Endocrine Actions of Sclerostin

硬化素的内分泌作用

• 批准号: 10527338
• 负责人: Ryan C Riddle
• 金额: --
• 依托单位: BALTIMORE VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10527338
• 关键词: Adipocytes; Adipose tissue; Adrenergic Agents; Adrenergic Agonists; Adrenergic Receptor; Aging; Antidiabetic Drugs; Biological Products; Body Composition; Bone Diseases; Bone Matrix; Brown Fat; Cardiovascular system; Chronic; Communication; Data; Degenerative Disorder; Dependovirus; Deposition; Development; Diabetes Mellitus; Diagnosis; Endocrine; Energy Supply; Energy consumption; Exhibits; Fatty acid glycerol esters; Feedback; Functional disorder; Funding; Gene Expression; Genes; Genetic; Genetic Transcription; Global Change; Glucose; Growth; High Fat Diet; Homeostasis; Hormone secretion; Housing; Human; Impairment; Ions; Link; Lipids; Lipolysis; Locomotion; LoxP-flanked allele; Mediating; Metabolic; Metabolic Bone Diseases; Metabolic Diseases; Metabolic dysfunction; Metabolism; Minerals; Modeling; Morphology; Mus; Obesity; Organ; Osteoblasts; Osteocalcin; Osteocytes; Osteogenesis; Osteopenia; Osteoporosis; Patients; Phenotype; Physiologic calcification; Physiological; Physiology; Prevention; Production; Proteins; Regulation; Reporting; Research Personnel; Serum; Signal Transduction; Skeleton; Stimulus; Testing; Thiazolidinediones; Thinness; Tissues; Veterans; WNT Signaling Pathway; Weight Gain; Work; adipocyte differentiation; age related; blood glucose regulation; bone; bone loss; bone mass; clinically significant; cohort; cold stress; desensitization; design; experimental study; fatty acid metabolism; fracture risk; glucose uptake; improved; in vivo; inhibitor; insulin sensitivity; loss of function mutation; military veteran; novel; overexpression; patient population; pharmacologic; response; side effect; subcutaneous; synergism; transcription factor; transcriptome sequencing

The skeleton, populated by large numbers of osteoblasts and osteocytes, requires a constant supply of energy-rich molecules to fuel the synthesis, deposition, and mineralization of bone matrix during bone modeling and remodeling. As a result, studies performed over the last decade have expanded our understanding of the physiologic functions of bone beyond locomotion, mineral ion storage, and protection of vital organs to now include the secretion of hormones that contribute to the regulation of whole-body metabolism. Our previous studies suggest that sclerostin, an osteocyte-secreted factor that inhibits Wnt signaling in bone, influences body composition and glucose homeostasis by augmenting adipocyte differentiation. Preliminary studies suggest that sclerostin may exert its effect on adipose tissue in vivo by modulating the sensitivity of adipocytes to -adrenergic signals that stimulate adipose tissue browning. In this renewal application, we will utilize a combination of genetic and pharmacological approaches to explore the interaction between endocrine sclerostin and -adrenergic signaling. Our hypothesis predicts that sclerostin deficiency leads to adipose tissue browning due to an increase in -adrenergic sensitivity; and the loss of negative feedback inhibition since sclerostin gene expression appears to be responsive to thermogenic signaling. Our approach will expand our understanding of the physiologic functions of sclerostin; and help to determine if sclerostin neutralization, now approved for the treatment of osteopenia/osteoporosis, can be leveraged to treat metabolic disorders like obesity and diabetes. We firmly believe that the information gained from our studies will improve understanding of how the metabolic activity of the skeleton impacts global metabolic activity. Such information is expected to significantly improve the diagnosis, management, treatment, and prevention of the related metabolic disturbances of diabetes and bone disease in aging Veterans.

骨骼由大量的成骨细胞和骨细胞组成，需要持续的