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Characterization of Neuropeptide Y (NPY) Y5 Receptor-Mediated Obesity in Mice: Chronic Intracerebroventricular Infusion of D-Trp³⁴NPY

Tsukuba Research Institute (S.M., A.I., H.I., H.S., Z.O., J.I., M.Y., M.O., J.S., T.Fuku., M.J., M.I., T.Fuka., A.K.), Banyu Pharmaceutical Co., Ltd., Tsukuba 300-2611, Japan; and Merck Research Laboratories (N.R.M., D.J.M., L.H.T.V.d.P.), Merck \|[amp ]\| Co., Inc., Rahway, New Jersey 07065

Address all correspondence and requests for reprints to: Dr. Akane Ishihara, Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., Okubo 3, Tsukuba 300-2611, Japan. E-mail: isihraan{at}banyu.co.jp.

To clarify the role of the neuropeptide Y (NPY) Y5 receptor subtype in energy homeostasis, the effect of the intracerebroventricular infusion of a selective Y5 agonist, D-Trp³⁴NPY, was investigated in C57BL/6J mice. Intracerebroventricular infusion of D-Trp³⁴NPY (5 and 10 µg/d) produced hyperphagia and body weight gain, accompanied by increased adipose tissue weight, hypercholesterolemia, hyperinsulinemia, and hyperleptinemia. Oral administration of a selective Y5 antagonist at a dose of 100 mg/kg twice a day completely suppressed all of these D-Trp³⁴NPY-induced changes, indicating that chronic activation of the Y5 receptor produces hyperphagia and obesity. In addition, D-Trp³⁴NPY still resulted in an increase in adipose tissue weight accompanied by hyperleptinemia and hypercholesterolemia, although D-Trp³⁴NPY-induced food intake was restricted by pair-feeding. Under the pair-fed condition, D-Trp³⁴NPY decreased hormone-sensitive lipase activity in white adipose tissue and uncoupling protein-1 mRNA expression in brown adipose tissue. These findings indicate that Y5-mediated obesity may involve metabolic changes, such as decreased lipolysis and thermogenesis, as well as hyperphagia. Therefore, the Y5 receptor can play a key role in regulating energy homeostasis.

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