Stable Isotopes for Tracing Mammalian-Cell Metabolism In Vivo

Metabolism is at the cornerstone of all cellular functions and mounting evidence of its deregulation in different diseases emphasizes the importance of a comprehensive understanding of metabolic regulation at the whole-organism level. Stable-isotope measurements are a powerful tool for probing cellular metabolism and, as a result, are increasingly used to study metabolism in in vivo settings. The additional complexity of in vivo metabolic measurements requires paying special attention to experimental design and data interpretation. Here, we review recent work where in vivo stable-isotope measurements have been used to address relevant biological questions within an in vivo context, summarize different experimental and data interpretation approaches and their limitations, and discuss future opportunities in the field. Stable-isotope measurements are increasingly used to probe mammalian-cell metabolism in vivo.The selection of stable-isotope tracer(s) and tracer administration approach is key to maximize the information extracted from in vivo measurements.Metabolic models integrating stable-isotope tracer measurements in tissues and plasma allow quantitative readouts of in vivo metabolism at the whole-organ/whole-body level to be obtained.Tissue heterogeneity and metabolic compartmentalization need to be considered during data interpretation.The development of single-cell/single-organelle metabolomic approaches will advance our understanding of in vivo metabolism.