Loss of OcaB Prevents Age-Induced Fat Accretion and Insulin Resistance by Altering B-Lymphocyte Transition and Promoting Energy Expenditure Sophie Carter, 1,2 Stéphanie Miard, 1 Alexandre Caron, 1,3 Sandrine Sallé-Lefort, 1,2 Philippe St-Pierre, 1,4 Fernando Forato Anhê, 1,4 Emilie Lavoie-Charland, 1,5 Pascale Blais-Lecours, 1,3 Marie-Claude Drolet, 1 Julie S. Lefebvre, 1 Julie Lacombe, 6 Yves Deshaies, 1,3 Jacques Couet, 1,3 Mathieu Laplante, 1,3 Mathieu Ferron, 6,7 Yohan Bossé, 1,5 André Marette, 1,3,4 Denis Richard, 1,3 David Marsolais, 1,3 and Frédéric Picard 1,2 Diabetes 2018;67:1285–1296 | https://doi.org/10.2337/db17-0558 The current demographic shift toward an aging population has led to a robust increase in the prevalence of age- associated metabolic disorders. Recent studies have demonstrated that the etiology of obesity-related insulin resistance that develops with aging differs from that induced by high-calorie diets. Whereas the role of adaptive immunity in changes in energy metabolism driven by nutritional challenges has recently gained attention, its impact on aging remains mostly unknown. Here we found that the number of follicular B2 lymphocytes and expres- sion of the B-cell-speci fic transcriptional coactivator OcaB increase with age in spleen and in intra-abdominal epididymal white adipose tissue (eWAT), concomitantly with higher circulating levels of IgG and impaired glucose homeostasis. Reduction of B-cell maturation and Ig production—especially that of IgG2c—by ablation of OcaB prevented age-induced glucose intolerance and insulin resistance and promoted energy expenditure by stim- ulating fatty acid utilization in eWAT and brown adipose tissue. Transfer of wild-type bone marrow in OcaB 2/2 mice replenished the eWAT B2-cell population and IgG levels, which diminished glucose tolerance, insulin sensitivity, and energy expenditure while increasing body weight gain in aged mice. Thus these findings demonstrate that upon aging, modifications in B-cell-driven adaptive immunity contribute to glucose intolerance and fat accretion. Recent studies have stressed the importance of the adaptive immune response in the pathogenesis of insulin resistance in diet-induced obesity (DIO) (1). In white adipose tissue (WAT), adipocytes are surrounded by cells from the innate and adaptive immune systems that modulate inflammatory status (2–4). In DIO models, the recruitment of B lymphocytes in WAT precedes the infiltration of inflammatory CD4 + and CD8 + T cells and macrophages (5,6), leading to Th1 polarization (7,8) and the production of IgG autoantibodies by B2 cells, which are major factors contributing to the development of insulin resistance (9). In contrast, B-regulatory (10), B1-a (11) and B1-b (12) cell subtypes have, through the secretion of IgM autoantibodies, been shown to favor insulin sensitization in the context of DIO. Aging is characterized by a redistribution and accumula- tion of lipids in visceral and ectopic adipose depots, reduced energy expenditure, and decreased glucose tolerance (13). However, the etiology of insulin resistance that develops with aging has been suggested to differ from that induced by 1 Centre de recherche de l’Institut universitaire de cardiologie et de pneumologie de Québec, Québec, QC, Canada 2 Faculty of Pharmacy, Université Laval, Québec, QC, Canada 3 Department of Medicine, Faculty of Medicine, Université Laval, Québec, QC, Canada 4 Institute for Nutrition and Functional Foods, Québec, QC, Canada 5 Department of Molecular Medicine, Faculty of Medicine, Université Laval, Québec, QC, Canada 6 Integrative and Molecular Physiology Research Unit, Institut de recherches cliniques de Montréal, Montréal, QC, Canada 7 Department of Medicine and Biochemistry, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada Corresponding author: Frédéric Picard, frederic.picard@criucpq.ulaval.ca. Received 15 May 2017 and accepted 19 February 2018. This article contains Supplementary Data online at http://diabetes .diabetesjournals.org/lookup/suppl/doi:10.2337/db17-0558/-/DC1. © 2018 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals .org/content/license. Diabetes Volume 67, July 2018 1285 OBESITY STUDIES