Peripherally Administered Y2-Receptor Antagonist BIIE0246 Prevents Diet-Induced Obesity in Mice With Excess Neuropeptide Y, but Enhances Obesity in Control Mice

Neuropeptide Y (NPY) is a neurotransmitter associated with feeding and obesity. We have constructed an NPY transgenic mouse model (OE- mouse), where targeted overexpression leads to increased levels of NPY in noradrenergic and adrenergic neurons. We previously showed that these mice become obese on a normal chow. Now we aimed to study the effect of a Western-type diet in OE- and wildtype (WT) mice, and to compare the genotype differences in the development of obesity, insulin resistance, and diabetes. Weight gain, glucose, and insulin tolerance tests, fasted plasma insulin, and cholesterol levels were assayed. We found that female OE- mice gained significantly more weight without hyperphagia or decreased activity, and showed larger white and brown fat depots with no difference in UCP-1 levels. They also displayed impaired glucose tolerance and decreased insulin sensitivity. OE- and WT males gained weight robustly, but no difference in the degree of adiposity was observed. However, 40% of but none of the WT males developed hyperglycaemia while on the diet. The present study shows that female OE- mice were not protected from the obesogenic effect of the diet suggesting that increased NPY release may predispose females to a greater risk of weight gain under high caloric conditions.

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Effects of the neuropeptide Y Y2 receptor antagonist BIIE0246 on presynaptic inhibition by neuropeptide Y in rat hippocampal slices

European Journal of Pharmacology ◽

10.1016/s0014-2999(00)00478-7 ◽

2000 ◽

Vol 404 (1-2) ◽

pp. 133-136 ◽

Cited By ~ 32

Author(s):

Thomas Weiser ◽

Heike A Wieland ◽

Henri N Doods

Keyword(s):

Neuropeptide Y ◽

Receptor Antagonist ◽

Presynaptic Inhibition ◽

Hippocampal Slices ◽

Y2 Receptor

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Neuropeptide Y reduces expression of social fear via simultaneous activation of Y1 and Y2 receptors

Journal of Psychopharmacology ◽

10.1177/0269881119862529 ◽

2019 ◽

Vol 33 (12) ◽

pp. 1533-1539 ◽

Cited By ~ 3

Author(s):

Johannes Kornhuber ◽

Iulia Zoicas

Keyword(s):

Neuropeptide Y ◽

Receptor Antagonist ◽

Social Experience ◽

Fear Extinction ◽

Dependent Manner ◽

Contextual Fear ◽

Y1 Receptor ◽

Y2 Receptor ◽

Social Fear ◽

Simultaneous Activation

Background: Neuropeptide Y (NPY) has anxiolytic effects and facilitates extinction of cued and contextual fear in rodents, thereby acting as a resilience factor against exaggerated fear responses after adverse events. We investigated whether NPY influences acquisition, expression and extinction of social fear in a mouse model of social fear conditioning (SFC). Methods: NPY was administered intracerebroventricularly before SFC or before social fear extinction with or without prior administration of Y1 and/or Y2 receptor antagonists. Results: We show that NPY affects SFC-induced social fear in a time point–dependent manner. When administered before SFC, NPY did not affect acquisition, expression and extinction of social fear. However, when administered before social fear extinction, NPY reduced expression of social fear via simultaneous activation of Y1 and Y2 receptors. As such, neither the Y1 receptor antagonist BIBO3304 trifluoroacetate nor the Y2 receptor antagonist BIIE0246 was able to block the effects of NPY completely. However, when administered in combination, they completely blocked the effects of NPY on social fear expression. Conclusions: These findings have important clinical implications, as they suggest that although medication strategies aimed at increasing brain NPY activity are unlikely to prevent the formation of aversive memories after a traumatic social experience, they might improve the recovery from a traumatic social experience by reducing the expression of social fear.

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