SEX-DEPENDENT RESPONSES TO THE FAT-TASTE ENHANCER NKS-3 IN A MURINE MODEL OF DIET-INDUCED OBESITY

Obesity is a major risk factor for metabolic and neuropsychiatric disorders, and is associated with systemic and central inflammation. Although obesity-related behavioural and inflammatory alterations exhibit sex differences, female individuals remain underrepresented in preclinical studies. The lingual fatty acid receptor CD36, involved in oro-gustatory fat perception and hedonic regulation of food intake, is downregulated following exposure to high-fat diets (HFD). NKS-3, a non-caloric high-affinity CD36 agonist, can be used as a pharmacological tool to modulate fat-taste signalling and to reduce obesity-induced inflammation. Whether CD36-targeted strategies such as NKS-3 differentially affect male and female individuals’ remains unclear. Here we used C57BL/6 mice to model diet-induced obesity. Animals were fed either a standard or HFD for 12 weeks, before being treated with NKS-3 (50 µM) or vehicle. The effects of NKS-3 were explored in male mice at different treatment durations and in females following prolonged exposure. Behavioural testing, metabolic measurements and extensive post-mortem analyses allowed us to evaluate sexual differences in obesity-related alterations and NKS-3 effects. Our preliminary results show an anxious-depressive-like phenotype induced by HFD which was more pronounced in male than female mice, and no significant improvement following NKS-3 treatment. Obese animals exhibited glucose intolerance and hyperinsulinemia, with NKS-3 reducing insulin levels only in male mice. NKS-3 also reduced obesity-induced neuroinflammation and normalized neuronal activation within the arcuate nucleus in obese male mice. Together, these findings highlight sex-dependent behavioural and metabolic responses to obesity and treatment response, and suggest a dissociation between inflammatory and behavioural outcomes.