Home LiteratureArticle Details
PMID: 23482447 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

CD40 deficiency in mice exacerbates obesity-induced adipose tissue inflammation, hepatic steatosis, and insulin resistance.

American journal of physiology. Endocrinology and metabolism ·Vol. 304 ·No. 9 ·2013-05-01 ·Pages E951-63

Guo CA, Kogan S, Amano SU, Wang M, Dagdeviren S, Friedline RH, Aouadi M, Kim JK, Czech MP

Abstract

The pathophysiology of obesity and type 2 diabetes in rodents and humans is characterized by low-grade inflammation in adipose tissue and liver. The CD40 receptor and its ligand CD40L initiate immune cell signaling promoting inflammation, but conflicting data on CD40L-null mice confound its role in obesity-associated insulin resistance. Here, we demonstrate that CD40 receptor-deficient mice on a high-fat diet display the expected decrease in hepatic cytokine levels but paradoxically exhibit liver steatosis, insulin resistance, and glucose intolerance compared with their age-matched wild-type controls. Hyperinsulinemic-euglycemic clamp studies also demonstrated insulin resistance in glucose utilization by the CD40-null mice compared with wild-type mice. In contrast to liver, adipose tissue in CD40-deficient animals harbors elevated cytokine levels and infiltration of inflammatory cells, particularly macrophages and CD8(+) effector T cells. In addition, ex vivo explants of epididymal adipose tissue from CD40(-/-) mice display elevated basal and isoproterenol-stimulated lipolysis, suggesting a potential increase of lipid efflux from visceral fat to the liver. These findings reveal that 1) CD40-null mice represent an unusual model of hepatic steatosis with reduced hepatic inflammation, and 2) CD40 unexpectedly functions in adipose tissue to attenuate its inflammation in obesity, thereby protecting against hepatic steatosis.

