Macrophage and T-reg Participation in the Adipose Tissue Inflammation of Obese Humans

Diane Mathis, Ph.D.

Joslin Diabetes Center

Funded in December, 2007: $285000 for 3 years
LAY SUMMARY . ABSTRACT . BIOGRAPHY . SELECTED PUBLICATIONS .

LAY SUMMARY

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Do Certain Immune Cells Promote Chronic Fat Cell Inflammation Associated with Diabetes?

Collaborating researchers at the Joslin Diabetes Center will investigate the immunological characteristics of the chronic inflammation associated with human weight gain and obesity that may underlie insulin resistance and diabetes.

Obesity is accompanied by chronic, low-grade inflammation, which is thought to promote insulin resistance, type 2 diabetes and other features of the “metabolic syndrome,” such as heart disease and atherosclerosis.  Fat tissue is a primary site for initiating this inflammation. Interestingly, fat tissue in different areas of the body such as under the skin or inside the belly (or abdomen) appears to behave differently.  The inflammation in abdominal fat, inside the belly and surrounding the internal organs, has a greater association with insulin resistance compared with subcutaneous fat under the skin.

Research in animals by these and other investigators has identified two major types of immune cells in fat tissue—macrophages and T cells—that appear to play major roles in the chronic inflammation associated with obesity and diabetes.  To test whether normal immune processes that ordinarily suppress inflammation are dysregulated in obesity, they will study adipose tissue from non-diabetic men and women who are scheduled for elective abdominal surgery.  Tissue samples will be removed during surgery from 30 consenting participants, half of whom are obese and half lean. 

The investigators will then quantify and characterize four types of immune cells in the adipose tissue that surrounds organs, and in the adipose tissue from under the skin. The four types of immune cells they will study are conventional immune macrophages; fat-laden macrophages (called “foam cells”); conventional immune T cells; and regulatory T cells.   Then they will analyze potential pro-inflammatory and anti-inflammatory interactions amongst the two types of macrophages (conventional and foam cell), the two types of T cells (conventional and regulatory), and fat-storing cells in the participants’ tissue samples.  They will also study these interactions in tissue culture.

The researchers anticipate that the obese (compared with the lean) participants will have increased levels of fat-laden macrophages and decreased levels of regulatory T cells, which in combination result in chronic inflammation, and that the chronic inflammation correlates with increased fat storage, and ultimately with insulin resistance and type 2 diabetes.

Significance: The findings may lead to clinical studies of anti-inflammatory treatments to prevent chronic inflammation in fat tissues, and potentially the onset of diabetes, in people who are obese.

ABSTRACT

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Macrophage and T-reg Participation in the Adipose Tissue Inflammation of Obese Humans

Obesity is accompanied by chronic, low-grade inflammation, which is thought to promote insulin resistance, type-2 diabetes, and other features of the “metabolic syndrome.” Adipose tissue is a primary site for initiating this inflammation, alterations in visceral fat having a greater association with insulin resistance than those in subcutaneous fat. Our three laboratories, with expertise in three very different areas, have recently joined forces to investigate the immunological underpinnings of the chronic inflammatory state associated with weight gain and obesity in mammals, in particular humans. Here, we propose to analyze in human fat the functions of what our (and others’) preliminary data have revealed are two key cell-types in rodent adipose tissue inflammation: macrophages and T cells. We will study immune system cell-types in adipose tissue from visceral and subcutaneous depots of lean and obese humans, including thirty non-diabetic men and women, aged 21-65 yr, specifically including 15 lean (BMI<27 kg/m2) and 15 obese (BMI>40 kg/m2) individuals.

The specific aims are to: 1) Enumerate and characterize conventional macrophages and lipid-laden foam-cell populations in visceral vs subcutaneous adipose tissue from lean vs obese humans; 2) Enumerate and characterize the T conventional (Tconv) and T regulatory (Treg) cell populations in visceral vs subcutaneous adipose tissue from lean vs obese humans; and 3) Analyze potential pro- vs anti-inflammatory interactions between macrophages (conventional and foam cell), T cells (Tconv and Treg) and adipocytes in human adipose tissue samples and in in vitro co-culture experiments. These studies attempt to translate novel, unpublished findings on mouse models to the human system, with the ultimate goal of addressing one of the 21st century’s most important health issues.

INVESTIGATOR BIOGRAPHIES

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Diane Mathis, Ph.D.

