# Thyroid hormone receptor β1 agonist therapy for the treatment of bone marrow adiposity in aging and obesity > **NIH NIH R21** · LOMA LINDA VETERANS ASSN RESEARCH & EDUC · 2020 · $219,750 ## Abstract 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 MGL319... ## Key facts - **NIH application ID:** 9893266 - **Project number:** 1R21AG062866-01A1 - **Recipient organization:** LOMA LINDA VETERANS ASSN RESEARCH & EDUC - **Principal Investigator:** SUBBURAMAN MOHAN - **Activity code:** R21 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2020 - **Award amount:** $219,750 - **Award type:** 1 - **Project period:** 2020-03-15 → 2021-12-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/9893266 ## Citation > US National Institutes of Health, RePORTER application 9893266, Thyroid hormone receptor β1 agonist therapy for the treatment of bone marrow adiposity in aging and obesity (1R21AG062866-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9893266. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*