Newly synthesized fatty acid analogue (NKS-3) rescues microglial reactivity in a murine model of diet-induced obesity

Obesity is a major risk factor for metabolic and neuropsychiatric disorders. High-fat diets have been shown to trigger systemic and central inflammation, particularly in the hypothalamus. The lingual CD36 receptor plays a crucial role in oro-gustatory perception and is downregulated in individuals with obesity. NKS-3, a non-caloric high affinity CD36 agonist, exerts systemic anti-inflammatory effects by reducing pro-inflammatory cytokines; however, its potential impact on neuroinflammation is not known. C57BL/6 male mice were fed with either a high-fat (HFD) or a standard (STD) diet for 12 weeks, followed by a 5-week treatment with either vehicle, a 0.2% linoleic acid solution (LA), or a 50µM NKS-3 solution. We assessed the effect of NKS-3 administration on emotionality using a battery of behavioural tests, as well as its influence on central inflammation. For this purpose, mouse brains were fixed after treatment for immunofluorescence staining targeting microglia-specific calcium binding proteins (IBA-1). Neuroinflammation was assessed by comparing the relative expression of IBA-1 and microglial density between experimental conditions in multiple cortical, subcortical, and hypothalamic regions. The behavioural evaluation revealed an anxio-depressive-like effect of sustained HFD regimen, which was not attenuated by NKS-3 administration. Animals fed a HFD exhibited elevated IBA-1 relative expression and increased microglial densities compared to those under the STD. This effect was counteracted in animals treated with NKS-3. Consequently, our findings suggest that NKS-3 possesses anti-neuroinflammatory properties at the central level. The observed robust anti-inflammatory effects support the potential utility of NKS-3 as a valuable pharmacological tool for treating obesity-related inflammation.