Neuropeptide Y (NPY) is a potent feeding stimulant. The orexigenic effect of NPY might be caused in part by the action of Y1 receptors. However, the existence of multiple NPY receptors including a possible novel feeding receptor has made it difficult to determine the relative importance of the Y1 receptor in feeding regulation. Herein we certified that the Y1 receptor is a major feeding receptor of NPY by using the potent and selective Y1 antagonist (-)-2-[1-(3-chloro-5-isopropyloxycarbonylaminophenyl)ethylamino]-6-[2-(5-ethyl-4-methyl-1,3-thiazol-2-yl)ethyl]-4-morpholinopyridine (J-115814) and Y1 receptor-deficient (Y1-/-) mice. J-115814 displaced (125)I-peptide YY binding to cell membranes expressing cloned human, rat, and murine Y(1) receptors with K(i) values of 1.4, 1.8, and 1.9 nM, respectively, and inhibited NPY (10 nM)-induced increases in intracellular calcium levels via human Y1 receptors (IC(50) = 6.8 nM). In contrast, J-115814 showed low affinities for human Y2 (K(i) > 10 microM), Y4 (K(i) = 640 nM) and Y5 receptors (K(i) = 6000 nM). Intracerebroventricular (ICV) (10-100 microg) and intravenous (IV) (0.3-30 mg/kg) administration of J-115814 significantly and dose-dependently suppressed feeding induced by ICV NPY (5 microg) in satiated Sprague-Dawley rats. Intraperitoneal (IP) administration of J-115814 (3-30 mg/kg) significantly attenuated spontaneous feeding in db/db and C57BL6 mice. Feeding induced by ICV NPY (5 microg) was unaffected by IP-injected J-115814 (30 mg/kg) in Y1-/- mice and was suppressed in wild-type and Y5-/- mice. These findings clearly suggest that J-115814 inhibits feeding behaviors through the inhibition of the typical Y1 receptor. We conclude that the Y1 receptor plays a key role in regulating food intake.

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Nociceptin/orphanin FQ (N/OFQ), an endogenous ligand for opioid receptor-like 1 (ORL1), is involved in various central functions, such as pain, psychological stress, locomotor activity, learning and memory, and feeding regulation. Of these functions, the role of N/OFQ in the regulation of feeding has been suggested by the fact that the central administration of N/OFQ leads to feeding behavior. However, the manner in which N/OFQ influences body weight control and subsequent obesity is unclear. To clarify the involvement of N/OFQ in the development of obesity, we evaluated the effects of intracerebroventricular infusion of N/OFQ on food intake and body weight in C57BL/6J mice that were fed a regular chow diet or moderately high-fat (MHF) diet (32.6% kcal fat). N/OFQ significantly increased food intake and body weight both in the regular diet- and MHF diet-fed mice, and these changes were more apparent in the MHF diet-fed mice. When we performed a pair-feeding study in N/OFQ intracerebroventricularly infused mice, N/OFQ did not cause body weight gain but increased white adipose tissue weight and plasma leptin, insulin, and cholesterol levels. N/OFQ reduced rectal temperature in pair-fed mice, in keeping with decreased UCP1 mRNA expression in brown adipose tissue. These results suggest that N/OFQ contributes to the development of obesity not only by inducing hyperphagia but also by decreasing energy expenditure.

An experiment was conducted to examine whether a potent, orally active and highly selective neuropeptide Y Y1 receptor antagonist attenuates hyperphagia and obesity in genetically obese Zucker fatty rats. Oral administration of the Y1 antagonist (30 and 100 mg kg−1, once daily for 2 weeks) significantly suppressed the daily food intake and body weight gain in Zucker fatty rats accompanied with a reduction of fat cell size and plasma corticosterone levels. Despite the fact that food intake was gradually returned to near the control level, the body weight of the treated animals remained significantly less when compared to that of the controls for the duration of the treatment. These results suggest that the Y1 receptor, at least in part, participate in pathophysiological feeding and/or fat accumulation observed in Zucker fatty rats. Y1 antagonists might be useful for the treatment of obesity. British Journal of Pharmacology (2002) 136, 341–346; doi:

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