PDF(Pubmed)
Abstract：
Thyroid hormone (TH) plays a crucial role in regulating the functions of both bone and adipose tissue. Given that TH exerts its cholesterol-lowering effects in hepatic tissue through the TH receptor-β (TRβ), we hypothesized that TRβ agonist therapy using MGL3196 (MGL) would be effective in treating increased adiposity and bone loss in response to a 12-week high-fat diet (HFD) in adult C57BL/6J mice. Transcriptional and serum profiling revealed that HFD-induced leptin promoted weight gain in both males and females, but MGL only suppressed leptin induction and weight gain in males. In vitro studies suggest that estrogen suppresses MGL activity in adipocytes, indicating that estrogen might interfere with MGL-TRβ function. Compared to systemic adiposity, HFD reduced bone mass in male but not female mice. Paradoxically, MGL treatment reversed macroscopic bone mineral density loss in appendicular bones, but micro-CT revealed that MGL exacerbated HFD-induced trabecular bone loss, and reduced bone strength. In studies on the mechanisms for HFD effects on bone, we found that HFD induced Rankl expression in male femurs that was blocked by MGL. By ex vivo assays, we found that RANKL indirectly represses osteoblast lineage allocation of osteoprogenitors by induction of inflammatory cytokines TNFα, IL-1β, and CCL2. Finally, we found that MGL functions in both systemic adiposity and bone by nongenomic TRβ signaling, as HFD-mediated phenotypes were not rescued in TRβ147F knockout mice with normal genomic but defective nongenomic TRβ signaling. Our findings demonstrate that the negative effects of HFD on body fat and bone phenotypes are impacted by MGL in a gender-specific manner.
摘要：
甲状腺激素（TH）在调节骨骼和脂肪组织的功能中起着至关重要的作用。鉴于TH通过TH受体β（TRβ）在肝组织中发挥其降胆固醇作用，我们假设使用MGL3196(MGL)的TRβ激动剂治疗可有效治疗成年C57BL/6J小鼠12周高脂饮食(HFD)所致的肥胖和骨丢失增加.转录和血清分析显示，HFD诱导的瘦素促进男性和女性的体重增加，但MGL只能抑制男性的瘦素诱导和体重增加。体外研究表明，雌激素抑制脂肪细胞MGL活性，提示雌激素可能干扰MGL-TRβ功能。与系统性肥胖相比，HFD降低了雄性小鼠而不是雌性小鼠的骨量。矛盾的是,MGL治疗逆转了阑尾骨的宏观BMD损失，但Micro-CT显示MGL加重了HFD诱导的骨小梁丢失,和骨骼强度。在研究HFD对骨的影响机制，我们发现HFD诱导男性股骨中的Rankl表达被MGL阻断。通过离体测定，我们发现RANKL通过诱导炎症细胞因子TNFα间接抑制骨祖细胞的成骨细胞谱系分配，IL-1β,CCL2。最后,我们发现MGL通过非基因组TRβ信号在全身肥胖和骨骼中起作用，因为在具有正常基因组但非基因组TRβ信号传导缺陷的TRβ147F敲除小鼠中,HFD介导的表型未被挽救.我们的发现表明，HFD对身体脂肪和骨骼表型的负面影响受到MGL以性别特异性方式的影响。