Keywords
CD40 CD8+ T cell adipose tissue inflammation hepatic steatosis insulin resistance
MeSH Terms
Adipocytes/metabolism Adipose Tissue/pathology Animals Blotting, Western CD40 Antigens/deficiency Diet Disease Progression Enzyme-Linked Immunosorbent Assay Fatty Liver/genetics,pathology Flow Cytometry Glucose Clamp Technique Glucose Tolerance Test Inflammation/genetics,pathology Insulin Resistance/genetics Lipid Metabolism/genetics Male Mice Mice, Inbred C57BL Mice, Knockout Obesity/genetics,pathology RNA/biosynthesis,genetics Real-Time Polymerase Chain Reaction
Chemicals
CD40 Antigens RNA
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Guo Chang-An
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Kogan Sophia
Amano Shinya U
Wang Mengxi
Dagdeviren Sezin
Friedline Randall H
Aouadi Myriam
Kim Jason K
Czech Michael P
References (51)
51 references, click to expand
  1. Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters.
    Nat Med. 2009 Aug;15(8):930-9 PMID: 19633656
  2. CD40L deficiency attenuates diet-induced adipose tissue inflammation by impairing immune cell accumulation and production of pathogenic IgG-antibodies.
    PLoS One. 2012;7(3):e33026 PMID: 22412980
  3. CD40 ligand inhibits endothelial cell migration by increasing production of endothelial reactive oxygen species.
    Circulation. 2002 Aug 20;106(8):981-6 PMID: 12186804
  4. Ectopic fat and insulin resistance.
    Curr Diab Rep. 2008 Jun;8(3):185-91 PMID: 18625114
  5. CD40-CD40L: linking pancreatic, adipose tissue and vascular inflammation in type 2 diabetes and its complications.
    Diab Vasc Dis Res. 2013 Mar;10(2):115-22 PMID: 22965071
  6. Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C, and IkappaB-alpha.
    Diabetes. 2002 Jul;51(7):2005-11 PMID: 12086926
  7. Targeting CD40L: a promising therapeutic approach.
    Clin Diagn Lab Immunol. 2004 Jul;11(4):635-41 PMID: 15242934
  8. Deletion of nicotinamide nucleotide transhydrogenase: a new quantitive trait locus accounting for glucose intolerance in C57BL/6J mice.
    Diabetes. 2006 Jul;55(7):2153-6 PMID: 16804088
  9. Differential expression and regulation of murine CD40 in regional vascular beds.
    Am J Physiol Heart Circ Physiol. 2006 Feb;290(2):H631-9 PMID: 16172156
  10. Type 2 diabetes and obesity metabolic interactions: common factors for breast cancer risk and novel approaches to prevention and therapy.
    Curr Diabetes Rev. 2012 Mar;8(2):116-30 PMID: 22268396
  11. Hepatic steatosis: a role for de novo lipogenesis and the transcription factor SREBP-1c.
    Diabetes Obes Metab. 2010 Oct;12 Suppl 2:83-92 PMID: 21029304
  12. Soluble CD40 ligand impairs the function of peripheral blood angiogenic outgrowth cells and increases neointimal formation after arterial injury.
    Circulation. 2010 Jan 19;121(2):315-24 PMID: 20048211
  13. Insulin resistance--a common link between type 2 diabetes and cardiovascular disease.
    Diabetes Obes Metab. 2006 May;8(3):237-49 PMID: 16634983
  14. The levels of soluble CD40 ligand and C-reactive protein in normal weight, overweight and obese people.
    Clin Med Res. 2010 Jul;8(2):89-95 PMID: 20660932
  15. Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB.
    Nat Med. 2005 Feb;11(2):183-90 PMID: 15685173
  16. CD40L deficiency ameliorates adipose tissue inflammation and metabolic manifestations of obesity in mice.
    Arterioscler Thromb Vasc Biol. 2011 Oct;31(10):2251-60 PMID: 21817098
  17. Unexpected trafficking of immune cells within the adipose tissue during the onset of obesity.
    Biochem Biophys Res Commun. 2009 Jul 10;384(4):482-5 PMID: 19422792
  18. Fats, inflammation and insulin resistance: insights to the role of macrophage and T-cell accumulation in adipose tissue.
    Proc Nutr Soc. 2011 Nov;70(4):408-17 PMID: 21835098
  19. Mechanisms linking obesity with cardiovascular disease.
    Nature. 2006 Dec 14;444(7121):875-80 PMID: 17167476
  20. Ectopic fat and insulin resistance: pathophysiology and effect of diet and lifestyle interventions.
    Int J Endocrinol. 2012;2012:983814 PMID: 22675355
  21. Obesity induces a phenotypic switch in adipose tissue macrophage polarization.
    J Clin Invest. 2007 Jan;117(1):175-84 PMID: 17200717
  22. The CD40 antigen and its ligand.
    Annu Rev Immunol. 1994;12:881-922 PMID: 7516669
  23. CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity.
    Nat Med. 2009 Aug;15(8):914-20 PMID: 19633658
  24. Dead adipocytes, detected as crown-like structures, are prevalent in visceral fat depots of genetically obese mice.
