An increasing number of studies have characterized the bone as an endocrine organ, and that bone secreted factors may not only regulate local bone remodeling, but also other tissues and whole-body metabolic functions. The precise nature of these regulatory factors and their roles at bridging the bone, bone marrow adipose tissue, extramedullary body fat and whole-body energy homeostasis are being explored. In this study, we report that KIAA1199, a secreted factor produced from bone and bone marrow, previously described as an inhibitor of bone formation, also plays a role at promoting adipogenesis. KIAA1199-deficient mice exhibit reduced bone marrow adipose tissue, subcutaneous and visceral fat tissue mass, blood cholesterol, triglycerides, free fatty acids and glycerol, as well as improved insulin sensitivity in skeletal muscle, liver and fat. Moreover, these mice are protected from the detrimental effects of high-fat diet feeding, with decreased obesity, lower blood glucose and glucose tolerance, as well as decreased adipose tissue inflammation, insulin resistance and hepatic steatosis. In human studies, plasma levels of KIAA1199 or its expression levels in adipose tissue are positively correlated with insulin resistance and blood levels of cholesterol, triglycerides, free fatty acids, glycerol, fasting glucose and HOMA-IR. Mechanistically, KIAA1199 mediates its effects on adipogenesis through modulating osteopontin-integrin and AKT / ERK signaling. These findings provide evidence for the role of bone secreted factors on coupling bone, fat and whole-body energy homeostasis.

Biomechanics Lab Institute of Mechanics Materials and Civil Engineering KU Leuven Leuven Belgium

Biomechanics Section Department of Mechanical Engineering KU Leuven Leuven Belgium

Department of Endocrinology and Metabolism Endocrine Research Laboratory Odense University Hospital and University of Southern Denmark Odense Dk 5230 Denmark

Department of Medicine Karolinska Institute Karolinska University Hospital Stockholm Sweden

Department of Pathophysiology Centre for Research on Diabetes Metabolism and Nutrition 3rd Faculty of Medicine Charles University Prague Czech Republic

Guangxi Key Laboratory of Tumor Immunology and Microenvironment Regulation Guilin Medical University Guilin Guangxi 541199 China

Institute of Pathology University of Southern Denmark Odense Denmark

Khalifa University College of Medicine and Health Sciences and Biotechnology Center Abu Dhabi United Arab Emirates

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