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.
Keywords: B-cell-activating factor (BAFF); adipose tissue browning; aging-dependent insulin resistance; brown adipose tissue; non-shivering thermogenesis.