    J Lipid Res. 2008 Jul;49(7):1562-8 PMID: 18390487
  25. A simple method for the isolation and purification of total lipides from animal tissues.
    J Biol Chem. 1957 May;226(1):497-509 PMID: 13428781
  26. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance.
    J Clin Invest. 2003 Dec;112(12):1821-30 PMID: 14679177
  27. The metabolically benign and malignant fatty liver.
    Diabetes. 2011 Aug;60(8):2011-7 PMID: 21788578
  28. Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes.
    Nat Rev Mol Cell Biol. 2008 May;9(5):367-77 PMID: 18401346
  29. Hepatic triacylglycerol accumulation and insulin resistance.
    J Lipid Res. 2009 Apr;50 Suppl:S74-9 PMID: 18997164
  30. Free fatty acids and insulin resistance.
    Curr Opin Clin Nutr Metab Care. 2007 Mar;10(2):142-8 PMID: 17285001
  31. CD40 ligand mediates inflammation independently of CD40 by interaction with Mac-1.
    Circulation. 2007 Mar 27;115(12):1571-80 PMID: 17372166
  32. Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkbeta.
    Science. 2001 Aug 31;293(5535):1673-7 PMID: 11533494
  33. Fat-specific protein 27, a novel lipid droplet protein that enhances triglyceride storage.
    J Biol Chem. 2007 Nov 23;282(47):34213-8 PMID: 17884815
  34. Obesity, autophagy and the pathogenesis of liver and pancreatic cancers.
    J Gastroenterol Hepatol. 2012 Mar;27 Suppl 2:10-4 PMID: 22320909
  35. Hyperinsulinemic-euglycemic clamp to assess insulin sensitivity in vivo.
    Methods Mol Biol. 2009;560:221-38 PMID: 19504253
  36. Cidea is associated with lipid droplets and insulin sensitivity in humans.
    Proc Natl Acad Sci U S A. 2008 Jun 3;105(22):7833-8 PMID: 18509062
  37. CD40L induces inflammation and adipogenesis in adipose cells--a potential link between metabolic and cardiovascular disease.
    Thromb Haemost. 2010 Apr;103(4):788-96 PMID: 20174757
  38. Eosinophils sustain adipose alternatively activated macrophages associated with glucose homeostasis.
    Science. 2011 Apr 8;332(6026):243-7 PMID: 21436399
  39. Mechanisms linking obesity to insulin resistance and type 2 diabetes.
    Nature. 2006 Dec 14;444(7121):840-6 PMID: 17167471
  40. Inflammation and the IKK beta/I kappa B/NF-kappa B axis in obesity- and diet-induced insulin resistance.
    Int J Obes Relat Metab Disord. 2003 Dec;27 Suppl 3:S49-52 PMID: 14704745
  41. Human fatty liver disease: old questions and new insights.
    Science. 2011 Jun 24;332(6037):1519-23 PMID: 21700865
  42. CD40 and CD154 in cell-mediated immunity.
    Annu Rev Immunol. 1998;16:111-35 PMID: 9597126
  43. CD14 deficiency impacts glucose homeostasis in mice through altered adrenal tone.
    PLoS One. 2012;7(1):e29688 PMID: 22253759
  44. A protective role for CD154 in hepatic steatosis in mice.
    Hepatology. 2010 Dec;52(6):1968-79 PMID: 21064031
  45. Natural killer T cells are involved in adipose tissues inflammation and glucose intolerance in diet-induced obese mice.
    Arterioscler Thromb Vasc Biol. 2010 Feb;30(2):193-9 PMID: 19910631
  46. The immune responses in CD40-deficient mice: impaired immunoglobulin class switching and germinal center formation.
    Immunity. 1994 Jun;1(3):167-78 PMID: 7534202
  47. The inflammatory receptor CD40 is expressed on human adipocytes: contribution to crosstalk between lymphocytes and adipocytes.
    Diabetologia. 2009 Jun;52(6):1152-63 PMID: 19183933
  48. Genetic differences among C57BL/6 substrains.
    Exp Anim. 2009 Apr;58(2):141-9 PMID: 19448337
  49. Reduction of atherosclerosis in mice by inhibition of CD40 signalling.
    Nature. 1998 Jul 9;394(6689):200-3 PMID: 9671306
  50. SIRT1 regulates TNF-α-induced expression of CD40 in 3T3-L1 adipocytes via NF-κB pathway.
    Cytokine. 2012 Nov;60(2):447-55 PMID: 22717288
  51. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease.
    J Clin Invest. 2005 May;115(5):1343-51 PMID: 15864352
Article Info
Journal
American journal of physiology. Endocrinology and metabolism
Abbr.
Am J Physiol Endocrinol Metab
ISSN
1522-1555
DOI
10.1152/ajpendo.00514.2012
Published
2013-05-01
Epub
2013-00-12
Pages
E951-63
Language
English
Region
United States
NLM ID
100901226
PMCID
PMC3651645
Subset
IM
Grants
NIDDK NIH HHS · U24-DK-093000 · United States
NIDDK NIH HHS · DK-085753 · United States
NIDDK NIH HHS · U24 DK093000 · United States
NIAID NIH HHS · AI-046629 · United States
NIDDK NIH HHS · R01 DK080756 · United States
External Links
PubMed source DOI: 10.1152/ajpendo.00514.2012 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2