To investigate the appetite regulation mechanism of low and high molecular weight yeast hydrolysate, neuropeptide Y (NPY) and tryptophan hydroxylase (TPH) expressions were analyzed in the brains on rats using immunohistochemical method; normal diet (control), 0.1 g/kg (BY-1) or 1.0 g/kg (BY-2) of yeast hydrolysate below 10 kDa, 0.1 g/kg (AY-1) or 1.0 g/kg (AY-2) of yeast hydrolysate of 10-30 kDa. Body weight gain was lower in the BY-2 (133.0 g) than in the control (150.1 g) (p < 0.05). Triacylglyceride, total cholesterol, and LDL-cholesterol levels were lower in the BY-2 as compared to control, BY-1 and AY-2 (p < 0.05). NPY staining intensities at paraventricular nucleus (PVN) were lower in the BY groups (BY-1: 96.1, BY-2: 88.6) as compared to the control (105.6) and AY groups (AY-1: 110.5, AY-2: 114.1) (p < 0.05). NPY expression at lateral hypothalamic area (LHA) was lower in the BY-2 (92.3) than in the control (98.9) (p < 0.05). The BY groups (BY-1: 143.9, BY-2: 154.6) had higher TPH staining intensities at dorsal raphe (DR) than the AY-2 (115.9) (p < 0.05). In conclusion, the results indicate that administering yeast hydrolysate of below 10 kDa to normal diet-fed rats reduced body weight gain and serum lipids by altering NPY and TPH expressions.