Subscribe to RSS
DOI: 10.1055/s-0030-1263124
© Georg Thieme Verlag KG Stuttgart · New York
The Anti-adipogenic Effect of Macrophage-conditioned Medium Requires the IKKβ/NF-κB Pathway
Publication History
received 28.05.2010
accepted 22.07.2010
Publication Date:
27 August 2010 (online)

Abstract
Macrophage-secreted factors inhibit adipogenesis, but the underlying mechanism is not well understood. Our objective was to determine if anti-adipogenic signaling pathways in human preadipocytes are activated by macrophage-conditioned medium (MacCM). Human abdominal subcutaneous stromal preadipocytes were treated with adipogenic inducers in either standard medium or medium conditioned by human THP-1 macrophages. THP-1-MacCM increased inhibitor of κB kinase β (IKKβ) phosphorylation, inhibitor of NF-κB α (IκBα) degradation, and NF-κB activity in human preadipocytes in a time-dependent manner. Concomitant treatment of human abdominal subcutaneous preadipocytes with sc-514, a selective inhibitor of IKKβ, prevented the inhibitory effect of THP-1-MacCM on lipid accumulation and expression of adipogenic markers. Our data indicate that activation of the preadipocyte IKKβ/NF-κB pathway is required for the anti-adipogenic effect of THP-1-MacCM on human adipogenesis.
Key words
preadipocytes - adipocyte differentiation - inflammation
References
- 1
Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AWJ.
Obesity is associated with macrophage accumulation in adipose tissue.
J Clin Invest.
2003;
112
1796-1808
MissingFormLabel
- 2
Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole J, Nichols A, Ross JS, Tartaglia LA, Chen H.
Chronic inflammation in fat plays a crucial role in the development of obesity-related
insulin resistance.
J Clin Invest.
2003;
112
1821-1830
MissingFormLabel
- 3
de Luca C, Olefsky JM.
Inflammation and insulin resistance.
FEBS Lett.
2008;
582
97-105
MissingFormLabel
- 4
Furuhashi M, Fucho R, Görgün CZ, Tuncman G, Cao HJ, Hotamisligil GS.
Adipocyte/macrophage fatty acid-binding proteins contribute to metabolic deterioration
through actions in both macrophages and adipocytes in mice.
J Clin Invest.
2008;
118
2640-2650
MissingFormLabel
- 5
Hotamisligil GS.
Inflammation and metabolic disorders.
Nature.
2006;
444
860-867
MissingFormLabel
- 6
Constant VA, Gagnon A, Landry A, Sorisky A.
Macrophage-conditioned medium inhibits the differentiation of 3T3-L1 and human abdominal
preadipocytes.
Diabetologia.
2006;
49
1402-1411
MissingFormLabel
- 7
Constant VA, Gagnon A, Yarmo M, Sorisky A.
The antiadipogenic effect of macrophage-conditioned medium depends on ERK1/2 activation.
Metabolism.
2008;
57
465-472
MissingFormLabel
- 8
Yarmo MN, Landry A, Molgat AS, Gagnon A, Sorisky A.
Macrophage-conditioned medium inhibits differentiation-induced Rb phosphorylation
in 3T3-L1 preadipocytes.
Exp Cell Res.
2009;
315
411-418
MissingFormLabel
- 9
Lacasa D, Taleb S, Keophiphath M, Miranville A, Clement K.
Macrophage-secreted factors impair human adipogenesis: involvement of proinflammatory
state in preadipocytes.
Endocrinology.
2007;
148
868-877
MissingFormLabel
- 10
Stienstra R, Duval C, Keshtkar S, van der Laak J, Kersten S, Müller M.
Peroxisome proliferator-activated receptor γ activation promotes infiltration of alternatively
activated macrophages into adipose tissue.
J Biol Chem.
2008;
283
22620-22627
MissingFormLabel
- 11
Heilbronn L, Smith SR, Ravussin E.
Failure of fat cell proliferation, mitochondrial function and fat oxidation results
in ectopic fat storage, insulin resistance and type 2 diabetes mellitus.
Int J Obesity.
2004;
28
S12-S21
MissingFormLabel
- 12
Dubois SG, Heilbronn LK, Smith SR, Albu JB, Kelley DE, Ravussin E.
Look AHEAD Adipose Research Group. Decreased expression of adipogenic genes in obese
subjects with type 2 diabetes.
Obesity.
2006;
14
1543-1552
MissingFormLabel
- 13
Karin M.
The IκB kinase – a bridge between inflammation and cancer.
Cell Res.
2008;
18
334-342
MissingFormLabel
- 14
Gustafson B, Hammarstedt A, Andersson CX, Smith U.
Inflamed adipose tissue: a culprit underlying the metabolic syndrome and atherosclerosis.
Arterioscler Thromb Vasc Biol.
2007;
27
2276-2283
MissingFormLabel
- 15
Lehmann JM, Lenhard JM, Oliver BB, Ringold GM, Kliewer SA.
