Mobilization of pro-inflammatory lipids in obese Plscr3-deficient mice.
BACKGROUND
The obesity epidemic has prompted the search for candidate genes capable of influencing adipose function. One such candidate, that encoding phospholipid scramblase 3 (PLSCR3), was recently identified, as genetic deletion of it led to lipid accumulation in abdominal fat pads and changes characteristic of metabolic syndrome. Because adipose tissue is increasingly recognized as an endocrine organ, capable of releasing small molecules that modulate disparate physiological processes, we examined the plasma from wild-type, Plscr1-/-, Plscr3-/- and Plscr1&3-/- mice. Using an untargeted comprehensive metabolite profiling approach coupled with targeted gene expression analyses, the perturbed biochemistry and functional redundancy of PLSCR proteins was assessed.


RESULTS
Nineteen metabolites were differentially and similarly regulated in both Plscr3-/- and Plscr1&3-/- animals, of which five were characterized from accurate mass, tandem mass spectrometry data and their correlation to the Metlin database as lysophosphatidylcholine (LPC) species enriched with C16:1, C18:1, C20:3, C20:5 and C22:5 fatty acids. No significant changes in the plasma metabolome were detected upon elimination of PLSCR1, indicating that increases in pro-inflammatory lipids are specifically associated with the obese state of Plscr3-deficient animals. Correspondingly, increases in white adipose lipogenic gene expression confirm a role for PLSCR3 in adipose lipid metabolism.


CONCLUSIONS
The untargeted profiling of circulating metabolites suggests no detectable functional redundancies between PLSCR proteins; however, this approach simultaneously identified previously unrecognized lipid metabolites that suggest a novel molecular link between obesity, inflammation and the downstream consequences associated with PLSCR3-deficiency.
Mutch
David M
DM
The Scripps Research Institute, Department of Molecular and Experimental Medicine, La Jolla, CA 92037, USA. dmmutch_sci@hotmail.com
O'Maille
Grace
G
Wikoff
William R
WR
Wiedmer
Therese
T
Sims
Peter J
PJ
Siuzdak
Gary
G
D052436:Adipose Tissue, White / Q000378:metabolism; D000818:Animals; D005227:Fatty Acids / Q000032:analysis; D020869:Gene Expression Profiling; D007249:Inflammation / Q000209:etiology*; D050356:Lipid Metabolism; D008244:Lysophosphatidylcholines / Q000737:chemistry; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000209:etiology*; D049294:Phospholipid Transfer Proteins / Q000172:deficiency* / Q000502:physiology; D053719:Tandem Mass Spectrometry
D005227:Fatty Acids; D008244:Lysophosphatidylcholines; D049294:Phospholipid Transfer Proteins; C493428:Plscr3 protein, mouse