The role of B cell estrogen signaling in menopause-associated metabolic dysfunction

ABSTRACT Obesity is prevalent in women in the peri- and postmenopausal years. After menopause, women experience greater risks of many diseases, including cardiovascular disease and type 2 diabetes (T2D). Estrogen (E2) loss alters body composition by increasing and redistributing body fat, and decreasing energy expenditure and metabolic flexibility. Together, these changes contribute to impaired whole-body metabolism. Adipose tissue (AT) immune cell infiltration is a hallmark and driver of metabolic dysfunction during weight gain and obesity. B cells express estrogen receptor alpha (ERα) and their role in initiating or promoting insulin resistance and weight gain by cytokine and antibody secretion, modulating other immune cells, and promoting AT inflammation and expansion is poorly understood. B cells accumulate in AT during weight gain and are required for obesity development in male mice. When compared with immune-competent mice, B cell-deficient mice have reduced weight gain and reduced fasting glucose levels after ovariectomy (OVX), a model of menopause. Recent findings suggest that while E2 replacement after experimentally induced menopause prevents weight gain and improves glucose metabolism, this effect is blunted in B cell ERα knockout mice. This finding demonstrates that B cell E2- ERα signaling is a modulator of menopause-associated weight gain. The menopause-specific effects of estrogen loss on B cell differentiation and trafficking into AT during peri and menopausal weight gain and with obesity are not fully understood. Our overall hypothesis is that the loss of E2-ERα signaling in B cells contributes to post- OVX weight gain by increasing proinflammatory cells and decreasing regulatory B cells in AT, ultimately resulting in AT expansion, metabolic dysfunction, and low-grade systemic inflammation during induced perimenopause and into menopause. We will use wild-type mice, B cell-deficient mice, and our B cell-specific ERα knockout female mice to: 1) determine how the progressive decline of E2 alters B cell phenotype and infiltration into AT during induced perimenopause and into menopause; 2) delineate B cell-mediated, E2-dependent effects on weight gain in the aged milieu; and 3) define whether weight gain is attributable to B cells programmed to a proinflammatory state by obesity or the loss of E2 signaling. These studies have the potential to uncover novel immune regulators of AT expansion during menopause, metabolic dysfunction, and the subsequent risk of developing age-related diseases.