Thyroid hormone receptor β1 agonist therapy for the treatment of bone marrow adiposity in aging and obesity

甲状腺激素受体β1激动剂疗法治疗衰老和肥胖症中的骨髓肥胖

• 批准号: 9893266
• 负责人: SUBBURAMAN MOHAN
• 金额: $ 21.98万
• 依托单位: LOMA LINDA VETERANS ASSN RESEARCH & EDUC
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-15 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9893266
• 关键词: Adipocytes; Adipose tissue; Adult; Adverse effects; Affect; Age; Aging; Agonist; Animals; Area; Binding; Bone Marrow; Bone Tissue; Bone remodeling; Brown Fat; Cardiovascular Diseases; Cells; Cholesterol; Chronic Disease; Dangerousness; Data; Deterioration; Development; Diabetes Mellitus; Diet; Disease; Dual-Energy X-Ray Absorptiometry; Energy Metabolism; Environment; Exhibits; Fracture; Future; GC 1 compound; Genes; Genomics; Goals; Grant; Growth; Health; Health Care Costs; Healthcare; Hematopoiesis; Hepatic Tissue; High Fat Diet; Histology; Human; Immunohistochemistry; In Vitro; Individual; Investigation; Link; Literature; Liver; Marrow; Measures; Mediating; Messenger RNA; Metabolic; Mus; Mutant Strains Mice; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Receptors; Obese Mice; Obesity; Osteoblasts; Osteogenesis; Osteoporosis; Pathway interactions; Pharmacology; Physiological; Play; Prevalence; Prevention; Property; Proteins; Public Health; Reverse Transcriptase Polymerase Chain Reaction; Risk; Role; Salvelinus; Signal Pathway; Signal Transduction; Signaling Molecule; Societies; Stromal Cells; Testing; Therapeutic; Thyroid Hormone Receptor; Thyroid Hormones; Thyroid hormone receptor alpha; Thyrotoxicosis; Time; Tissues; United States; Work; age effect; age group; age related; aged; base; bone; bone health; bone loss; bone mass; bone quality; comorbidity; cost effective; effective therapy; hypercholesterolemia; improved; in vivo; inhibitor/antagonist; innovation; microCT; mimetics; mortality; new therapeutic target; non-genomic; novel therapeutic intervention; obesity treatment; osteogenic; receptor; response; skeletal; small molecule; substantia spongiosa

Abstract Affecting more than 1 in 3 adults in the United States, obesity is a major public health threat, putting millions at in- creased risk of osteoporosis, type 2 diabetes, cardiovascular disease, and all-cause mortality. Age-related changes in the adipose tissue are known underlying causes for many age-related diseases including osteoporosis. Although obesity is char- acterized by an excess of white adipose tissue (WAT), bone marrow adipose tissue (MAT) is among the least studied adipose depots and may play an important role in skeletal health and energy metabolism, as MAT can exhibit properties of both WAT and metabolically active brown adipose tissue (BAT). An attractive therapeutic approach for treating obesity and its comorbidities is the so-called browning of WAT in which WAT is induced to behave similarly to BAT. Thyroid hormone (TH) is an important regulator of adipose tissues and energy metabolism. While TH is known to induce browning of WAT, systemic TH administration is not a viable strategy for treating obesity as TH exerts a wide range of effects on nearly every tissue in the body, and the adverse effects of thyrotoxicosis are much too dangerous. For this reason, recent studies have targeted specific downstream effectors in the TH signaling pathway to leverage some of TH’s beneficial effects while avoiding unwanted adverse effects. In our preliminary studies, we have found that treatment with a TRβ1 specific agonist, GC-1, can decrease marrow adiposity and upregulate BAT marker genes in bone marrow stromal cells (BMSCs). However, GC-1 is now known to exert off-target effects that are detrimental to other tissues. Based on our new preliminary data, we propose to test the following two specific aims in this R21 grant to investigate the role and mechanism of action of the highly selective TRβ mimetic, MGL3196, in regulating functional browning of MAT during aging and diet-induced obesity. In Aim 1, we will test the hypothesis that activation of TRβ1 signaling using MGL3196 reduces MAT, induces functional browning of MAT, and improves bone quality in obese and aged mice. Adult (4 m) and aged (18 m) C57BL/6J mice will be fed with low- or high-fat diet for 12 weeks and treated daily with MGL3196 or vehicle. The consequence of MGL3196 treatment on high-fat diet-induced marrow adiposity and bone quality will be evaluated by DXA, micro-CT, and histology. The expression of WAT, browning of WAT, BAT, and bone markers will be evaluated at the mRNA and protein levels by real-time RT-PCR and immunohistochemistry. The MGL3196 effect on browning of white adipocytes and lineage commit- ment of BMSCs towards osteoblastic and adipocytic lineages will be evaluated. In Aim 2, we will test the hypothesis that MGL3196 effects on browning of MAT are mediated via nongenomic TRβ–PI3K signaling by using TRβ147F mutant mice with intact genomic but disrupted nongenomic TRβ–PI3K signaling. We will measure changes in MAT and bone quality in response to MGL3196 treatment. To confirm the role of PI3K signaling in mediating the nongenomic MGL3196 response, we will measure changes in PI3K/Akt signaling in response to MGL3196 treatment in primary cultures of BMSCs. We will also determine if treatment of BMSCs with pharmacological inhibitors of PI3K signaling blocks the induction of BAT markers by MGL3196. We believe that the potential impact of evaluating the utility MGL3196 to treat MAT and under- standing its mechanism of action is huge based on the anticipated increase in obesity-related healthcare expenses in the U.S.

