B-1a Lymphocytes Attenuate Insulin Resistance

• DOI: 10.2337/db14-0554
• Publication Date: 2014-09-24T05:38:07Z
• Authors: Lei Shen; Melissa Hui Yen Chng; Michael N. Alonso; Robert Yuan; Daniel A. Winer; Edgar G. Engleman
• Keywords: Blood Glucose; Male; 0301 basic medicine; 2. Zero hunger; B-Lymphocyte Subsets; Middle Aged; Dietary Fats; Interleukin-10; Mice, Inbred C57BL; Mice; 03 medical and health sciences; Gene Expression Regulation; Immunoglobulin M; Glucose Intolerance; Animals; Humans; Female; Obesity; Immunology and Transplantation; Insulin Resistance

Obesity-associated insulin resistance, a common precursor of type 2 diabetes, is characterized by chronic inflammation of tissues, including visceral adipose tissue (VAT). Here we show that B-1a cells, a subpopulation of B lymphocytes, are novel and important regulators of this process. B-1a cells are reduced in frequency in obese high-fat diet (HFD)-fed mice, and EGFP interleukin-10 (IL-10) reporter mice show marked reductions in anti-inflammatory IL-10 production by B cells in vivo during obesity. In VAT, B-1a cells are the dominant producers of B cell–derived IL-10, contributing nearly half of the expressed IL-10 in vivo. Adoptive transfer of B-1a cells into HFD-fed B cell–deficient mice rapidly improves insulin resistance and glucose tolerance through IL-10 and polyclonal IgM-dependent mechanisms, whereas transfer of B-2 cells worsens metabolic disease. Genetic knockdown of B cell–activating factor (BAFF) in HFD-fed mice or treatment with a B-2 cell–depleting, B-1a cell–sparing anti-BAFF antibody attenuates insulin resistance. These findings establish B-1a cells as a new class of immune regulators that maintain metabolic homeostasis and suggest manipulation of these cells as a potential therapy for insulin resistance.