{"doi":"10.1101/2025.09.11.675492","title":"Novel fat-taste enhancers modulate functional connectivity of the reward system following sustained activation of gustatory pathways in mice","abstract":"Abstract Humans and rodents exhibit an innate preference for dietary fat, and dysfunction of lingual fat-taste receptors CD36 and GPR120 in obesity suggests that impaired oro-sensory lipid detection may contribute to its development. Rodent models with reduced fat-taste sensitivity display increased fat intake, highlighting the role of taste perception in dietary regulation. The newly developed NKS-3 and NKS-5, high-affinity agonists for CD36 and CD36/GPR120 receptors, respectively, induce early fat satiation and reduce both fat-rich food intake and body weight gain in diet-induced obese mice. However, the neural mechanisms underlying these effects remain unclear. Here, we investigated the response of the reward system to a sustained activation of CD36 and GPR120 via fat-taste enhancers NKS-3 and NKS-5 compared to linoleic acid (LA). Male C57BL/6JRj mice (N=88) received oral administration of vehicle, 0.2% LA, 50 µM NKS-3 or 75 µM NKS-5 for 10 days. The immunohistochemical analysis of cerebral FosB neuronal expression revealed a reorganization of the functional network connectivity. Behavioral assessments over an additional 10-day period in a second cohort of animals detected no adverse motivational, compulsive-like, depressive or anxiogenic effect of the treatments. Our findings suggest that our fat-taste enhancers may offer a promising therapeutic strategy against obesity, leveraging the oral-gut-brain axis to regulate fat-rich food intake.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":574965,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9464,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1482992,"name":"Lucas Jantzen","orcid":null,"position":1,"is_corresponding":false},{"id":1482993,"name":"C Houdayer","orcid":null,"position":2,"is_corresponding":false},{"id":859519,"name":"Émmanuel Haffen","orcid":"0000-0002-4091-518X","position":3,"is_corresponding":false},{"id":1482568,"name":"Aziz Hichami","orcid":"0000-0003-4331-5152","position":4,"is_corresponding":false},{"id":1217087,"name":"Naim Akhtar Khan","orcid":"0000-0002-8930-9332","position":5,"is_corresponding":false},{"id":1365183,"name":"Vincent Van Waes","orcid":"0000-0003-0568-7836","position":6,"is_corresponding":false},{"id":1482567,"name":"Lidia Cabeza","orcid":"0000-0001-7500-4012","position":0,"is_corresponding":true}],"reference_count":29,"raw_metadata":null,"created_at":"2026-07-19T02:57:44.572630Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}