抽象的 在美国影响超过三分之一的成年人，肥胖是一个主要的公共卫生威胁，使数百万 造成骨质疏松症，2型糖尿病，心血管疾病和全因死亡率的风险。与年龄有关的变化 脂肪组织是许多与年龄相关疾病在内的许多与骨质疏松症（包括骨质疏松症）的根本原因。虽然肥胖是char- 骨髓脂肪组织（MAT）被过量的白色脂肪组织（WAT）所吸引 沉积物并可能在骨骼健康和能量代谢中发挥重要作用，因为垫子都可以表现出两者的特性 WAT和代谢活跃的棕色脂肪组织（BAT）。一种有吸引力的治疗方法来治疗肥胖症及其 合并症是所谓的WAT褐变，其中WAT的行为与BAT相似。甲状腺激素 （Th）是脂肪组织和能量代谢的重要调节剂。虽然众所周知会诱发wat的褐变，但 系统性管理并不是对待肥胖症的可行策略 体内的组织和甲状腺毒性的不良影响太危险了。因此，最近的研究有 在TH信号通路中有针对性的特定下游效应，以利用TH的某些有益效果 避免不必要的不​​良影响。在我们的初步研究中，我们发现用TRβ1特异性激动剂治疗， GC-1可以降低骨髓基质细胞（BMSC）中的骨髓肥胖和上调蝙蝠标记基因。然而， 现在已知GC-1会发挥对其他组织有害的靶向效应。根据我们的新初步数据，我们 在此R21赠款中测试以下两个具体目标，以调查作用的作用和机制 高度选择性的TRβ模拟物，MGL3196，在衰老和饮食诱导的肥胖症期间MAT的调节功能褐变。 在AIM 1中，我们将测试以下假设：使用MGL3196的TRβ1信号传导降低MAT，诱导功能 MAT褐变，并改善肥胖和老年小鼠的骨质质量。成人（4 m）和年龄（18 m）C57BL/6J小鼠将 用低脂或高脂饮食喂养12周，并每天用MGL3196或车辆治疗。 MGL3196的结果 DXA，Micro-CT和组织学评估高脂饮食诱导的骨髓肥胖和骨质质量的治疗。 WAT，WAT，BAT和骨标记物的褐变表达将在mRNA和蛋白质水平上评估 实时RT-PCR和免疫组织化学。 MGL3196对白色脂肪细胞褐变的影响和谱系提交 - 将评估BMSC朝着成骨细胞和脂肪细胞谱系的方法。在AIM 2中，我们将检验以下假设。 MGL3196对MAT褐变的影响是通过使用TRβ147F突变小鼠通过非原始体TRβ -PI3K信号传导介导的 具有完整的基因组，但被破坏的非原位TRβ– PI3K信号传导。我们将测量垫子和骨质的变化 对MGL3196治疗的反应。为了确认PI3K信号传导在介导非原始组MGL3196响应中的作用， 我们将根据BMSC的原发性培养物中的MGL3196处理，测量PI3K/AKT信号传导的变化。我们将 还可以确定使用PI3K信号传导的药物抑制剂对BMSC的处理是否阻止了BAT的诱导 MGL3196的标记。我们认为，评估公用事业MGL3196的潜在影响治疗垫子和不足 基于美国肥胖相关的医疗费用的预期增加，其行动机制非常巨大