Bone formation is a highly energy-demanding process that can be impacted by metabolic disorders.Glucose has been considered the principal substrate for osteoblasts,although fatty acids are also important for osteoblas...Bone formation is a highly energy-demanding process that can be impacted by metabolic disorders.Glucose has been considered the principal substrate for osteoblasts,although fatty acids are also important for osteoblast function.Here,we report that osteoblasts can derive energy from endogenous fatty acids stored in lipid droplets via lipolysis and that this process is critical for bone formation.As such,we demonstrate that osteoblasts accumulate lipid droplets that are highly dynamic and provide the molecular mechanism by which they serve as a fuel source for energy generation during osteoblast maturation.Inhibiting cytoplasmic lipolysis leads to both an increase in lipid droplet size in osteoblasts and an impairment in osteoblast function.The fatty acids released by lipolysis from these lipid droplets become critical for cellular energy production as cellular energetics shifts towards oxidative phosphorylation during nutrient-depleted conditions.In vivo,conditional deletion of the ATGL-encoding gene Pnpla2 in osteoblast progenitor cells reduces cortical and trabecular bone parameters and alters skeletal lipid metabolism.Collectively,our data demonstrate that osteoblasts store fatty acids in the form of lipid droplets,which are released via lipolysis to support cellular bioenergetic status when nutrients are limited.Perturbations in this process result in impairment of bone formation,specifically reducing ATP production and overall osteoblast function.展开更多
Bone mineral, adipose tissue and energy metabolism are interconnected by a complex and multilevel series of networks. Calcium and phosphorus are utilized for insulin secretion and synthesis of high energy compounds. A...Bone mineral, adipose tissue and energy metabolism are interconnected by a complex and multilevel series of networks. Calcium and phosphorus are utilized for insulin secretion and synthesis of high energy compounds. Adipose tissue store lipids and cholecalciferol, which, in turn, can influence calcium balance and energy expenditure. Hormones long-thought to solely modulate energy and mineral homeostasis may influence adipocytic function. Osteoblasts are a target of insulin action in bone. Moreover, endocrine mediators, such as osteocalcin, are synthesized in the skeleton but regulate carbohydrate disposal and insulin secretion. Finally, osteoblasts and adipocytes originate from the same mesenchymal progenitor. The mutual crosstalk between osteoblasts and adipocytes within the bone marrow microenvironment plays a crucial role in bone remodeling. In the present review we provide an overview of the reciprocal control between bone and energy metabolism and its clinical implications.展开更多
Enhanced bone marrow adipogenesis and impaired osteoblastogenesis have been observed in obesity,suggesting that the metabolic microenvironment regulates bone marrow adipocyte and osteoblast progenitor differentiation ...Enhanced bone marrow adipogenesis and impaired osteoblastogenesis have been observed in obesity,suggesting that the metabolic microenvironment regulates bone marrow adipocyte and osteoblast progenitor differentiation fate.To determine the molecular mechanisms,we studied two immortalized murine cell lines of adipocyte or osteoblast progenitors(BMSCs^adipo and BMSC^sosteo,respectively)under basal and adipogenic culture conditions.At baseline,BMSCs^adipo,and BMSCs^osteo exhibit a distinct metabolic program evidenced by the presence of specific global gene expression,cellular bioenergetics,and metabolomic signatures that are dependent on insulin signaling and glycolysis in BMSCs^osteo versus oxidative phosphorylation in BMSCs^adipo.To test the flexibility of the metabolic program,we treated BMSCsadipo with parathyroid hormone,S961(an inhibitor of insulin signaling)and oligomycin(an inhibitor of oxidative phosphorylation).The treatment induced significant changes in cellular bioenergetics that were associated with decreased adipocytic differentiation.Similarly,12 weeks of a high-fat diet in mice led to the expansion of adipocyte progenitors,enhanced adipocyte differentiation and insulin signaling in cultured BMSCs.Our data demonstrate that BMSC progenitors possess a distinct metabolic program and are poised to respond to exogenous metabolic cues that regulate their differentiation fate.展开更多
