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.
Highlights
Glucose homeostasis is a tightly regulated process coordinated by insulin and glucagon secretion
Since it has been reported that INS2-cre expression is found in the brain, we performed radio-ligand binding experiments on hypothalamic slices derived from control and Y1lox/lox/INS2cre/+ mice using the Y1 receptor preferring radiolabeled ligand, [Leu31,Pro34]neuropeptide Y (NPY)
Hypothalamic Y1 receptor expression were similar in control and Y1lox/lox/INS2cre/+ mice as assessed by quantitative RT-PCR (Supplementary Fig. 1b), demonstrating that Y1 receptor expression in the hypothalamus is unaffected by INS2-cre expression
Summary
Glucose homeostasis is a tightly regulated process coordinated by insulin and glucagon secretion. Located within the islets of Langerhans, pancreatic β-cells synthesize the hormone insulin, which is secreted primarily in response to elevated blood glucose concentrations[1,2]. In addition to this glucose dependent pathway, it is widely recognised that nutrients and hormones such as leptin, fatty acids, growth hormone and glucagon like peptide-1 (GLP-1) can regulate insulin release[3,4,5]. PYY, a 36 amino acid peptide released from L-type cells of the gut and a member of the NPY family, is well recognised for its role to inhibit feeding and increase energy expenditure through activation of hypothalamic Y-receptors[13,16,17]. The global deletion of Y1 receptors in mice leads to the development of obesity and impaired feeding[13,16,33], and it remains unclear as to whether hyperinsulinemia is the direct cause of Y1 receptor deficiency in the pancreas or the secondary effect of obesity
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