Imaging mass spectrometry demonstrates age-related decline in human adipose plasticity
Christelle Guillermier, Pouneh K. Fazeli, Soomin Kim, Mingyue Lun, Jonah P. Zuflacht, Jessica Milian, Hang Lee, Hugues Francois-Saint-Cyr, Francois Horreard, David Larson, Evan D. Rosen, Richard T. Lee, Claude P. Lechene, Matthew L. Steinhauser
Christelle Guillermier, Pouneh K. Fazeli, Soomin Kim, Mingyue Lun, Jonah P. Zuflacht, Jessica Milian, Hang Lee, Hugues Francois-Saint-Cyr, Francois Horreard, David Larson, Evan D. Rosen, Richard T. Lee, Claude P. Lechene, Matthew L. Steinhauser
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Resource and Technical Advance Aging Endocrinology

Imaging mass spectrometry demonstrates age-related decline in human adipose plasticity

Abstract

Quantification of stable isotope tracers has revealed the dynamic state of living tissues. A new form of imaging mass spectrometry quantifies isotope ratios in domains much smaller than a cubic micron, enabling measurement of cell turnover and metabolism with stable isotope tracers at the single-cell level with a methodology we refer to as multi-isotope imaging mass spectrometry. In a first-in-human study, we utilize stable isotope tracers of DNA synthesis and de novo lipogenesis to prospectively measure cell birth and adipocyte lipid turnover. In a study of healthy adults, we elucidate an age-dependent decline in new adipocyte generation and adipocyte lipid turnover. A linear regression model suggests that the aging effect could be mediated by a decline in insulin-like growth factor-1 (IGF-1). This study therefore establishes a method for measurement of cell turnover and metabolism in humans with subcellular resolution while implicating the growth hormone/IGF-1 axis in adipose tissue aging.

Authors

Christelle Guillermier, Pouneh K. Fazeli, Soomin Kim, Mingyue Lun, Jonah P. Zuflacht, Jessica Milian, Hang Lee, Hugues Francois-Saint-Cyr, Francois Horreard, David Larson, Evan D. Rosen, Richard T. Lee, Claude P. Lechene, Matthew L. Steinhauser

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Figure 3

Age-dependent decline in homeostatic adipogenesis in human SAT.

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Age-dependent decline in homeostatic adipogenesis in human SAT. (A) 2H-l...
(A) 2H-labeled and unlabeled adipocyte nuclei after 4-week 2H-water–labeling pulse and 6-month chase. The 2H/1H HSI image (top right) shows label localized to the nucleus of a putative new adipocyte (arrows), in contrast to the unlabeled nucleus (bottom right, arrows). Scale ranges from background natural abundance to 100% (or 2 times) background. Scale bar: 5 μm. (B) Schematic depicting the hypothesized labeling of an adipocyte that matures during 2H-water labeling. 2H-labeling is expected to be high due to the developmental surge in lipid storage that occurs when a progenitor differentiates into a mature lipid-storing adipocyte. Prior analyses of the fate of 2H-water have established incorporation of 2H atoms by enzymatic reactions involved in pathways of intermediate metabolism, including gluconeogenesis, glycolysis, and the TCA cycle, thereby leading to the labeling of both the glycerol and fatty acid precursors of triglycerides. (C) 2H-high adipocyte lipid droplet (arrows). A small subset of such cells persisted after 6-month chase. (D) Correlation between the frequency of 2H-labeled adipocyte nuclei as shown in A and 2H-high adipocyte lipid droplets as shown in C at the 6-month chase time point (n = 9 subjects). (E) Negative correlation between projected adipocyte birth rate and subject age demonstrated for both measurements of new adipocyte formation (2H-labeled adipocyte nuclei and 2H-high adipocyte lipid droplets) (n = 9 subjects). (F) Positive correlation between projected yearly adipocyte birth rates and serum IGF-1 levels at 6-month chase time point (n = 9 subjects). (D–F) Data obtained by univariate regression.