAT, vesicular GABA transporter; WAT, white adipose tissue. For references: blue characters, study performed only on males; black characters, study performed in both males and females.…”