Neuromedin U receptor 2 knockdown in the paraventricular nucleus modifies behavioral responses to obesogenic high-fat food and leads to increased body weight

Abstract

Neuromedin U (NMU) is a highly conserved neuropeptide which regulates food intake and body weight. Transgenic mice lacking NMU are hyperphagic and obese, making NMU a novel target for understanding and treating obesity. Neuromedin U receptor 2 (NMUR2) is a high-affinity receptor for NMU found in discrete regions of the central nervous system, in particular the paraventricular nucleus of the hypothalamus (PVN), where it may be responsible for mediating the anorectic effects of NMU. We hypothesized that selective knock down of NMUR2 in the PVN of rats would increase their sensitivity to the reinforcing properties of food resulting in increased intake and preference for high-fat obesogenic food. To this end, we used viral-mediated RNAi to selectively knock down NMUR2 gene expression in the PVN. In rats fed a standard chow, NMUR2 knockdown produced no significant effect on food intake or body weight. However, when the same rats were fed a high-fat diet (45% fat), they consumed significantly more food, gained more body weight, and had increased feed efficiency relative to controls. Furthermore, NMUR2 knockdown rats demonstrated significantly greater binge-type food consumption of the high-fat diet and showed a greater preference for higher-fat food. These results demonstrate that NMUR2 signaling in the PVN regulates consumption and preference for high-fat foods without disrupting feeding behavior associated with non-obesogenic standard chow.

Gamma-Aminobutyric Acidergic Projections From the Dorsal Raphe to the Nucleus Accumbens Are Regulated by Neuromedin U

“…The grids were place on drops of the following solutions: normal goat serum diluted in Tris buffer (5%, 1 hour); NMUR2 antiserum (1:25, Novus Biologicals, Littleton, CO; NBP1-02351, 24 hours), goat anti-rabbit IgG-gold (20 nm, Ted Pella, Redding, CA; 1 hour), rinsed and post-stained prior to analysis. Specificity of the NMUR2 antibody was previously validated (26). Additionally, grids incubated in diluent lacking the primary antisera resulted in a complete lack of immunogold staining on the grids.…”

“…Colocalization of the tracer virus expressing green fluorescent protein (GFP) with NMUR2 in the NAcSh was visualized using fluorescent immunohistochemistry (26). Briefly, the sections were unmasked, blocked and incubated in primary antibodies.…”

“…The knockdown vector used was an AAV6 with shRNA against Nmur2 or scrambled shRNA control (26) that was microinjected bilaterally into the NAcSh. Total microinjection volume for NAcSh was 2 µL.…”

Fat Preference: A Novel Model of Eating Behavior in Rats

“…Lastly, our results could be interpreted as a preference for lower carbohydrates and not for higher fat. However, rats prefer increasing (not decreasing) carbohydrate content 14,15 reducing the validity of this interpretation.…”

“…As the rats have a bias toward eating high-fat food, a significantly decreased preference high-fat food represents a possible pharmacologically relevant change in food composition choices. Indeed, neuromedin U receptor 2 expression has recently been shown to alter fat preference using this model 15 . The colored food (Table 1) makes it easy to determine any spillage before daily food weighing (Figure 2).…”