Study Title:

Antihistamines Prevent Obesity and Diabetes

Study Abstract

Obesity and its associated metabolic syndromes represent a growing global challenge, yet mechanistic understanding of this pathology and current therapeutics are unsatisfactory. We discovered that CD4+ T lymphocytes, resident in visceral adipose tissue (VAT), control insulin resistance in mice with diet-induced obesity (DIO). Analyses of human tissue suggest that a similar process may also occur in humans. DIO VAT-associated T cells show severely biased T cell receptor V repertoires, suggesting antigen-specific expansion. CD4+ T lymphocyte control of glucose homeostasis is compromised in DIO progression, when VAT accumulates pathogenic interferon- (IFN-)-secreting T helper type 1 (TH1) cells, overwhelming static numbers of TH2 (CD4+GATA-binding protein-3 (GATA-3)+) and regulatory forkhead box P3 (Foxp3)+ T cells. CD4+ (but not CD8+) T cell transfer into lymphocyte-free Rag1-null DIO mice reversed weight gain and insulin resistance, predominantly through TH2 cells. In obese WT and ob/ob (leptin-deficient) mice, brief treatment with CD3-specific antibody or its F(ab')2 fragment, reduces the predominance of TH1 cells over Foxp3+ cells, reversing insulin resistance for months, despite continuation of a high-fat diet. Our data suggest that the progression of obesity-associated metabolic abnormalities is under the pathophysiological control of CD4+ T cells. The eventual failure of this control, with expanding adiposity and pathogenic VAT T cells, can successfully be reversed by immunotherapy.

Study Information

Shawn Winer, Yin Chan, Geoffrey Paltser, Dorothy Truong, Hubert Tsui, Jasmine Bahrami, Ruslan Dorfman, Yongqian Wang, Julian Zielenski, Fabrizio Mastronardi, Yuko Maezawa, Daniel J Drucker, Edgar Engleman, Daniel Winer & H.-Michael Dosch.
Normalization of obesity-associated insulin resistance through immunotherapy.
Nature Medicine
2009 July
1.Neuroscience & Mental Health Program, Research Institute, The Hospital for Sick Children, University of Toronto Departments of Pediatrics & Immunology, Toronto, Ontario, Canada.

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