Dr. Diane Mathis obtained a B.Sc. from Wake Forest University and a Ph.D. from the University of Rochester. She performed postdoctoral studies at the Laboratoire de Génétique Moléculaire des Eucaryotes in Strasbourg, France, and at Stanford University Medical Center. She returned to France at the end of 1983, establishing a laboratory at the Institut de Genetique et de Biologie Moleculaire et Cellulaire in Strasbourg, in conjunction with Dr. Christophe Benoist. The lab moved to the Joslin Diabetes Center at the end of 1999. Dr. Mathis is currently a Professor of Medicine at Brigham and Women’s Hospital and Harvard Medical School, and is an Associate Research Director and Head of the Section on Immunology and Immunogenetics at Joslin, where she holds the William T. Young Chair in Diabetes Research. She is Director of the JDRF Center on Immunological Tolerance in Type-1 Diabetes at HMS, a Principal Faculty Member at the Harvard Stem Cell Institute and an Associate Faculty Member of The Broad Institute. Dr. Mathis was elected to the US National Academy of Sciences in 2003 and to the German Academy in 2007.

The lab works in the fields of T cell differentiation and autoimmunity, with a special emphasis on exploiting the most advanced transgenic and gene-targeting technology to engineer new mouse models.

Dr. Steven Shoelson is an internationally recognized leader in diabetes research.  He received a Ph.D. in chemistry and a medical degree from the University of Chicago. After completing internship and residency training at the Brigham and Women’s Hospital in Boston, he joined the faculty at the Joslin Diabetes Center, and has stayed at the Joslin throughout his professional career.  Dr. Shoelson currently heads the Section on Cellular and Molecular Physiology, and is the Helen and Morton Adler Chair and an Associate Director of Research at the Joslin Diabetes Center.  He is Professor of Medicine and an affiliated member in the Department of Biological Chemistry and Molecular Pharmacology at Harvard Medical School. He has received numerous awards and honors, including a Burroughs Wellcome Fund Scholar Award in Experimental Therapeutics, the Excellence in Diabetes Research Award of the Juvenile Diabetes Research Foundation, and a MERIT award from the NIH.

Dr. Shoelson’s research focuses on understanding the pathogenesis of insulin resistance and type 2 diabetes, with a special interest in the link between obesity and inflammation.

Dr. Allison Goldfine is recognized as a leader in clinical diabetes research.  She received her medical degree from the University of Pennsylvania.  After completing internship and residency training in Internal Medicine at the University of Massachusetts in Worcester, she joined the Joslin Diabetes Center for subspecialty training in Endocrinology and Diabetes, and has stayed at the Joslin as faculty throughout her professional career.  Dr. Goldfine is currently Assistant Director of Clinical Research at the Joslin Diabetes Center.  She is an Assistant Professor of Medicine at Harvard Medical School. She has received numerous awards and honors, including a career development award from the American Diabetes Association.

Dr. Goldfine’s research focuses on understanding the physiologic processes underlying insulin resistance and type 2 diabetes in people, with a special interest in new therapies to treat or prevent development of diabetes and its complications. In other research, Dr. Shoelson’s laboratory recently discovered and created three-dimensional structures of the gene and protein mutations that cause maturity-onset diabetes of the young (MODY), a form of type 2 diabetes that is appearing more frequently among young people—an alarming trend related to increased obesity among the young. The findings of Dr. Shoelson’s laboratory create the potential for improved treatments.

SELECTED PUBLICATIONS

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Klunk WE, Engler H, Nordberg A, Wang Y, Blomqvist G, Holt DP, Bergstrom M, Savitcheva I, Huang G-F, Estrada S, Ausen B, Debnath ML, Barletta J, Price JC, Sandell J, Lopresti BJ, Wall A, Koivisto P, Antoni G, Mathis CA, Langstrom B.  Imaging Brain Amyloid in Alzheimer’s Disease Using the Novel PET Tracer PIB.  Annals of Neurology 2004; 55: 306-319.

Mathis CA, Wang Y, Klunk WE.  Imaging b-Amyloid Plaques and Neurofibrillary Tangles in the Aging Human Brain.  Current Pharmaceutical Design 2004; 10: 1469-1492.

Sadowski M, Pankiewicz J, Scholtzova H, Tsai J, Li Y, Carp RI, Meeker HC, Gambetti P, Debnath M, Mathis CA, Shao L, Gan W-B, Klunk WE, Wisniewski T.  Targeting Prion Amyloid Deposits In Vivo.  J. Neuropath. Exptl. Neurol. 2004; 63: 775-784.

Brendza RP, Bacskai BJ, Cirrito JR, Simmons KA, Skoch JM, Klunk WE, Mathis CA, Bales KR, Paul SM, Hyman BT, Holtzman DM.  Anti-Ab antibody treatment promotes the rapid recovery of amyloid-associated neuritic dystrophy in PDAPP transgenic mice.  J. Clinical Investigation 2005; 115:428-433.

Mathis CA, Klunk WE, Price JC, DeKosky ST.  Imaging technology for neurodegenerative diseases:  Progress toward detection of specific pathologies.  Archives of Neurology 2005; 62:196-200.

