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.
Nature Medicine – Springer Journals
Published: Jul 26, 2009
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