Intranasal neuropeptide Y suppresses food intake, reduces sucrose preference and increases circulating corticosterone in obese mice

Obesity is associated with an increased risk of psychiatric disorders and altered reward processing. Neuropeptide Y (NPY) links metabolic state, reward-driven behavior, and emotional processing. We therefore tested whether intranasal (i.n.) NPY modifies high-fat diet (HFD)-induced behavioral alterations. Male C57BL/6J mice were fed HFD (48% kcal fat) or control diet for 8 weeks and assessed for anxiety-like behavior using the light/dark box test (LDT), self-care behavior using the splash test, and sucrose-directed ingestive behavior using sucrose intake and sucrose preference (SP). A separate cohort of control- and HFD-fed mice received i.n. NPY or vehicle, followed by assessment of SP and ingestive behavior after 3, 24 and 48 h. Neuroendocrine and inflammatory parameters were measured in blood, brain, and colon. HFD reduced sucrose-directed ingestive behavior, reflected by reduced sucrose intake and SP, without significantly affecting anxiety-like behavior in the LDT or self-care behavior in the splash test. HFD reduced hypothalamic Npy mRNA and peptide levels as well as circulating corticosterone, while the evaluated inflammation-related markers remained unchanged. I.n. NPY had no effect after 24 or 48 h but reduced sucrose intake and SP, and increased circulating corticosterone 3 h after administration specifically in HFD-fed animals. In contrast, i.n. NPY reduced food intake and body weight after 3 h, independent of diet. Because these effects were consistent with neuropeptide Y receptor Y2 (NPY2R)-mediated actions, we tested i.n. NPY in HFD-fed Npy2r-deficient mice. In these mice, i.n. NPY did not affect sucrose intake, SP, food intake, or corticosterone, consistent with a potential involvement of NPY2R.