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.

摘要