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

Bobae Kim,Chang-Kee Hyun

doi:10.3390/ijms21145121

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.

Highlights

B-cell-activating factor (BAFF), a member of the tumor necrosis factor (TNF) ligand family, is a cytokine that plays an important role in the proliferation and differentiation of B cells, which has been shown to be a ligand for receptors: BAFF receptor (BAFF-R), B-cell maturation antigen (BCMA) and transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI) [1]
Mice chronically fed a high-fat diet had significant increases in the levels of BAFF in serum and visceral adipose tissue [5], and BAFF-R knockout mice were protected from diet-induced adiposity and insulin resistance [6]. 3T3-L1 adipocytes treated with recombinant BAFF protein showed increased expression of resistin and proinflammatory cytokines, decreased production of adiponectin and impaired insulin-mediated glucose uptake [5]
Aged (10-month-old) mice showed significantly increased body weight accompanied with impaired glucose and insulin tolerance when compared to young (2-month-old) counterparts, indicating that aging is associated with insulin resistance (Figure 1A–C)

Summary

Introduction

B-cell-activating factor (BAFF), a member of the tumor necrosis factor (TNF) ligand family, is a cytokine that plays an important role in the proliferation and differentiation of B cells, which has been shown to be a ligand for receptors: BAFF receptor (BAFF-R), B-cell maturation antigen (BCMA) and transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI) [1]. BAFF was originally identified as a secretory protein in immunocytes, recent studies have described that mature adipocytes produce BAFF and its receptors, suggesting a role of BAFF in the regulation of energy metabolism [2]. It has recently been reported that a circulating BAFF level is positively correlated with body mass index in individuals with obesity [3], and patients with non-alcoholic fatty liver disease have increased levels of serum BAFF [4]. Mice chronically fed a high-fat diet had significant increases in the levels of BAFF in serum and visceral adipose tissue [5], and BAFF-R knockout mice were protected from diet-induced adiposity and insulin resistance [6]. It has recently been reported that obesity-associated insulin resistance and hepatic steatosis were ameliorated in BAFF-deficient mice fed a high-fat diet [7]

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Results

Conclusion