| First Author | Chougule A | Year | 2023 |
| Journal | Front Endocrinol (Lausanne) | Volume | 14 |
| Pages | 1145467 | PubMed ID | 37181042 |
| Mgi Jnum | J:346000 | Mgi Id | MGI:7483292 |
| Doi | 10.3389/fendo.2023.1145467 | Citation | Chougule A, et al. (2023) Osteocytes contribute via nuclear receptor PPAR-alpha to maintenance of bone and systemic energy metabolism. Front Endocrinol (Lausanne) 14:1145467 |
| abstractText | INTRODUCTION: The view that bone and energy metabolism are integrated by common regulatory mechanisms is broadly accepted and supported by multiple strands of evidence. This includes the well-characterized role of the PPARgamma nuclear receptor, which is a common denominator in energy metabolism and bone metabolism. Little is known, however, about the role of PPARalpha nuclear receptor, a major regulator of lipid metabolism in other organs, in bone. METHODS: A side-by-side comparative study of 5-15 mo old mice with global PPARalpha deficiency (alpha(KO)) and mice with osteocyte-specific PPARalpha deficiency (alphaOT(KO)) in order to parse out the various activities of PPARalpha in the skeleton that are of local and systemic significance. This study included transcriptome analysis of PPARalpha-deficient osteocytes, and analyses of bone mass and bone microarchitecture, systemic energy metabolism with indirect calorimetry, and differentiation potential of hematopoietic and mesenchymal bone cell progenitors. These analyses were paired with in vitro studies of either intact or silenced for PPARalpha MLO-A5 cells to determine PPARalpha role in osteocyte bioenergetics. RESULTS: In osteocytes, PPARalpha controls large number of transcripts coding for signaling and secreted proteins which may regulate bone microenvironment and peripheral fat metabolism. In addition, PPARalpha in osteocytes controls their bioenergetics and mitochondrial response to stress, which constitutes up to 40% of total PPARalpha contribution to the global energy metabolism. Similarly to alpha(KO) mice, the metabolic phenotype of alphaOT(KO) mice (both males and females) is age-dependent. In younger mice, osteocyte metabolism contributes positively to global energetics, however, with aging the high-energy phenotype reverts to a low-energy phenotype and obesity develops, suggesting a longitudinal negative effect of impaired lipid metabolism and mitochondrial dysfunction in osteocytes deficient in PPARalpha. However, bone phenotype was not affected in alphaOT(KO) mice except in the form of an increased volume of marrow adipose tissue in males. In contrast, global PPARalpha deficiency in alpha(KO) mice led to enlarged bone diameter with a proportional increase in number of trabeculae and enlarged marrow cavities; it also altered differentiation of hematopoietic and mesenchymal marrow cells toward osteoclast, osteoblast and adipocyte lineages, respectively. DISCUSSION: PPARalpha role in bone is multileveled and complex. In osteocytes, PPARalpha controls the bioenergetics of these cells, which significantly contributes to systemic energy metabolism and their endocrine/paracrine function in controlling marrow adiposity and peripheral fat metabolism. |
