K Mori, Laboratory of Molecular and Cellular Biochemistry, Kyushu University, Fukuoka, Japan.
A Mizokami, Oral Health/Brain Health/Total Health Research Center, Kyushu University, Fukuoka, Japan.
J Endocrinol. 2022 May 31;254(1):27-36. doi: 10.1530/JOE-21-0424.
Menopausal women are susceptible to visceral obesity, which increases the risk of metabolic disorders. However, the mechanisms of menopause-induced visceral fat accumulation are not fully understood. Circulating levels of receptor activator of nuclear factor-kappa B (NF-κB) ligand (RANKL) are elevated in an animal model of menopause. RANKL, a multifunctional cytokine, activates the NF-κB pathway, which serves as a pivotal mediator of inflammatory responses. Here, we investigated whether RANKL-induced non-canonical NF-κB pathway activation induces inflammation and lipid accumulation in adipose tissues. RANKL induced Tnfa expression via the non-canonical NF-κB pathway in bone marrow cells. We therefore analyzed aly/aly mice, in which the non-canonical NF-κB pathway is not activated, owing to an inactive form of NF-κB-inducing kinase. A postmenopausal obesity model was generated by ovariectomy and subsequent high-fat and high-sucrose diet feeding. In aly/aly mice with postmenopausal obesity, serum RANKL levels were elevated, and hepatic lipid accumulation and adipocyte hypertrophy were suppressed, resulting in reduced macrophage infiltration and inflammatory cytokine mRNA expression in visceral adipose tissue. Furthermore, aly/aly mice showed protection from glucose intolerance and insulin resistance, which were observed in ovariectomized WT obese mice. These findings indicate that non-canonical NF-κB pathway activation via serum RANKL elevation contributes to postmenopausal obesity.
绝经后妇女易患内脏肥胖，这会增加代谢紊乱的风险。然而，绝经引起内脏脂肪堆积的机制尚不完全清楚。在绝经动物模型中，核因子-κB（NF-κB）受体激活剂（RANKL）的循环水平升高。RANKL 是一种多功能细胞因子，可激活 NF-κB 途径，该途径是炎症反应的关键介质。在这里，我们研究了 RANKL 诱导的非经典 NF-κB 途径激活是否会引起脂肪组织的炎症和脂质积累。RANKL 通过骨髓细胞中的非经典 NF-κB 途径诱导 Tnfa 表达。因此，我们分析了aly/aly 小鼠，由于 NF-κB 诱导激酶的无活性形式，其非经典 NF-κB 途径未被激活。通过卵巢切除术和随后的高脂肪和高蔗糖饮食喂养，建立绝经后肥胖模型。在绝经后肥胖的 aly/aly 小鼠中，血清 RANKL 水平升高，肝脂质积累和脂肪细胞肥大受到抑制，导致内脏脂肪组织中巨噬细胞浸润和炎性细胞因子 mRNA 表达减少。此外，在卵巢切除的 WT 肥胖小鼠中观察到的葡萄糖不耐受和胰岛素抵抗在 aly/aly 小鼠中得到了保护。这些发现表明，血清 RANKL 升高导致的非经典 NF-κB 途径激活有助于绝经后肥胖。
