The metabolic syndrome in mice overexpressing neuropeptide Y in noradrenergic neurons

Abstract

A gain-of-function polymorphism in human neuropeptide Y () gene (rs16139) associates with metabolic disorders and earlier onset of type 2 diabetes (T2D). Similarly, mice overexpressing NPY in noradrenergic neurons (OE-NPY) display obesity and impaired glucose metabolism. In this study, the metabolic syndrome-like phenotype was characterized and mechanisms of impaired hepatic fatty acid, cholesterol and glucose metabolism in pre-obese (2-month-old) and obese (4-7-month-old) OE-NPY mice were elucidated. Susceptibility to T2D was assessed by subjecting mice to high caloric diet combined with low-dose streptozotocin. Contribution of hepatic Y1-receptor to the phenotype was studied using chronic treatment with an Y1-receptor antagonist, BIBO3304. Obese OE-NPY mice displayed hepatosteatosis and hypercholesterolemia preceded by decreased fatty acid oxidation and accelerated cholesterol synthesis. Hyperinsulinemia in early obese state inhibited pyruvate- and glucose-induced hyperglycemia, and deterioration of glucose metabolism of OE-NPY mice developed with aging. Furthermore, streptozotocin induced T2D only in OE-NPY mice. Hepatic inflammation was not morphologically visible, but upregulated hepatic anti-inflammatory pathways and increased 8-isoprostane combined with increased serum resistin and decreased interleukin 10 pointed to increased NPY-induced oxidative stress that may predispose OE-NPY mice to insulin resistance. Chronic treatment with BIBO3304 did not improve the metabolic status of OE-NPY mice. Instead, downregulation of beta-1-adrenoceptors suggests indirect actions of NPY via inhibition of sympathetic nervous system. In conclusion, changes in hepatic fatty acid, cholesterol and glucose metabolism favoring energy storage contribute to the development of NPY-induced metabolic syndrome, and the effect is likely mediated by changes in sympathetic nervous system activity.

Increased Energy Expenditure, Lipolysis and Hyperinsulinemia Confer Resistance to Central Obesity and Type 2 Diabetes in Mice Lacking Alpha2α-Adrenoceptors

“…Hepatic triglycerides were assayed from liver samples (n = 3-4/group) according to a previously published method [36]. Expression of genes related to β-oxidation, and fatty acid (FA) storage and metabolism were studied with qPCR.…”

Metformin normalizes the structural changes in glycogen preceding prediabetes in mice overexpressing neuropeptide Y in noradrenergic neurons

“…The glycogen structure was elucidated in a genetically modified mouse model of prediabetes, OE‐NPY DβH mouse, at an age prior to manifestation of overt IGT in order to evaluate our previous findings of increased hepatic glycogen cycling (ie, increased mRNA expression of glycogen synthase and phosphorylase) preceding glycogen accumulation . Despite equal glycogen contents and similar glucose tolerance between the genotypes, changes in the molecular structure of glycogen in OE‐NPY DβH hepatocytes, that is, increased content of the stabile fraction and decreased content of the labile fraction supported by decreased filling of the 10th tier in the glycogen molecules, suggest that increased glycogen synthesis and degradation takes place before prediabetes.…”

“…Homozygous male OE‐NPY DβH mice (n = 9‐11/group) were used in this study with their wild‐type (WT) controls. Generation of the transgenic homozygous OE‐NPY DβH mice, maintained on a C57BL/6N inbred background, and their metabolic phenotype have been described in detail previously . The age of the mice in the current experiment was 4 months at the initiation of metformin treatment, which is the borderline age when the first signs of IR (ie, increased glucose‐stimulated insulinemia and IGT) start to emerge eventually leading to clear prediabetic phenotype at the age of 7 months.…”

“…These mice are known to develop prediabetes with obesity, IR and IGT with age, and show increased susceptibility to T2D induced by high caloric diet and low-dose streptozotocin. [24][25][26] Hepatic accumulation of triglycerides and glycogen seem to play an important role in the development of prediabetes and streptozotocin-induced diabetes in the model. 24 Our previous findings suggest that increased glycogen cycling precedes glycogen accumulation, but it is not known, whether the changes are detected also in the glycogen structure.…”

“…The state preceding impaired glucose tolerance (IGT) was modeled by a transgenic mouse overexpressing neuropeptide Y (NPY) in noradrenergic neurons (OE‐NPY DβH ). These mice are known to develop prediabetes with obesity, IR and IGT with age, and show increased susceptibility to T2D induced by high caloric diet and low‐dose streptozotocin . Hepatic accumulation of triglycerides and glycogen seem to play an important role in the development of prediabetes and streptozotocin‐induced diabetes in the model .…”