Neuropeptide Y Signaling in the Lateral Hypothalamus Modulates Diet Component Selection and is Dysregulated in a Model of Diet-Induced Obesity

The preclinical multicomponent free-choice high-fat high-sucrose (fcHFHS) diet has strong validity to model diet-induced obesity (DIO) and associated maladaptive molecular changes in the central nervous system. fcHFHS-induced obese rats demonstrate increased sensitivity to intracerebroventricular infusion of the orexigenic Neuropeptide Y (NPY). The brain region-specific effects of NPY signaling on fcHFHS diet component selection are not completely understood. For example, fcHFHS-fed rats have increased intake of chow and fat following intracerebroventricular NPY infusion, whereas NPY administration in the nucleus accumbens, a key hub of the reward circuitry, specifically increases fat intake. Here, we investigated whether NPY infusion in the lateral hypothalamic area (LHA), which is crucially involved in the regulation of intake, regulates fcHFHS component selection, and if LHA NPY receptor subtypes 1 or 5 (NPYR1/5) are involved. Male Wistar rats were fed a chow or fcHFHS diet for at least seven days, and received intra-LHA vehicle or NPY infusions in a cross-over design. Diet component intake was measured two hours later. Separate experimental designs were used to test the efficacy of NPY1R- or NPY5R antagonism to prevent the orexigenic effects of intra-LHA NPY. Intra-LHA NPY increased caloric intake in chow- and fcHFHS-fed rats. This effect was mediated specifically by chow intake in fcHFHS-fed rats. The orexigenic effects of intra-LHA NPY were prevented by NPY1R and NPY5R antagonism in chow-fed rats, but only by NPY5R antagonism in fcHFHS-fed rats. Thus, NPY signaling has brain region-specific effects on fcHFHS component selection and LHA NPYR sensitivity is dysregulated during consumption of a fcHFHS diet.