Much evidence provides strong support for the concept that bone and energy metabolism are integrated by common regulatory mechanisms. Thus, metabolic regulators can play a vital role in regulation of bone mass whereas bone can regulate whole body metabolism through its paracrine and endocrine activity. There is not much known about the function of two well-known metabolic regulators, Carboxypeptidase-E and Peroxisome Proliferator-Activated Receptor α (PPARα), in controlling bone mass.The nuclear receptor PPARα is a major regulator of energy production and lipid metabolism in muscle and liver, and pharmacologic target for fibrates, a class of drugs used to treat dyslipidemia. Mice with global deficiency of PPARα are metabolically impaired in response to fasting and high-fat diet, however their bone phenotype has not been analyzed in detail. We have found that PPARα is relatively highly expressed in osteocytes, which constitute up to 90-95% of bone cells and which play a crucial role in the process of bone remodeling. Considering osteocytes abundance, the contribution of osteocytic PPARα to the regulation of bone and global energy metabolism has been anticipated and provided basis for the following study. We have developed a novel mouse model with deletion of PPARα specifically in osteocytes (αOTKO), using Cre-Lox system by pairing 10kb DMP-1 Cre mice with PPARα fl/fl mice. We compared bone and metabolic phenotypes of PPARα OT KO (αOTKO) with global PPARα KO (αKO) mice. As compared to respective control animals, bone phenotype of αOTKO mice is unchanged, while αKO mice have a larger bone cavity which is associated with increased bone resorption, increased number of osteoclasts (OC), slightly decreased bone formation and decreased number of osteoblasts (OB). Interestingly, both αOTKO and αKO animals have increased marrow fat volume in tibia bone. Consistently, ex vivo studies showed that differentiation of bone marrow mesenchymal stem cells (BMSCs) toward adipocytes (AD) is increased in both αOTKO and αKO, as measured in Colony Forming Units assay. In contrast, OC differentiation from a pool of bone marrow hematopoietic stem cells (HSCs) is increased only in αKO and not affected in αOTKO. These findings suggest that PPARα in osteoclasts, which is absent in αKO mice, may be involved in the structural differences observed in global PPARα null mice, while PPARα in osteocytes is mainly contributing to the marrow fat deposition. However and surprisingly, both αOTKO and αKO animals are characterized with increased energy expenditure, suggesting that osteocytic PPARα deficiency contributed to the systemic or global effect of PPARα loss. This phenotype was only seen in adult (5 mo old) mice. However, aged (15 mo old) αOTKO mice showed obese phenotype accompanied with reduced energy expenditure suggesting that osteocytes are important component of fatty acid metabolism and osteocytic PPARα is essential for this process. Additionally, primary osteocytes isolated from αKO showed 1488 differentially expressed transcripts in Next Generation Sequencing analysis. Using DAVID functional clustering analysis, we identified clusters of genes related to osteogenesis, differentiation and secreted proteins to be down-regulated while apoptotic genes were up-regulated in αKO osteocytes, as compared to osteocytes with intact PPARα. In summary, PPARα expressed in HSC and MSC plays an important role in the maintenance of bone structure and marrow adiposity, while osteocyte specific PPARα controls marrow adiposity, perhaps via osteocyte paracrine activity, and significantly contributes to the global energy metabolism on two levels, PPARα-controlled fatty acids metabolism in osteocytes and/or osteocyte endocrine activity controlling fat metabolism in adipose tissue. For the support of the latter, we found that αOTKO mice develop metabolically active beiging phenotype in inguinal fat, which may contribute to the increased energy metabolism observed in adult mice. These findings are the first evidence for the essential contribution of PPARα nuclear receptor in bone to the control of bone homeostasis and energy metabolism, and position PPARα as a potential target to treat bone and metabolic diseases, simultaneously.Carboxypeptidase E (CPE), also known as obesity susceptibility protein or neurotrophic factor-α1 (NF-α1), is recognized for its function in processing pro-hormones including pro-insulin 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 a high volume of marrow fat. Interestingly, while metabolic deficit of CPEKO mice develops early in life, bone deficit develops in older age, suggesting that CPE bone-specific activities differ from its enzymatic activities. Indeed, mCPEKI 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 CPEKO mice, but their bone mass is normal. In addition, differentiation of marrow hematopoietic cells toward TRAP+ multinucleated osteoclasts is highly increased in CPEKO, but normal in mCPEKI mice. Moreover, in murine skeletal stem cells, non-enzymatic trophic CPE activated ERK signaling and increased cell proliferation and mitochondrial activity. Treatment of pre-osteoblastic 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 under osteogenic conditions. These findings suggest that non-enzymatic and trophic activities of CPE regulate bone mass, while 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.In summary, modulating the activities of metabolic regulators, such as PPARα and CPE, may lead to a potential therapy to improve bone mass and treat metabolic disorders, such as obesity, while improving quality of life.