Male Igfbp2-/-mice have a significant reduction in bone mass and administration of a peptide that contains the insulin-like growth factor binding protein-2(IGFBP-2) receptor-binding domain stimulates bone formation in...Male Igfbp2-/-mice have a significant reduction in bone mass and administration of a peptide that contains the insulin-like growth factor binding protein-2(IGFBP-2) receptor-binding domain stimulates bone formation in these animals. Female Igfbp2-/-mice do not have this phenotype but following ovariectomy(OVX) lose more bone than OVX wild-type mice. This suggests that in the absence of estrogen, IGFBP-2 is required to maintain bone mass. Therefore these studies were undertaken to determine if this peptide could stimulate bone acquisition in OVX rats. OVX rats were divided into seven treatment groups: sham animals, OVX animals, OVX animals receiving a control scrambled peptide, or one of three doses of the active peptide termed PEG-HBD-1(0.7, 2,and 6 mg·kg^(-1)) and an OVX group receiving parathyroid hormone(PTH)(50 μg·kg-1 per day). The peptides were administered for8 weeks. DXA revealed a significant reduction in femoral and tibial areal bone mineral density(aBMD) after OVX, whereas treatment with the high-dose peptide increased aBMD by 6.2% ± 2.4%(P < 0.01) compared to control peptide; similar to the increase noted with PTH(5.6% ± 3.0%, P < 0.01). Similar increases were noted with two lower doses of the peptide(3.8% ± 1.5%, P < 0.05 for low dose; 3.1% ± 1.6%, P = 0.07 for middle dose). Micro CT showed that the OVX control peptide animals had reductions of 41% and64% in femoral trabecular BV/TV and trabecular number, respectively. All three doses of the peptide increased bone volume/total volume(BV/TV) significantly, while the low and middle doses increased trabecular number. Cortical BV/TV and thickness at the midshaft increased significantly with each dose of peptide(18.9% ± 9.8%, P < 0.01 and 14.2% ± 7.9%, P < 0.01 for low dose; 23.7% ±10.7%, P < 0.001 and 15.8% ± 6.1%, P < 0.001 for middle dose; 19.0% ± 6.9%, P < 0.01 and 16.2% ± 9.7%, P < 0.001 for high dose)and with PTH(25.8% ± 9.2%, P < 0.001 and 19.4% ± 8.8%, P < 0.001). Histomorphometry showed that the lowest dose of peptide stimulated BV展开更多
The Euclidean single facility location problem (ESFL) and the Euclidean multiplicity lo-cation problem (EMFL) are two special nonsmooth convex programming problems which haveattracted a largr literature. For the ESFL... The Euclidean single facility location problem (ESFL) and the Euclidean multiplicity lo-cation problem (EMFL) are two special nonsmooth convex programming problems which haveattracted a largr literature. For the ESFL problem. there are algorithms which converge bothglobally and quadratically For the EMFL problem, there are some quadratically convergentalgorithms. but for global convergencel they all need nontrivial assumptions on the problem.In this paper, we present an algorithm for EMFL. With no assumption on the problem, it isproved that from any initial point, this algorithm generates a sequence of points which convergesto the closed convex set of optimal solutions of EMFL.展开更多
基金supported by National Institutes of Health(NIH),the National Institute of Arthritis and Musculoskeletal and Skin Diseases(NIAMS)Grant K01AR072123(ER-R)the American Society of Bone and Mineral Research(ASBMR)Rising Star awardprovided by NIH-National Institute of Diabetes and Digestive and Kidney Disease(NIDDK)Grant DK116056(MPC)。
文摘Bone formation is a highly energy-demanding process that can be impacted by metabolic disorders.Glucose has been considered the principal substrate for osteoblasts,although fatty acids are also important for osteoblast function.Here,we report that osteoblasts can derive energy from endogenous fatty acids stored in lipid droplets via lipolysis and that this process is critical for bone formation.As such,we demonstrate that osteoblasts accumulate lipid droplets that are highly dynamic and provide the molecular mechanism by which they serve as a fuel source for energy generation during osteoblast maturation.Inhibiting cytoplasmic lipolysis leads to both an increase in lipid droplet size in osteoblasts and an impairment in osteoblast function.The fatty acids released by lipolysis from these lipid droplets become critical for cellular energy production as cellular energetics shifts towards oxidative phosphorylation during nutrient-depleted conditions.In vivo,conditional deletion of the ATGL-encoding gene Pnpla2 in osteoblast progenitor cells reduces cortical and trabecular bone parameters and alters skeletal lipid metabolism.Collectively,our data demonstrate that osteoblasts store fatty acids in the form of lipid droplets,which are released via lipolysis to support cellular bioenergetic status when nutrients are limited.Perturbations in this process result in impairment of bone formation,specifically reducing ATP production and overall osteoblast function.
文摘Bone mineral, adipose tissue and energy metabolism are interconnected by a complex and multilevel series of networks. Calcium and phosphorus are utilized for insulin secretion and synthesis of high energy compounds. Adipose tissue store lipids and cholecalciferol, which, in turn, can influence calcium balance and energy expenditure. Hormones long-thought to solely modulate energy and mineral homeostasis may influence adipocytic function. Osteoblasts are a target of insulin action in bone. Moreover, endocrine mediators, such as osteocalcin, are synthesized in the skeleton but regulate carbohydrate disposal and insulin secretion. Finally, osteoblasts and adipocytes originate from the same mesenchymal progenitor. The mutual crosstalk between osteoblasts and adipocytes within the bone marrow microenvironment plays a crucial role in bone remodeling. In the present review we provide an overview of the reciprocal control between bone and energy metabolism and its clinical implications.
