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. 1. Introduction Neuropeptide Y (NPY) is one of the most common peptides in the brain and an abundant neurotransmitter in the peripheral sympathetic nervous system (SNS). NPY has been linked to several disorders associated with metabolic syndrome. It plays a well-established role in the hypothalamic control of body energy balance by promoting feeding and lipid storage in white adipose tissue (WAT) [1]. However, in pair-fed rats, central NPY administration still leads to increased fat accumulation, which suggests that NPY has an important role in promoting adiposity independent of food intake [2]. NPY outside the hypothalamus in the regulation of energy homeostasis has not been widely studied, although NPY and its receptors are located in key peripheral tissues, such as WAT, liver, and pancreas. NPY inhibits lipolysis in adipocytes via Y1 receptors [3], and could modulate adipose tissue expansion by regulating angiogenesis [4]. NPY also inhibits insulin release via pancreatic Y1 receptors [5]. On the other hand, NPY in the brainstem could modulate sympathetic tone, which is known to have multiple effects on energy homeostasis. To address the role of NPY colocalized with noradrenaline in SNS and brain noradrenergic neurons, we created a transgenic mouse model (OE- mouse), where NPY
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