Matsuoka Y, Shao L, Debnath M, Lafrancois J, Becker A, Gray A, Aisen P, Mathis C, Klunk W, Duff K. An Abeta sequestration approach using non-antibody Abeta binding agents. Current Alzheimer Research 2005; 2:265-268.

Buckner RL, Snyder AZ, Shannon BJ, LaRossa G, Sachs R, Fotenos AF, Sheline YI, Klunk WE, Mathis CA, Morris JC, Mintun MA.  Molecular, structural, and functional characterization of Alzheimer's disease: evidence for a relationship between default activity, amyloid, and memory.  J Neuroscience 2005; 25:7709-7717.

Price JC, Klunk WE, Lopresti BJ, Lu X, Hoge JA, Ziolko SK, Holt DP, Meltzer CC, Dekosky ST, Mathis CA.  Kinetic modeling of amyloid binding in humans using PET imaging and Pittsburgh Compound-B.    J. Cerebral Blood Flow and Metabolism 2005; 25:1528-1547.

Klunk WE, Lopresti BJ, Ikonomovic MD, Lefterov IM, Koldamova RP, Abrahamson EE, Debnath ML, Holt DP, Huang G-F, Shao Li, DeKosky ST, Price JC, Mathis CA.  The Binding of the PET Tracer, Pittsburgh Compound-B (PIB), Reflects the Amount of Ab in Alzheimer’s Disease Brain, but not in PS1/APP Mouse Brain.  J. Neuroscience 2005; 25:10598-10606.

Lopresti BJ, Klunk WE, Mathis CA, Hoge JA, Ziolko SK, Lu X, Meltzer CC, Schimmel K, Tsopelas N, DeKosky ST, Price JC.  Simplified Quantification of Pittsburgh Compound-B Amyloid Imaging PET Studies:  A Comparative Analysis.  J. Nuclear Medicine 2005; 46:1959-1972.

Fagan AM, Mintun MA, Mach RH, Lee S-Y, Dence CS, Shah AR, LaRossa GN, Spinner ML, Klunk WE, Mathis CA, DeKosky ST, Morris JC and Holtzman DM.  Inverse relationship between in vivo amyloid imaging load and CSF Ab42 in humans.  Annals of Neurology 2006; 59:512-519.

Mintun MA, Larossa GN, Sheline YI, Dence CS, Lee SY, Mach RH, Klunk WE, Mathis CA, DeKosky ST, Morris JC.  [11C]PIB in a nondemented population: potential antecedent marker of Alzheimer disease.  Neurology 2006; 67:446-52.

Ziolko SK, Weissfeld LA, Klunk WE, Mathis CA, Hoge JA, Lopresti BJ, DeKosky ST, Price JC. Evaluation of voxel-based methods for the statistical analysis of PIB PET amyloid imaging studies in Alzheimer's disease.  Neuroimage 2006; 33: 94-102.

Ikonomovic MD, Abrahamson EE, Isanski BA, Debnath ML, Mathis CA, DeKosky ST, Klunk WE. X-34 labeling of abnormal protein aggregates during the progression of Alzheimer's disease.  Methods in Enzymology 2006; 412: 123-44. 

Bacskai BJ, Frosch MP, Freeman SH, Raymond SB, Augustinack JC, Johnson KA, Irizarry MC, Klunk WE, Mathis CA, DeKosky ST, Hyman BT, Growdon JH.  Molecular imaging with Pittsburgh Compound-B confirmed at autopsy.  Arch. Neurology 2007; 64:431-434.

Rabinovici GD, Furst, AJ, O’Neil JP, Racine CA, Mormino EC, Baker SL, Chetty S, Patel P, Pagliaro TA, Klunk WE, Mathis CA, Rosen HJ, Miller BL and Jagust W. 11C-PIB PET imaging in Alzheimer disease and frontotemporal lobar degeneration.  Neurology 2007; 68:1205-12.

Zhou Y, Resnick SM, Ye W, Fan H, Holt D, Klunk WE, Mathis CA, Dannals R, Wong DF. Using a reference tissue model with spatial constraint to quantify [11C]Pittsburgh compound B PET for early diagnosis of Alzheimer’s disease.  Neuroimage 2007; 36:298-312.

Rowe CC, Ng S, Ackermann U, Gong SJ, Pike K, Savage G, Cowie T, Dickinson K, Maruff P, Darby D, Smith C , Woodward M, Merory J, Tochon-Danguy H, O’Keefe G, Klunk WE, Mathis CA, Price JC, Masters CL, Villemagne VL.  Imaging b-Amyloid Burden in Aging and Dementia. Neurology 2007; 68:1718-25.

