Metabolic, skeletal, and cartilage effects of a high-fat diet and the therapeutic impact of MGL3196 are age- and sex-dependent in mice

Aged individuals with type 2 diabetes (T2D) may suffer from complications of common comorbid conditions like osteoporosis or osteoarthritis. MGL3196 (MGL) is a therapeutic thyroid hormone receptor beta (TR beta) agonist that has been shown to rescue non-alcoholic steatohepatitis by enhancing lipid metabolism. In a previous study, we demonstrated that MGL treatment protected against high-fat diet (HFD)-induced adiposity but increased HFDinduced trabecular bone loss in male mice. In this study, we explored the impact of MGL treatment on adiposity, bone, and cartilage in aged-21-month-old C57BL/6J mice after a 12-week HFD regimen. Our results show that MGL reduced body weight as well as adverse effects caused by HFD adiposity, in male mice only. Aged HFD-fed male mice experienced cortical bone loss, in contrast to the trabecular bone loss observed in adult male mice. Notably, MGL treatment further exacerbated the cortical bone loss. Mechanical testing of tibias from aged male mice by 3-point bending revealed a reduced maximum load and tibia stiffness with HFD and MGL treatment. Transcriptome analyses for cortical bone formation regulators unveiled a decreased expression of Wnt16 and increased expression of the Wnt inhibitor, Sost, in the bones of HFD-fed male mice. Additionally, measurements of articular cartilage indicated that MGL treatment reduced articular cartilage degradation in both sexes, which was attributed to aging and a HFD. Our findings suggest tailored therapies are necessary to address the adverse effects of a HFD on fat, bone, and cartilage metabolism, specifically considering factors such as age and sex.