IN TWO SEPARATE PROSPECTIVE COHORT STUDIES, INCREASED PLASMA ERYTHRITOL PREDICTED RISK FOR WEIGHT GAIN AND TYPE 2 DIABETES MELLITUS (T2DM) UP TO 20 YEARS BEFORE DISEASE ONSET, BUT THE CAUSAL MECHANISMS UNDERLYING THE ASSOCIATION HAVE NOT BEEN DEFINED. UNDERSTANDING THIS RELATIONSHIP IS IMPORTANT BECAUSE ERYTHRITOL, A FOUR-CARBON SUGAR ALCOHOL, IS AVAILABLE FROM BOTH ENDOGENOUS AND EXOGENOUS SOURCES. ERYTHRITOL WAS RECENTLY SHOWN TO BE SYNTHESIZED FROM GLUCOSE BY HUMAN METABOLISM, BUT THIS NEWLY UNCOVERED METABOLIC PATHWAY IS LARGELY UNCHARACTERIZED. SIMILARLY, ERYTHRITOL IS USED INCREASINGLY AS A NON-CALORIC SWEETENER AND FOOD ADDITIVE BECAUSE ACUTE DOSES ARE RAPIDLY CLEARED IN URINE. THE EFFECTS OF CHRONICALLY ELEVATED ERYTHRITOL LEVELS HAVE NOT BEEN ASSESSED, THOUGH STUDIES IN MODEL SYSTEMS INDICATE THAT ERYTHRITOL EXPOSURE CAUSES CHANGES IN ENERGY METABOLISM GENE EXPRESSION. OUR OVERALL OBJECTIVES ARE TO: 1) DEFINE METABOLIC REGULATORY MECHANISMS THAT GOVERN RATES OF ENDOGENOUS ERYTHRITOL PRODUCTION, AND 2) IDENTIFY "DOWNSTREAM" METABOLIC TARGETS AND SIGNALING PATHWAYS INFLUENCED BY ERYTHRITOL EXPOSURE. OUR CENTRAL HYPOTHESIS IS THAT INCREASED ERYTHRITOL PRODUCTION IS AN ALTERNATIVE MEANS OF METABOLIZING AND DISPOSING OF GLUCOSE IN RESPONSE TO POSITIVE ENERGY BALANCE. THE CENTRAL HYPOTHESIS WILL BE TESTED USING TWO SPECIFIC AIMS: 1) DEFINE THE METABOLIC DETERMINANTS THAT LEAD TO INCREASED ENDOGENOUS ERYTHRITOL SYNTHESIS, AND 2) DETERMINE THE EFFECT OF ELEVATED PLASMA ERYTHRITOL ON GENE EXPRESSION. THE FIRST AIM WILL EMPLOY MOUSE MODELS OF HUMAN GENETIC VARIANTS COMBINED WITH STATE-OF-THE-ART STABLE ISOTOPE TRACER AND METABOLIC FUNCTION TECHNOLOGIES TO CHARACTERIZE THE GENETIC AND DIETARY DETERMINANTS LEADING TO INCREASED PLASMA ERYTHRITOL. THE SECOND AIM WILL INTERROGATE THE RELATIONSHIP BETWEEN CHRONIC DIETARY ERYTHRITOL EXPOSURE AND CHANGES IN METABOLIC FUNCTION AND METABOLIC GENE EXPRESSION IN OBESE C57BL6/J MICE. THE PROPOSED RESEARCH IS INNOVATIVE IN CONCEPT, AS ENDOGENOUS ERYTHRITOL PRODUCTION FROM GLUCOSE IS A NEWLY RECOGNIZED HUMAN METABOLIC PATHWAY. THE PROPOSED RESEARCH IS SIGNIFICANT IN THAT IT WILL UNCOVER THE ROLE OF ELEVATED PLASMA ERYTHRITOL IN THE DEVELOPMENT OF T2DM AND WEIGHT GAIN AND FUNDAMENTALLY ADVANCE OUR UNDERSTANDING OF CENTRAL ENERGY METABOLISM AND ITS REGULATION. ULTIMATELY, THESE STUDIES HAVE THE POTENTIAL TO INFORM USE OF THIS NOVEL METABOLIC PATHWAY FOR CHRONIC DISEASE PREVENTION AND TREATMENT.