Metabolic Optimization Through Diet/Lifestyle Improvements For Youth

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Dysregulated sphingolipid ceramide (Cer) metabolism impairs mitochondrial function, insulin sensitivity and vascular reactivity and has been identified as a central common pathway towards the dyslipidemia, central adiposity, hyperglycemia, and hypertension that define metabolic syndrome, characteriz...

Dysregulated sphingolipid ceramide (Cer) metabolism impairs mitochondrial function, insulin sensitivity and vascular reactivity and has been identified as a central common pathway towards the dyslipidemia, central adiposity, hyperglycemia, and hypertension that define metabolic syndrome, characterized as cardiometabolic risk (CMR). The decrease in insulin sensitivity that occurs with age and predisposes to metabolic syndrome is preventable, a reflection of changes in body composition rather than the aging process itself. Ectopic fat, not fat mass per se, drives CMR, but despite mounting concern about rising prevalence of pediatric CMR in America and globally, the use of plasma Cer as potentially mechanistic biomarkers of ectopic fat and lipotoxicity has not been well explored. This may be driven in part by our incomplete understanding of i) the consequences of Cer dysregulation in pediatric CMR; ii) putative interactions between Cer and ectopic lipotoxicity; and iii) how lifestyle, notably nutrition, impacts Cer metabolism. Information in these areas may support use of plasma Cers as sensitive, prognostic biomarkers to guide more effective preventive lifestyle management of aberrant weight gain and associated CMR. In preliminary work, the investigators compared plasma sphingolipid profiles in obese adolescents and their parent/adult caretakers (PAC). Data from this study demonstrated that Cers (notably C:14 and C:16) are associated with dyslipidemia in both adults and youth. The investigators also found that 2-mo of a daily nutrient bar supplementation (coupled with weekly group counseling and exercise) significantly decreased plasma Cers more effectively than counseling and physical exercise alone, without change in traditional biomarkers but the extent of Cer reduction correlated with improved dyslipidemia. The investigators also found that 10 days of dietary fructose reduction in obese pre-adolescents significantly lowers cers in direct proportion to the clearance of ectopic hepatic adiposity. If study hypotheses are supported, these findings will identify sensitive Cer biomarkers of CMR with putative mechanistic insight to mitochondrial function requisite for insulin sensitivity, metabolic flexibility, lipolysis, and weight loss, that might therefore be used to monitor early success in lifestyle change trials.

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