IN DAIRY CATTLE, THE DEVELOPMENT OF INSULIN RESISTANCE IN SKELETAL MUSCLE AND ADIPOSE TISSUE IS A KEY MATERNAL ADAPTATION TO SPARE GLUCOSE AND OTHER NUTRIENTS FOR THE MAMMARY SYNTHESIS OF MILK IN EARLY LACTATION. UNFORTUNATELY, UNCONTROLLED POSTPARTUM INSULIN RESISTANCE MAY CONTRIBUTE TO SEVERE BODY FAT MOBILIZATION AND PREDISPOSE DAIRY COWS TO METABOLIC DISEASES INCLUDING FATTY LIVER AND KETOSIS. IN MID-LACTATION COWS, INSULIN SENSITIVITY IS ENHANCED AND NUTRIENT UTILIZATION SHIFTS TOWARDS BODY FAT DEPOSITION AND AWAY FROM THE MAMMARY GLAND TO LIMIT MILK PRODUCTION. APPROACHES THAT MODULATE INSULIN SENSITIVITY AS A MEANS TO REDUCE ADIPOSE TISSUE BREAKDOWN OR ENHANCE GLUCOSE PARTITIONING TOWARDS THE MAMMARY GLAND FOR MILK SYNTHESIS HAVE POTENTIAL TO IMPROVE COW HEALTH AND MILK PRODUCTION EFFICIENCY (MILK PRODUCED PER UNIT OF FEED INTAKE) DEPENDING ON STAGE OF LACTATION. BY ADDRESSING THE ANIMAL NUTRITION, GROWTH AND LACTATION PROGRAM AREA PRIORITY, OUR GOAL IS TO DEFINE THE MECHANISMSTHAT MEDIATE INSULIN RESISTANCE IN DAIRY COWS. IN NON-RUMINANTS WITH TYPE 2 DIABETES, EXCESS FATTY ACIDS TRIGGER THE SYNTHESIS OF A SPHINGOLIPID CALLED CERAMIDE, WHICH IN TURN CAUSES INSULIN RESISTANCE. OUR BODY OF WORK SUGGESTS THAT THE DE NOVO SYNTHESIS AND ACCUMULATION OF CERAMIDE IN RESPONSE TO ADIPOSE TISSUE BREAKDOWN ALSO INHIBITS INSULIN SENSITIVITY TO SPARE GLUCOSE FOR MILK PRODUCTION IN DAIRY CATTLE. OUR DATA ALSO SUGGESTS THAT CERAMIDE MEDIATES THE ABILITY OF SOMATOTROPIN TO INHIBIT INSULIN ACTION AND PROMOTE LACTATION. THE CERAMIDE HYPOTHESIS WILL BE TESTED BY UTILIZING A VALIDATED PHARMACOLOGICAL APPROACH TO INHIBIT SERINE PALMITOYLTRANSFERASE WITHIN THE DE NOVO CERAMIDE SYNTHESIS PATHWAY TO DETERMINE WHETHER CERAMIDE CAUSES INSULIN RESISTANCE AND SPARES GLUCOSE FOR LACTATION IN DAIRY COWS. THIS ANIMAL SCIENCE RESEARCH IS IMPORTANT BECAUSE INCREASES IN MILK PRODUCTION EFFICIENCY AND IMPROVEMENTS IN ANIMAL HEALTH ARE NEEDED TO SUPPORT A SUSTAINABLE DAIRY INDUSTRY. BY CHARACTERIZING THE MECHANISMS OF INSULIN RESISTANCE IN CATTLE, WE CAN THEN WORK TOWARDS DEVELOPING NUTRITIONAL APPROACHES TO TARGET THESE MECHANISMS AND THUS ENHANCE MILK PRODUCTION AND HEALTH IN CATTLE.