Klunk WE, Price JC, Mathis CA, Tsopelas ND, Lopresti BJ, Ziolko SK, Bi W, Ikonomovic MD, Saxton J, Snitz E, Pollen DA, Moonis M, Lippa CF, Swearer J, Johnson KA, Rentz DM, Fischman AJ, Aizenstein H, DeKosky ST.  Amyloid Deposition Begins in the Striatum of Presenilin-1 Mutation Carriers from Two Unrelated Pedigrees.  J. Neurosci. 2007: 27:6174-6184.

Mathis CA, Lopresti BJ, Klunk WE.  Impact of amyloid imaging on drug development in Alzheimer’s disease.  Nuclear Medicine and Biology 2007; 34:809-822.

Johnson KA, Gregas M, Becker JA, Kinnecom K, Salat DH, Moran EK, Smith EE, Rosand J, Rentz DM, Klunk WE, Mathis CA, Price JC, DeKosky ST, Fischman AJ and Greenberg SM. Imaging of Amyloid Burden and Distribution in Cerebral Amyloid Angiopathy with Pittsburgh Compound B.  Annals of Neurology 2007;  62:229-234.

Pike KE, Savage G, VillemagneVL, Ng S, Moss SA, Maruff P, Mathis CA, Klunk WE, Masters CL, Rowe CC.  β-amyloid imaging and memory in nondemented individuals: Evidence for preclinical Alzheimer’s disease.  Brain 2007; 130:2837-2844.

Drzezga A, Grimmer T, Henriksen G, Stangier I, Perneczky R, Diehl-Schmid J, Mathis CA, Klunk WE, Price J, DeKosky S, Wester H, Schwaiger M, and Kurz A.  Imaging of amyloid-plaques and cerebral glucose metabolism in semantic dementia and Alzheimer’s disease.  NeuroImage 2008; 39:619-633.

Jack CR Jr, Lowe VJ, Senjem ML, Weigand SD, Kemp BJ, Shiung MM, Knopman DS, Boeve BF, Klunk WE, Mathis CA, Petersen RC.  11C-PiB and structural MRI provide complementary information in imaging of Alzheimer's disease and amnestic mild cognitive impairment.  Brain 2008; 131:665-80.

Bolmont T, Haiss F, Eicke D,  Radde R, Mathis CA, Klunk WE, Kohsaka S, Jucker M, Calhoun ME.  Dynamics of the Microglial/Amyloid Interaction Indicate a Role in Plaque Maintenance.  J Neurosci. 2008; 28:4283-92.

Ikonomovic MD, Klunk WE, Abrahamson EE, Mathis CA, Price JC, Tsopelas ND, Lopresti BJ, Ziolko SK, Bi W, Paljug WR, Debnath ML, Hope CE, Isanski BA, Hamilton RL and DeKosky ST. Post-mortem correlates of in vivo PiB-PET amyloid imaging in a typical case of Alzheimer’s disease.  Brain 2008; 131:1630-1645.

Raji CA, Becker JT, Tsopelas ND, Price JC, Mathis CA, Saxton JA, Lopresti BJ, Hoge JA, Ziolko SK, Dekosky ST, Klunk WE.  Characterizing regional correlation, laterality and symmetry of amyloid deposition in mild cognitive impairment and Alzheimer's disease with Pittsburgh Compound B.               J Neurosci Methods 2008;  172:277-282.

Venneti S, Lopresti BJ, Wang G, Hamilton RL, Mathis CA, Klunk WE, Apte UM, Wiley CA.  PK11195 labels activated microglia in Alzheimer's disease and in vivo in a mouse model using PET.  Neurobiology of Aging. 2008; Jan 4 [Epub ahead of print].

Grimmer T, Henriksen G, Wester H, Först H, Klunk WE, Mathis CA, Kurz A, Drzezga A.  Clinical severity of Alzheimer's disease is associated with PIB uptake in PET.  Neurobiology of Aging 2008; Mar 16 [Epub ahead of print].

Butters MA, William E. Klunk WE, Mathis CA, Price JC, Ziolko SK, Hoge JA, Tsopelas ND, Lopresti BJ, Reynolds CF III, DeKosky ST, Meltzer CC.  Imaging Alzheimer's Pathology in Late-Life Depression with PET and Pittsburgh Compound-B.  Alzheimer Disease & Associated Disorders 2008; Jun 17 [Epub ahead of print].

Aizenstein HJ, Nebes RD, Saxton JA, Price JC, Mathis CA, Tsopelas ND, Ziolko S, Snitz B, Houck P, Bi W, Cohen A, Lopresti BJ, DeKosky ST, Halligan E, Klunk WE.  Amyloid deposition is frequent and often is ot associated with significant cognitive impairment in the elderly.  Archives of Neurology 2008; (in press).