Project Grant 20226701837186

**AWARDS ISSUED PRIOR TO JANUARY 20, 2025, WERE FUNDED UNDER PREVIOUS ADMINISTRATIONS AND MAY NOT REFLECT THE PRIORITIES AND POLICIES OF THE CURRENT ADMINISTRATION.** OBESITY AND ASSOCIATED DISEASES SUCH AS NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) HAVE REACHED EPIDEMIC LEVEL.NAFLD'S GLOBAL PREVALENCE IS 20-30% IN GENERAL POPULATION AND 80% IN OBESE PEOPLE.EPIDEMIOLOGICAL DATA SUGGEST THAT DIETS THAT EMPHASIZE FRUITS AND VEGETABLE (F & V) REDUCE RISK FOR OBESITY-ASSOCIATED DISEASES INCLUDING NAFLD. HOWEVER, ONLY A FEW STUDIES USING SINGLE F & V OR THEIR EXTRACTS HAVE TESTED THIS HYPOTHESIS. OUR PRELIMINARY STUDIES SHOW THAT FEEDING MICE A DIET SUPPLEMENTED WITH 15% (W/W) OF A MIXTURE OF F & V COMMONLY CONSUMED BY AMERICANS PROTECTS AGAINST NAFLD IN OBESE AND LEAN MICE BY 48.4% AND 28.5%. THE MECHANISM FOR F & V-INDUCED PROTECTION AGAINST NAFLD IS NOT UNDERSTOOD, YET, IS URGENTLY NEEDED TO EXPAND EVIDENCE-BASED SUPPORT FOR DIETARY GUIDELINES OF INCREASE F & V CONSUMPTION TO PREVENT CHRONIC DISEASES. WHILE DIETARY INTERVENTIONS TO PREVENT NAFLD HAVE FOCUSED ON WEIGHT LOSS, LITERATURE AND OUR PRELIMINARY DATA SUGGEST THAT OTHER FACTORS THAN MAINTAINING ENERGY BALANCE CONTRIBUTE TO NAFLD DEVELOPMENT. IDENTIFYING THESE FACTORS THROUGH INVESTIGATING THE UNDERLYING MECHANISMS OF F & V-INDUCED PREVENTION OF NAFLD WILL HELP DEVELOP MORE EFFICIENT STRATEGIES TO COMBAT NAFLD. WE HAVE IDENTIFIED NOVEL PATHWAYS (CERAMIDE AND GUT MICROBIOME) THROUGH WHICH F & V MAY EXERT THEIR BENEFICIAL EFFECTS IN PREVENTING NAFLD, HOWEVER, THEIR CAUSAL ROLE AND RELATIVE CONTRIBUTION TO THE PROTECTIVE EFFECT OF F & V ARE NOT KNOWN. THUS, IN THIS PROPOSAL WE AIM TO ADDRESS THIS GAP IN KNOWLEDGE. RESULTS FROM THE PROPOSED STUDIES WILL EXPAND THE KNOWLEDGE BASE TO SUPPORT AND IMPLEMENT THE CURRENT DIETARY GUIDELINES AND HELP DEVELOP EFFECTIVE DIETARY INTERVENTIONS TO COMBAT NAFLD.