基金supported by the Novo Nordisk Foundation (MT) and the Novo Nordisk Foundation (MK, NNF15OC0016284)a research grant from the Odense University Hospital (R29-A1374)
文摘Enhanced bone marrow adipogenesis and impaired osteoblastogenesis have been observed in obesity,suggesting that the metabolic microenvironment regulates bone marrow adipocyte and osteoblast progenitor differentiation fate.To determine the molecular mechanisms,we studied two immortalized murine cell lines of adipocyte or osteoblast progenitors(BMSCs^adipo and BMSC^sosteo,respectively)under basal and adipogenic culture conditions.At baseline,BMSCs^adipo,and BMSCs^osteo exhibit a distinct metabolic program evidenced by the presence of specific global gene expression,cellular bioenergetics,and metabolomic signatures that are dependent on insulin signaling and glycolysis in BMSCs^osteo versus oxidative phosphorylation in BMSCs^adipo.To test the flexibility of the metabolic program,we treated BMSCsadipo with parathyroid hormone,S961(an inhibitor of insulin signaling)and oligomycin(an inhibitor of oxidative phosphorylation).The treatment induced significant changes in cellular bioenergetics that were associated with decreased adipocytic differentiation.Similarly,12 weeks of a high-fat diet in mice led to the expansion of adipocyte progenitors,enhanced adipocyte differentiation and insulin signaling in cultured BMSCs.Our data demonstrate that BMSC progenitors possess a distinct metabolic program and are poised to respond to exogenous metabolic cues that regulate their differentiation fate.
基金supported by grant from Alize PharmaⅢand the Harrington Scholar Program of Harrington Research Foundation
文摘Male Igfbp2-/-mice have a significant reduction in bone mass and administration of a peptide that contains the insulin-like growth factor binding protein-2(IGFBP-2) receptor-binding domain stimulates bone formation in these animals. Female Igfbp2-/-mice do not have this phenotype but following ovariectomy(OVX) lose more bone than OVX wild-type mice. This suggests that in the absence of estrogen, IGFBP-2 is required to maintain bone mass. Therefore these studies were undertaken to determine if this peptide could stimulate bone acquisition in OVX rats. OVX rats were divided into seven treatment groups: sham animals, OVX animals, OVX animals receiving a control scrambled peptide, or one of three doses of the active peptide termed PEG-HBD-1(0.7, 2,and 6 mg·kg^(-1)) and an OVX group receiving parathyroid hormone(PTH)(50 μg·kg-1 per day). The peptides were administered for8 weeks. DXA revealed a significant reduction in femoral and tibial areal bone mineral density(aBMD) after OVX, whereas treatment with the high-dose peptide increased aBMD by 6.2% ± 2.4%(P < 0.01) compared to control peptide; similar to the increase noted with PTH(5.6% ± 3.0%, P < 0.01). Similar increases were noted with two lower doses of the peptide(3.8% ± 1.5%, P < 0.05 for low dose; 3.1% ± 1.6%, P = 0.07 for middle dose). Micro CT showed that the OVX control peptide animals had reductions of 41% and64% in femoral trabecular BV/TV and trabecular number, respectively. All three doses of the peptide increased bone volume/total volume(BV/TV) significantly, while the low and middle doses increased trabecular number. Cortical BV/TV and thickness at the midshaft increased significantly with each dose of peptide(18.9% ± 9.8%, P < 0.01 and 14.2% ± 7.9%, P < 0.01 for low dose; 23.7% ±10.7%, P < 0.001 and 15.8% ± 6.1%, P < 0.001 for middle dose; 19.0% ± 6.9%, P < 0.01 and 16.2% ± 9.7%, P < 0.001 for high dose)and with PTH(25.8% ± 9.2%, P < 0.001 and 19.4% ± 8.8%, P < 0.001). Histomorphometry showed that the lowest dose of peptide stimulated BV
基金This research is supported in part by the Air Force Office of Scientific Research Grant AFOSR-87-0127, the National Science Foundation Grant DCR-8420935 and University of Minnesota Graduate School Doctoral Dissertation Fellowship awarded to G.L. Xue
文摘 The Euclidean single facility location problem (ESFL) and the Euclidean multiplicity lo-cation problem (EMFL) are two special nonsmooth convex programming problems which haveattracted a largr literature. For the ESFL problem. there are algorithms which converge bothglobally and quadratically For the EMFL problem, there are some quadratically convergentalgorithms. but for global convergencel they all need nontrivial assumptions on the problem.In this paper, we present an algorithm for EMFL. With no assumption on the problem, it isproved that from any initial point, this algorithm generates a sequence of points which convergesto the closed convex set of optimal solutions of EMFL.
