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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 PPARg nuclear receptor, which is a common denominator in energy metabolism and bone metabolism. Little is known, however, about the role of PPARa 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 PPARa deficiency (aKO) and mice with osteocyte-specific PPARa deficiency (aOTKO) in order to parse out the various activities of PPARa in the skeleton that are of local and systemic significance. This study included transcriptome analysis of PPARa-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 PPARa MLO-A5 cells to determine PPARa role in osteocyte bioenergetics. Results: In osteocytes, PPARa controls large number of transcripts coding for signaling and secreted proteins which may regulate bone microenvironment and peripheral fat metabolism. In addition, PPARa in osteocytes controls their bioenergetics and mitochondrial response to stress, which constitutes up to 40% of total PPARa contribution to the global energy metabolism. Similarly to aKO mice, the metabolic phenotype of aOTKO 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 PPARa. However, bone phenotype was not affected in aOTKO mice except in the form of an increased volume of marrow adipose tissue in males. In contrast, global PPARa deficiency in aKO mice led to enlarged bone diameter with a proportional increase in number of trabeculae and enlarged marrow 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 PPARg nuclear receptor, which is a common denominator in energy metabolism and bone metabolism. Little is known, however, about the role of PPARa 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 PPARa deficiency (aKO) and mice with osteocyte-specific PPARa deficiency (aOTKO) in order to parse out the various activities of PPARa in the skeleton that are of local and systemic significance. This study included transcriptome analysis of PPARa-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 PPARa MLO-A5 cells to determine PPARa role in osteocyte bioenergetics. Results: In osteocytes, PPARa controls large number of transcripts coding for signaling and secreted proteins which may regulate bone microenvironment and peripheral fat metabolism. In addition, PPARa in osteocytes controls their bioenergetics and mitochondrial response to stress, which constitutes up to 40% of total PPARa contribution to the global energy metabolism. Similarly to aKO mice, the metabolic phenotype of aOTKO 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 PPARa. However, bone phenotype was not affected in aOTKO mice except in the form of an increased volume of marrow adipose tissue in males. In contrast, global PPARa deficiency in aKO mice led to enlarged bone diameter with a proportional increase in number of trabeculae and enlarged marrow 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 PPARg nuclear receptor, which is a common denominator in energy metabolism and bone metabolism. Little is known, however, about the role of PPARa 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 PPARa deficiency (aKO) and mice with osteocyte-specific PPARa deficiency (aOTKO) in order to parse out the various activities of PPARa in the skeleton that are of local and systemic significance. This study included transcriptome analysis of PPARa-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 PPARa MLO-A5 cells to determine PPARa role in osteocyte bioenergetics. Results: In osteocytes, PPARa controls large number of transcripts coding for signaling and secreted proteins which may regulate bone microenvironment and peripheral fat metabolism. In addition, PPARa in osteocytes controls their bioenergetics and mitochondrial response to stress, which constitutes up to 40% of total PPARa contribution to the global energy metabolism. Similarly to aKO mice, the metabolic phenotype of aOTKO 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 PPARa. However, bone phenotype was not affected in aOTKO mice except in the form of an increased volume of marrow adipose tissue in males. In contrast, global PPARa deficiency in aKO 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: PPARa role in bone is multileveled and complex. In osteocytes, PPARa 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. [ABSTRACT FROM AUTHOR]

Bone and energy metabolism are integrated by common regulatory mechanisms. Carboxypeptidase E (CPE), also known as obesity susceptibility protein or neurotrophic factor‐α1, is recognized for its function in processing prohormones, including proinsulin and pro‐opiomelanocortin polypeptide. Independent of its enzymatic activity, CPE may also act as a secreted factor with divergent roles in neuroprotection and cancer growth; however, its role in the regulation of bone mass and skeletal cell differentiation is unknown. Male mice with global deficiency in CPE are characterized with profound visceral obesity, low bone mass in both appendicular and axial skeleton, and high volume of marrow fat. Interestingly, although metabolic deficit of CPE KO mice develops early in life, bone deficit develops in older age, suggesting that CPE bone‐specific activities differ from its enzymatic activities. Indeed, mutated CPE knockin (mCPE KI) mice ectopically expressing CPE‐E342Q, a mutated protein lacking enzymatic activity, develop the same obese phenotype and accumulate the same volume of marrow fat as CPE KO mice, but their bone mass is normal. In addition, differentiation of marrow hematopoietic cells toward tartrate‐resistant acid phosphatase‐positive multinucleated osteoclasts is highly increased in CPE KO mice, but normal in mCPE KI mice. Moreover, in murine skeletal stem cells, nonenzymatic trophic CPE has activated ERK signaling, increased cell proliferation and increased mitochondrial activity. Treatment of preosteoblastic cells with intact or mutated recombinant CPE led to a transient accumulation of small lipid droplets, increased oxidative phosphorylation, and increased cellular dependence on fatty acids as fuel for energy production. In human marrow aspirates, CPE expression increases up to 30‐fold in osteogenic conditions. These findings suggest that nonenzymatic and trophic activities of CPE regulate bone mass, whereas marrow adiposity is controlled by CPE enzymatic activity. Thus, CPE can be positioned as a factor regulating simultaneously bone and energy metabolism through a combination of shared and distinct mechanisms. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]