B-Cell-Activating Factor Depletion Ameliorates Aging-Dependent Insulin Resistance via Enhancement of Thermogenesis in Adipose Tissues

Abstract

Impaired glucose tolerance is a common feature associated with human aging, which is caused by defects in insulin secretion, insulin action or both. Recent studies have suggested that B-cell-activating factor (BAFF), a cytokine that modulates proliferation and differentiation of B cells, and its receptors are expressed in mature adipocytes and preadipocytes, proposing BAFF as a potential regulator of energy metabolism. In this study, we show that systemic BAFF depletion improves aging-dependent insulin resistance. In aged (10-month-old) BAFF−/− mice, glucose tolerance and insulin sensitivity were significantly improved despite higher adiposity as a result of expansion of adipose tissues compared to wild-type controls. BAFF−/− mice displayed an improved response to acute cold challenge, commensurate with the up-regulated expression of thermogenic genes in both brown and subcutaneous adipose tissues. These changes were found to be mediated by both increased M2-like (alternative) macrophage activation and enhanced leptin and FGF21 production, which may account for the improving effect of BAFF depletion on insulin resistance. In addition, leptin-deficient mice (ob/ob) showed augmented BAFF signaling concomitant with impaired thermogenic activity, identifying BAFF as a suppressive factor to thermogenesis. Our findings suggest that suppression of BAFF could be a therapeutic approach to attenuate aging-dependent insulin resistance.

Influence of SARS-CoV-2 Status and Aging on the Nasal and Fecal Immunological Profiles of Elderly Individuals Living in Nursing Homes

“…Interestingly, BAFF/TNFSF13B is considered as a potential anti-aging target since its concentration is particularly elevated in senescent cells and suppression of its production reduces IL6 secretion and senescent-associated phenotypes [ 34 ]. In fact, suppression of this cytokine has been suggested as a therapeutic approach to minimize aging-dependent insulin resistance [ 35 ].…”

Fat‐associated lymphoid clusters: Supporting visceral adipose tissue B cell function in immunity and metabolism

“…103 Another study identified higher mRNA expression of M2 macrophage markers and anti-inflammatory cytokines in the adipose tissue of BAFF deficient mice, although alterations in AT B cells were not directly examined. 104 Conversely, reconstitution of HFD fed, B cell deficient mice with B2 cells isolated from the VAT of HFD fed, wild-type mice increased the percentage of M1 polarized adipose tissue macrophages, production of IL-6 and IL1b and NFκb signaling in the recipient's VAT, and also led to impaired glucose tolerance. This elegantly demonstrating the pro-inflammatory, pathogenic phenotype of adipose B2 cells in this model of dietary-induced obesity.…”

“…More direct evidence of the specific effect of B2 cells was observed with the selective depletion of peripheral B2 cells in HFD mice with an anti‐B‐cell activating factor (BAFF) antibody, which reduced VAT IgG production and improved glucose tolerance 103 . Another study identified higher mRNA expression of M2 macrophage markers and anti‐inflammatory cytokines in the adipose tissue of BAFF deficient mice, although alterations in AT B cells were not directly examined 104 . Conversely, reconstitution of HFD fed, B cell deficient mice with B2 cells isolated from the VAT of HFD fed, wild‐type mice increased the percentage of M1 polarized adipose tissue macrophages, production of IL‐6 and IL1b and NF‐κb signaling in the recipient's VAT, and also led to impaired glucose tolerance.…”