Central nervous system IL-17R expression influences weight gain by altering food-intake and fat-mass accumulation

Abstract

Abstract Cytokines influence innate behaviors in mice and IL-17a may function within the hypothalamus to reduce food-intake. We examine contributions of nervous system IL-17R expression on mouse feeding behavior following obesogenic diet exposure. We crossed IL-17Ra f/fand Synapsin1-Cre or Na v1.8-Cre mice to generate pan-neuronal (Syn-Cre IL-17Ra f/f) or peripheral neuronal- (Na-v1.8-Cre IL17Ra f/f) IL-17R knockout mice, respectively. Body weights of male and female mice were measured over 10-weeks of 60% high-fat diet (HFD) feeding. 60% HFD fed male Syn-Cre IL-17Ra f/fand IL-17Ra f/fmice underwent metabolic phenotyping and body composition analyses. Syn-Cre IL-17Ra f/fand IL-17Ra f/fmice received CNS penetrant Nrf2 activator Dimethyl-Fumarate (DMF) to assess whether pharmacological inhibition of IL-17a secretion alters HFD induced weight gain. Male and female Syn-Cre IL-17Ra f/fbut not Na-v1.8-Cre IL17Ra f/fmice displayed a 15–20% reduction in bodyweight after 10-weeks of HFD feeding (male p=0.00046, female p=0.0061). DMF treatment did not impact body weight. Syn-Cre IL-17Ra f/ftrended towards a reduction in food-intake and meal numbers when compared to IL-17Ra f/fmice. Syn-Cre IL-17Ra f/fhad a significant reduction in fat mass (total p=0.01, %total p=0.04) and lean mass (total p=0.03 and %total p=0.04). In sum, loss of central but not peripheral nervous system expression of IL-17R robustly and significantly blunts weight gain following chronic exposure to an obesogenic diet. This decrease in body weight was associated with a decrease in total fat mass. Our data suggest that a population of IL-17R expressing neurons within the brain influence food-intake by modulating feeding behaviors associated with meal frequency. NIH funding sources include F31-DK127728 and T32-DK07563