Peroxisome proliferator-activated receptors alpha and gamma are activated by indomethacin
and other non-steroidal anti-inflammatory drugs.
J Biol Chem.
1997;
272
3406-3410
MissingFormLabel
- 16
Gagnon A, Landry A, Sorisky A.
IKKβ and the anti-adipogenic effect of platelet-derived growth factor in human abdominal
subcutaneous preadipocytes.
J Endocrinol.
2009;
201
75-80
MissingFormLabel
- 17
Molgat AS, Gagnon A, Sorisky A.
Preadipocyte apoptosis is prevented by macrophage-conditioned medium in a PDGF-dependent
manner.
Am J Physiol Cell Physiol.
2009;
296
C757-C765
MissingFormLabel
- 18
Gagnon A, Chen C-S, Sorisky A.
Activation of protein kinase B and induction of adipogenesis by insulin in 3T3-L1
preadipocytes. Contribution of phosphoinositide-3,4,5-trisphosphate versus phosphoinositide-3,4-bisphosphate.
Diabetes.
1999;
48
691-698
MissingFormLabel
- 19
Laemmli UK.
Cleavage of structural proteins during the assembly of the head of bacteriophage T4.
Nature.
1970;
227
680-685
MissingFormLabel
- 20
Karin M, Yamamoto Y, Wang QM.
The IKK NF-κB system: a treasure trove for drug development.
Nat Rev Drug Discov.
2004;
3
17-26
MissingFormLabel
- 21
Kishore N, Sommers C, Mathialagan S, Guzova J, Yao M, Hauser S, Huynh K, Bonar S, Mielke C, Albee L, Weier R, Graneto M, Hanau C, Perry T, Tripp CS.
A selective IKK-2 inhibitor blocks NF-κB-dependent gene expression in interleukin-1β-stimulated
synovial fibroblasts.
J Biol Chem.
2003;
278
32861-32871
MissingFormLabel
- 22
Andrae J, Gallini R, Betsholtz C.
Role of platelet-derived growth factors in physiology and medicine.
Genes Dev.
2008;
22
1276-1312
MissingFormLabel
- 23
Hauner H, Rohrig K, Petruschke T.
Effects of epidermal growth factor (EGF), platelet-derived growth factor (PDGF) and
fibroblast growth factor (FGF) on human adipocyte development and function.
Eur J Clin Invest.
1995;
25
90-96
MissingFormLabel
- 24
Suzawa M, Takada I, Yanagisawa J, Ohtake F, Ogawa S, Yamauchi T, Kadowaki T, Takeuchi Y, Shibuya H, Gotoh Y, Matsumoto K, Kato S.
Cytokines suppress adipogenesis and PPAR-γ function through the TAK1/TAB1/NIK cascade.
Nat Cell Biol.
2003;
5
224-230
MissingFormLabel
- 25
Kosaka C, Masuda J, Shimokado K, Zen K, Yokota T, Sasaguri T, Ogata J.
Interferon-γ suppresses PDGF production from THP-1 cells and blood monocyte-derived
macrophages.
Atherosclerosis.
1992;
97
75-87
MissingFormLabel
- 26
Auwerx J.
The human leukemia cell line, THP-1: a multifunctional model for the study of monocyte-macrophage
differentiation.
Experientia.
1991;
47
22-31
MissingFormLabel
- 27
Bassols J, Ortega FJ, Moreno-Navarrete JM, Peral B, Ricart W, Fernández-Real JM.
Study of the proinflammatory role of human differentiated omental adipocytes.
J Cell Biochem.
2009;
107
1107-1117
MissingFormLabel
- 28
Lu C, Kumar PA, Fan Y, Sperling MA, Menon RK.
A novel effect of growth hormone on macrophage modulates macrophage-dependent adipocyte
differentiation.
Endocrinology.
2010;
151
189-199
MissingFormLabel
- 29
Entenmann G, Hauner H.
Relationship between replication and differentiation in cultured human adipocyte precursor
cells.
Am J Physiol.
1996;
270
C1011-C1016
MissingFormLabel
- 30
Tang Q-Q, Otto TC, Lane MD.
Mitotic clonal expansion: a synchronous process required for adipogenesis.
Proc Natl Acad Sci USA.
2003;
100
44-49
MissingFormLabel
- 31
Arner E, Westermark PO, Spalding KL, Britton T, Ryden M, Frisen J, Bernard S, Arner P.
Adipocyte turnover: relevance to human adipose tissue morphology.
Diabetes.
2010;
59
105-109
MissingFormLabel
- 32
Skurk T, Kempf K, Kolb H, Hauner H.
Herder. Expression and secretion of RANTES (CCL5) in human adipocytes in response to immunological
stimuli and hypoxia.
Horm Metab Res.
2009;
183-189
MissingFormLabel
Correspondence
Dr. A. Sorisky
Ottawa Hospital Research
Institute
501 Smyth Road Ottawa
K1 H 8L6 Ontario
Canada
Phone: +1/613/737 8899 #73320
Fax: +1/613/737 8803
Email: asorisky@ohri.ca