Yu, Z, et al. Rapamycin and Dietary Restriction Induce Metabolically Distinctive Changes in Mouse Liver. J Gerontol A Biol Sci Med Sci, 2014.
Metabolon results led to:
• Identification of the mechanism of rapamycin-induced insulin resistance
• Development of a co-administration strategy to prevent or treat rapamycin-induced IR
Dietary restriction (DR) and rapamycin (Rapa) are shown to extend life span. However, chronic treatment with Rapa can result insulin resistance (IR). To understand the molecular basis of IR caused by Rapa, investigators performed liver metabolomics on mice treated with Rapa or on DR. While DR activated the entire process of fatty acid metabolism Rapa failed to engage fatty acid β-oxidation and ketogenesis. This inability was traced to specific molecular events including a lack of upregulation of β-hydroxybutyrate dehydrogenase and fatty acid transporters. The resulting accumulation of fatty acids and accompanying dyslipidemia are the plausible source of insulin resistance. The understanding of the specific defect induced by Rapa then allowed investigators to rescue the defect pharmacologically with metformin. Thus, metabolomics was able to elucidate a detailed molecular chain of events for Rapa-induced IR that then led to a potential pharmacological strategy to prevent or treat it.