Journal Article

Normalization of obesity-associated insulin resistance through immunotherapy

Zielenski, Julian, Bahrami, Jasmine, Tsui, Hubert, Dorfman, Ruslan, Dosch, H.-Michael, Chan, Yin, Truong, Dorothy, Drucker, Daniel J, Mastronardi, Fabrizio, Paltser, Geoffrey, Engleman, Edgar, Winer, Shawn, Wang, Yongqian, Winer, Daniel, Maezawa, Yuko

2009

Overview

In these new reports, three different research groups independently find that various T cell populations are crucial mediators of obesity-induced metabolic dysfunction. They also show that pharmacological approaches that target these T cells are beneficial, thus opening the door to possible new therapeutic approaches to treating obesity-related diseases such as diabetes ( pages 846–847 , 914–920 and 930–939 ). 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 α repertoires, suggesting antigen-specific expansion. CD4 + T lymphocyte control of glucose homeostasis is compromised in DIO progression, when VAT accumulates pathogenic interferon-γ (IFN-γ)-secreting T helper type 1 (T H 1) cells, overwhelming static numbers of T H 2 (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 T H 2 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 T H 1 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: Adipose tissue / Adipose Tissue - immunology / Adipose Tissue - metabolism / Adipose Tissue - pathology / Animals / Biomedical and Life Sciences / Biomedicine / Cancer Research / Care and treatment / CD4-Positive T-Lymphocytes - immunology / CD4-Positive T-Lymphocytes - pathology / CD4-Positive T-Lymphocytes - physiology / Cell Separation / Complications and side effects / Diet / Glucose - metabolism / Health aspects / Homeodomain Proteins - genetics / Homeostasis - immunology / Immunotherapy / Immunotherapy - methods / Infectious Diseases / Insulin resistance / Insulin Resistance - immunology / Lymphocytes / Metabolic Diseases / Metabolic disorders / Methods / Mice / Mice, Inbred C57BL / Mice, Knockout / Mice, Obese / Molecular Medicine / Neurosciences / Obesity / Obesity - complications / Obesity - immunology / Obesity - pathology / Obesity - therapy / Pathology / Patient outcomes / Risk factors / T cells