Laurent Vergnes1, Graeme R Davies1, Jason Y Lin1, Michael W Yeh1, Masha J Livhits1, Avital Harari1, Michael E Symonds1, Harold S Sacks1, Karen Reue1. 1. Department of Human Genetics (L.V., J.Y.L., K.R.), David Geffen School of Medicine at UCLA, Los Angeles, California; Academic Division of Child Health, Obstetrics and Gynaecology (G.R.D., M.E.S.), School of Medicine, Queen's Medical Centre, The University of Nottingham, Nottingham, United Kingdom; Section of Endocrine Surgery (M.W.Y., M.J.L., A.H.), David Geffen School of Medicine at UCLA, Los Angeles, California; Endocrinology and Diabetes Division (H.S.S.), VA Greater Los Angeles Healthcare System, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California; Molecular Biology Institute (K.R.), University of California, Los Angeles, Los Angeles, California.
Abstract
CONTEXT: Patients with pheochromocytoma (pheo) show presence of multilocular adipocytes that express uncoupling protein 1 within periadrenal (pADR) and omental (OME) fat depots. It has been hypothesized that this is due to adrenergic stimulation by catecholamines produced by the pheo tumors. OBJECTIVE: To characterize the prevalence and respiratory activity of brown-like adipocytes within pADR, OME, and SC fat depots in human adult pheo patients. DESIGN: This was an observational cohort study. SETTING: The study took place in a university hospital. PATIENTS: We studied 46 patients who underwent surgery for benign adrenal tumors (21 pheos and 25 controls with adrenocortical adenomas). MAIN OUTCOME MEASURE: We characterized adipocyte browning in pADR, SC, and OME fat depots for histological and immunohistological features, mitochondrial respiration rate, and gene expression. We also determined circulating levels of catecholamines and other browning-related hormones. RESULTS: Eleven of 21 pheo pADR adipose samples, but only one of 25 pADR samples from control patients exhibited multilocular adipocytes. The pADR browning phenotype was associated with higher plasma catecholamines and raised uncoupling protein 1. Mitochondria from multilocular pADR fat of pheo patients exhibited increased rates of coupled and uncoupled respiration. Global gene expression analysis in pADR fat revealed enrichment in β-oxidation genes in pheo patients with multilocular adipocytes. No SC or OME fat depots exhibited aspects of browning. CONCLUSION: Browning of the pADR depot occurred in half of pheo patients and was associated with increased catecholamines and mitochondrial activity. No browning was detected in other fat depots, suggesting that other factors are required to promote browning in these depots.
CONTEXT: Patients with pheochromocytoma (pheo) show presence of multilocular adipocytes that express uncoupling protein 1 within periadrenal (pADR) and omental (OME) fat depots. It has been hypothesized that this is due to adrenergic stimulation by catecholamines produced by the pheo tumors. OBJECTIVE: To characterize the prevalence and respiratory activity of brown-like adipocytes within pADR, OME, and SC fat depots in human adult pheo patients. DESIGN: This was an observational cohort study. SETTING: The study took place in a university hospital. PATIENTS: We studied 46 patients who underwent surgery for benign adrenal tumors (21 pheos and 25 controls with adrenocortical adenomas). MAIN OUTCOME MEASURE: We characterized adipocyte browning in pADR, SC, and OME fat depots for histological and immunohistological features, mitochondrial respiration rate, and gene expression. We also determined circulating levels of catecholamines and other browning-related hormones. RESULTS: Eleven of 21 pheo pADR adipose samples, but only one of 25 pADR samples from control patients exhibited multilocular adipocytes. The pADR browning phenotype was associated with higher plasma catecholamines and raised uncoupling protein 1. Mitochondria from multilocular pADR fat of pheo patients exhibited increased rates of coupled and uncoupled respiration. Global gene expression analysis in pADR fat revealed enrichment in β-oxidation genes in pheo patients with multilocular adipocytes. No SC or OME fat depots exhibited aspects of browning. CONCLUSION: Browning of the pADR depot occurred in half of pheo patients and was associated with increased catecholamines and mitochondrial activity. No browning was detected in other fat depots, suggesting that other factors are required to promote browning in these depots.
