Metabolic signatures of cultured human adipocytes from metabolically healthy versus unhealthy obese individuals.
OBJECTIVE
Among obese subjects, metabolically healthy and unhealthy obesity (MHO/MUHO) can be differentiated: the latter is characterized by whole-body insulin resistance, hepatic steatosis, and subclinical inflammation. Aim of this study was, to identify adipocyte-specific metabolic signatures and functional biomarkers for MHO versus MUHO.


METHODS
10 insulin-resistant (IR) vs. 10 insulin-sensitive (IS) non-diabetic morbidly obese (BMI >40 kg/m2) Caucasians were matched for gender, age, BMI, and percentage of body fat. From subcutaneous fat biopsies, primary preadipocytes were isolated and differentiated to adipocytes in vitro. About 280 metabolites were investigated by a targeted metabolomic approach intracellularly, extracellularly, and in plasma.


RESULTS
Among others, aspartate was reduced intracellularly to one third (p = 0.0039) in IR adipocytes, pointing to a relative depletion of citric acid cycle metabolites or reduced aspartate uptake in MUHO. Other amino acids, already known to correlate with diabetes and/or obesity, were identified to differ between MUHO's and MHO's adipocytes, namely glutamine, histidine, and spermidine. Most species of phosphatidylcholines (PCs) were lower in MUHO's extracellular milieu, though simultaneously elevated intracellularly, e.g., PC aa C32∶3, pointing to increased PC synthesis and/or reduced PC release. Furthermore, altered arachidonic acid (AA) metabolism was found: 15(S)-HETE (15-hydroxy-eicosatetraenoic acid; 0 vs. 120pM; p = 0.0014), AA (1.5-fold; p = 0.0055) and docosahexaenoic acid (DHA, C22∶6; 2-fold; p = 0.0033) were higher in MUHO. This emphasizes a direct contribution of adipocytes to local adipose tissue inflammation. Elevated DHA, as an inhibitor of prostaglandin synthesis, might be a hint for counter-regulatory mechanisms in MUHO.


CONCLUSIONS
We identified adipocyte-inherent metabolic alterations discriminating between MHO and MUHO.
Helmholtz Zentrum München, German Research Center for Environmental Health, Institute of Experimental Genetics, Genome Analysis Center, Neuherberg, Germany; Department of Internal Medicine IV, Division of Endocrinology, Diabetology, Angiology, Nephrology, and Clinical Chemistry, University Hospital, Eberhard Karls University, Tübingen, Germany; German Center for Diabetes Research, Neuherberg, Germany; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center München at the Eberhard Karls University of Tübingen, Tübingen, Germany.
Anja
A
Böhm
Helmholtz Zentrum München, German Research Center for Environmental Health, Institute of Experimental Genetics, Genome Analysis Center, Neuherberg, Germany.
Anna
A
Halama
Department of General, Visceral and Transplant Surgery, University Hospital, Eberhard Karls University, Tübingen, Germany.
Tobias
T
Meile
Department of General, Visceral and Transplant Surgery, University Hospital, Eberhard Karls University, Tübingen, Germany.
Marty
M
Zdichavsky
Department of Internal Medicine IV, Division of Endocrinology, Diabetology, Angiology, Nephrology, and Clinical Chemistry, University Hospital, Eberhard Karls University, Tübingen, Germany; German Center for Diabetes Research, Neuherberg, Germany; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center München at the Eberhard Karls University of Tübingen, Tübingen, Germany.
Rainer
R
Lehmann
Helmholtz Zentrum München, German Research Center for Environmental Health, Institute of Experimental Genetics, Genome Analysis Center, Neuherberg, Germany; Department of Internal Medicine IV, Division of Endocrinology, Diabetology, Angiology, Nephrology, and Clinical Chemistry, University Hospital, Eberhard Karls University, Tübingen, Germany; German Center for Diabetes Research, Neuherberg, Germany; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center München at the Eberhard Karls University of Tübingen, Tübingen, Germany.
Cora
C
Weigert
Department of Internal Medicine IV, Division of Endocrinology, Diabetology, Angiology, Nephrology, and Clinical Chemistry, University Hospital, Eberhard Karls University, Tübingen, Germany; German Center for Diabetes Research, Neuherberg, Germany; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center München at the Eberhard Karls University of Tübingen, Tübingen, Germany.
Andreas
A
Fritsche
Department of Internal Medicine IV, Division of Endocrinology, Diabetology, Angiology, Nephrology, and Clinical Chemistry, University Hospital, Eberhard Karls University, Tübingen, Germany; German Center for Diabetes Research, Neuherberg, Germany; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center München at the Eberhard Karls University of Tübingen, Tübingen, Germany.
Norbert
N
Stefan
Department of General, Visceral and Transplant Surgery, University Hospital, Eberhard Karls University, Tübingen, Germany.
Alfred
A
Königsrainer
Helmholtz Zentrum München, German Research Center for Environmental Health, Institute of Experimental Genetics, Genome Analysis Center, Neuherberg, Germany; Department of Internal Medicine IV, Division of Endocrinology, Diabetology, Angiology, Nephrology, and Clinical Chemistry, University Hospital, Eberhard Karls University, Tübingen, Germany; German Center for Diabetes Research, Neuherberg, Germany; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center München at the Eberhard Karls University of Tübingen, Tübingen, Germany.
Hans-Ulrich
HU
Häring
Helmholtz Zentrum München, German Research Center for Environmental Health, Institute of Experimental Genetics, Genome Analysis Center, Neuherberg, Germany; German Center for Diabetes Research, Neuherberg, Germany; Chair of Experimental Genetics, Technical University München, Freising-Weihenstephan, Germany.
Martin Hrabě
MH
de Angelis
Helmholtz Zentrum München, German Research Center for Environmental Health, Institute of Experimental Genetics, Genome Analysis Center, Neuherberg, Germany; German Center for Diabetes Research, Neuherberg, Germany; Chair of Experimental Genetics, Technical University München, Freising-Weihenstephan, Germany.
Jerzy
J
Adamski
Helmholtz Zentrum München, German Research Center for Environmental Health, Institute of Experimental Genetics, Genome Analysis Center, Neuherberg, Germany; Department of Internal Medicine IV, Division of Endocrinology, Diabetology, Angiology, Nephrology, and Clinical Chemistry, University Hospital, Eberhard Karls University, Tübingen, Germany; German Center for Diabetes Research, Neuherberg, Germany; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center München at the Eberhard Karls University of Tübingen, Tübingen, Germany.
Harald
H
Staiger
D017667:Adipocytes / Q000378:metabolism* / Q000473:pathology; D000328:Adult; D001095:Arachidonic Acids / Q000378:metabolism*; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D007333:Insulin Resistance; D008297:Male; D008875:Middle Aged; D009767:Obesity, Morbid / Q000378:metabolism* / Q000473:pathology
D001095:Arachidonic Acids