INTRANASAL NPY PRODUCES Y2-DEPENDENT SUPPRESSION OF SUCROSE PREFERENCE IN OBESE MICE

Obesity is associated with increased risk of psychiatric disorders and altered reward processing. Neuropeptide Y (NPY) is one of the links between obesity, affective emotional behavior, and reward sensitivity. In this work, we tested whether a Western-like high-fat diet (HFD; 48% kcal from fat, primarily palm oil) induces behavioral alterations in mice and whether intranasal (i.n.) NPY (100 µg /mouse) modifies these outcomes. Male C57BL/6J mice were fed HFD or control diet for 8 weeks and then assessed for anxiety-like behavior (dark–light box), self-care (splash test), and anhedonia (sucrose intake and sucrose preference, SP). To provide mechanistic context, we assessed metabolic and inflammatory readouts. Diet-induced obesity produced anhedonia, with reduced sucrose intake and restricted SP (p < 0.05), without affecting anxiety-like or self-care behaviors. HFD lowered circulating corticosterone (p < 0.01), while plasma cytokines, colonic myeloperoxidase, and the tryptophan–kynurenine ratio remained unchanged. HFD also reduced hypothalamic NPY mRNA and peptide levels (p < 0.01). Unexpectedly, i.n. NPY further reduced sucrose intake and SP in HFD-fed mice measured 3 hours after administration (p < 0.01). Moreover, i.n. NPY reduced food intake and increased circulating corticosterone measured 3 hours after administration, irrespective of diet (p < 0.05). As the pattern pointed to Y2 receptor involvement, we evaluated i.n. NPY in Y2 receptor–knockout, HFD-fed mice, in which it no longer affected sucrose intake, SP, or food intake—supporting Y2-dependent actions. Our findings warrant further study of i.n. NPY, as its effects differed from those of regional or intracerebroventricular injections.