Authors: Matthias Johannes Betz; Marc Slawik; Martin E Lidell; Andrea Osswald; Mikael Heglind; Daniel Nilsson; Urs Daniel Lichtenauer; Brigitte Mauracher; Thomas Mussack; Felix Beuschlein; Sven Enerbäck Journal: J Clin Endocrinol Metab Date: 2013-06-06 Impact factor: 5.958
Authors: Kosaku Shinoda; Ineke H N Luijten; Yutaka Hasegawa; Haemin Hong; Si B Sonne; Miae Kim; Ruidan Xue; Maria Chondronikola; Aaron M Cypess; Yu-Hua Tseng; Jan Nedergaard; Labros S Sidossis; Shingo Kajimura Journal: Nat Med Date: 2015-03-16 Impact factor: 53.440
Authors: Wouter D van Marken Lichtenbelt; Joost W Vanhommerig; Nanda M Smulders; Jamie M A F L Drossaerts; Gerrit J Kemerink; Nicole D Bouvy; Patrick Schrauwen; G J Jaap Teule Journal: N Engl J Med Date: 2009-04-09 Impact factor: 91.245
Authors: Aaron M Cypess; Sanaz Lehman; Gethin Williams; Ilan Tal; Dean Rodman; Allison B Goldfine; Frank C Kuo; Edwin L Palmer; Yu-Hua Tseng; Alessandro Doria; Gerald M Kolodny; C Ronald Kahn Journal: N Engl J Med Date: 2009-04-09 Impact factor: 91.245
Authors: Siegfried Ussar; Kevin Y Lee; Simon N Dankel; Jeremie Boucher; Max-Felix Haering; Andre Kleinridders; Thomas Thomou; Ruidan Xue; Yazmin Macotela; Aaron M Cypess; Yu-Hua Tseng; Gunnar Mellgren; C Ronald Kahn Journal: Sci Transl Med Date: 2014-07-30 Impact factor: 17.956
Authors: Anouk A J J van der Lans; Joris Hoeks; Boudewijn Brans; Guy H E J Vijgen; Mariëlle G W Visser; Maarten J Vosselman; Jan Hansen; Johanna A Jörgensen; Jun Wu; Felix M Mottaghy; Patrick Schrauwen; Wouter D van Marken Lichtenbelt Journal: J Clin Invest Date: 2013-07-15 Impact factor: 14.808
Authors: Aaron M Cypess; Andrew P White; Cecile Vernochet; Tim J Schulz; Ruidan Xue; Christina A Sass; Tian Liang Huang; Carla Roberts-Toler; Lauren S Weiner; Cathy Sze; Aron T Chacko; Laura N Deschamps; Lindsay M Herder; Nathan Truchan; Allison L Glasgow; Ashley R Holman; Alina Gavrila; Per-Olof Hasselgren; Marcelo A Mori; Michael Molla; Yu-Hua Tseng Journal: Nat Med Date: 2013-04-21 Impact factor: 53.440
Authors: David Patsouris; Peter Qi; Abdikarim Abdullahi; Mile Stanojcic; Peter Chen; Alexandra Parousis; Saeid Amini-Nik; Marc G Jeschke Journal: Cell Rep Date: 2015-11-12 Impact factor: 9.423
Authors: Frode Norheim; Yehudit Hasin-Brumshtein; Laurent Vergnes; Karthickeyan Chella Krishnan; Calvin Pan; Marcus M Seldin; Simon T Hui; Margarete Mehrabian; Zhiqiang Zhou; Sonul Gupta; Brian W Parks; Axel Walch; Karen Reue; Susanna M Hofmann; Arthur P Arnold; Aldons J Lusis Journal: Cell Metab Date: 2019-01-10 Impact factor: 27.287
Authors: Rebeca Acin-Perez; Linsey Stiles; Orian S Shirihai; Ilan Y Benador; Anton Petcherski; Michaela Veliova; Gloria A Benavides; Sylviane Lagarrigue; Arianne Caudal; Laurent Vergnes; Anne N Murphy; Georgios Karamanlidis; Rong Tian; Karen Reue; Jonathan Wanagat; Harold Sacks; Francesca Amati; Victor M Darley-Usmar; Marc Liesa; Ajit S Divakaruni Journal: EMBO J Date: 2020-05-20 Impact factor: 11.598
Authors: Daniel L Sun; Soumya Poddar; Roy D Pan; Ethan W Rosser; Evan R Abt; Juno Van Valkenburgh; Thuc M Le; Vincent Lok; Selena P Hernandez; Janet Song; Joanna Li; Aneta Turlik; Xiaohong Chen; Chi-An Cheng; Wei Chen; Christine E Mona; Andreea D Stuparu; Laurent Vergnes; Karen Reue; Robert Damoiseaux; Jeffrey I Zink; Johannes Czernin; Timothy R Donahue; Kendall N Houk; Michael E Jung; Caius G Radu Journal: RSC Med Chem Date: 2020-02-24