PPARG in osteocytes controls cell bioenergetics and systemic energy metabolism independently of sclerostin levels in circulation

作者：Sudipta Baroi, Piotr J. Czernik, Mohd Parvez Khan, Joshua Letson, Emily M. Crowe, Amit Chougule, Patrick R. Griffin, Clifford J. Rosen, Beata Lecka‐Czernik · 发表于：Molecular Metabolism · 年份：2024 · DOI：10.1016/j.molmet.2024.102000 · 被引用次数：9 · 研究领域：Peroxisome Proliferator-Activated Receptors、Bone Metabolism and Diseases、Bone health and osteoporosis research

The skeleton is one of the largest organs in the body, wherein metabolism is integrated with systemic energy metabolism. However, the bioenergetic programming of osteocytes, the most abundant bone cells coordinating bone metabolism, is not well defined. Here, using a mouse model with partial penetration of an osteocyte-specific PPARG deletion, we demonstrate that PPARG controls osteocyte bioenergetics and their contribution to systemic energy metabolism independently of circulating sclerostin levels, which were previously correlated with metabolic status of extramedullary fat depots. In vivo and in vitro models of osteocyte-specific PPARG deletion, i.e. Dmp1CrePparγflfl male and female mice (γOTKO) and MLO-Y4 osteocyte-like cells with either siRNA-silenced or CRISPR/Cas9-edited Pparγ. As applicable, the models were analyzed for levels of energy metabolism, glucose metabolism, and metabolic profile of extramedullary adipose tissue, as well as the osteocyte transcriptome, mitochondrial function, bioenergetics, insulin signaling, and oxidative stress. Circulating sclerostin levels of γOTKO male and female mice were not different from control mice. Male γOTKO mice exhibited a high energy phenotype characterized by increased respiration, heat production, locomotion and food intake. This high energy phenotype in males did not correlate with “beiging” of peripheral adipose depots. However, both sexes showed a trend for reduced fat mass and apparent insulin resistance without changes...