The circulating metabolome of human starvation
Matthew L. Steinhauser, Benjamin A. Olenchock, John O’Keefe, Mingyue Lun, Kerry A. Pierce, Hang Lee, Lorena Pantano, Anne Klibanski, Gerald I. Shulman, Clary B. Clish, Pouneh K. Fazeli
Matthew L. Steinhauser, Benjamin A. Olenchock, John O’Keefe, Mingyue Lun, Kerry A. Pierce, Hang Lee, Lorena Pantano, Anne Klibanski, Gerald I. Shulman, Clary B. Clish, Pouneh K. Fazeli
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Research Article Endocrinology Metabolism

The circulating metabolome of human starvation

Abstract

The human adaptive starvation response allows for survival during long-term caloric deprivation. Whether the physiology of starvation is adaptive or maladaptive is context dependent: activation of pathways by caloric restriction may promote longevity, yet in the context of caloric excess, the same pathways may contribute to obesity. Here, we performed plasma metabolite profiling of longitudinally collected samples during a 10-day, 0-calorie fast in humans. We identify classical milestones in adaptive starvation, including the early consumption of gluconeogenic amino acids and the subsequent surge in plasma nonesterified fatty acids that marks the shift from carbohydrate to lipid metabolism, and demonstrate findings, including (a) the preferential release of unsaturated fatty acids and an associated shift in plasma lipid species with high degrees of unsaturation and (b) evidence that acute, starvation-mediated hypoleptinemia may be a driver of the transition from glucose to lipid metabolism in humans.

Authors

Matthew L. Steinhauser, Benjamin A. Olenchock, John O’Keefe, Mingyue Lun, Kerry A. Pierce, Hang Lee, Lorena Pantano, Anne Klibanski, Gerald I. Shulman, Clary B. Clish, Pouneh K. Fazeli

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Figure 4

Starvation-mediated dynamics of plasma phospholipids.

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Starvation-mediated dynamics of plasma phospholipids. (A) Spaghetti plot...
(A) Spaghetti plot of phospholipids for each subject, color-coded by phospholipid class. SM, sphingomyelin; PC, phosphatidylcholines; PE, phosphatidylethanolamines; PS, phosphatidylserines; LPC, lysophosphatidylcholines; LPE, lysophosphatidylethanolamines. (B) Mean phosphatidylethanolamine and phosphatidylcholine values relative to baseline (dashed line). (C) Mean lysophosphatidylethanolamine and lysophosphatidylcholine values relative to baseline (dashed line). Lysophosphatidylethanolamines/lysophosphatidylcholines are catabolic products resulting from fatty acid release from phosphatidylethanolamine and phosphatidylcholine, respectively (shown in B). (D) Mean ceramide levels relative to baseline (dashed line), which, together with PC and PE, serve as substrate for sphingomyelin synthesis. (E) Mean diacylglycerol (DAG) levels relative to baseline. Diacylglycerol is a byproduct of sphingomyelin synthesis. (F) Mean sphingomyelin levels relative to baseline (dashed line). (G) Mean phosphatidylcholine and phosphatidylethanolamine plasmalogen values relative to baseline (dashed line). (B–G) Blue dots signify negative levels relative to baseline; red dots signify positive levels relative to baseline. Dots become progressively darker as a function of fasting duration. Phospholipids listed on the x axis are ordered with an increasing number of double bonds from left to right. *P < 0.05, comparing day 10 value to baseline (false discovery rate adjustment for multiple comparisons).