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Caloric Restriction and/or SGLT2 Inhibition Improve Glucose Tolerance and Elicit Metabolic Adaptations in the OLETF Rat Model of Metabolic Syndrome

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Caloric restriction (CR) is an effective intervention to acutely reduce adiposity and total body mass (BM) to improve insulin resistance and ameliorate metabolic derangements. However, CR also results in metabolic adaptations, including increase expression of orexigenic hormones, decreased resting metabolic rate, and prioritization of gluconeogenesis and lipolysis as fuel sources, which in combination promote a higher caloric intake and facilitate the regain of body mass. In the first original study presented in this dissertation we demonstrated that acute, severe (50%) CR in the obese, insulin resistant OLETF rat, elicits improvements in insulin resistance and plasma lipid profiles. However, these improvements were accompanied by a large collateral loss of lean body mass, and were abrogated after partial recovery of body mass following CR. The next study showed, via assessment of plasma metabolomic profiles, that lipolysis and proteolysis, but not gluconeogenesis, reverted towards pre-caloric restriction levels following recovery of body mass, providing a partial explanation of why insulin resistance rapidly returned following mass recovery, and confirmed the presence of extensive lean tissue catabolism. In the third study, we showed that moderate (30%) CR improved insulin resistance and kidney function, albeit not as profoundly as 50% CR, while preserving body mass. However, when combined with administration of a SGLT2 inhibitor, 30% CR further improved insulin sensitivity via changes in muscle and liver metabolism, without causing hypoglycemia or lean tissue catabolism. Together these findings contribute to the current body of knowledge on the metabolic impact of caloric restriction via implementation of different degrees of CR in a rat model that recapitulates the progression of metabolic syndrome observed in humans. Moreover, this work contributes novel findings on the metabolic consequences of regaining fat mass, or “rebound effect”, along with results that support the potential of a simultaneous intervention of moderate CR and SGLT2 inhibition as a potential means to successfully improve glucose tolerance and lower blood pressure.

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