Abstract

Obesity is closely associated with low-bone-mass disorder. Discoidin domain receptor 2 (DDR2) plays essential roles in skeletal metabolism, and is probably involved in fat metabolism. To test the potential role of DDR2 in fat and fat-bone crosstalk, Ddr2 conditional knockout mice (Ddr2Adipo) were generated in which Ddr2 gene is exclusively deleted in adipocytes by Adipoq Cre. We found that Ddr2Adipo mice are protected from fat gain on high-fat diet, with significantly decreased adipocyte size. Ddr2Adipo mice exhibit significantly increased bone mass and mechanical properties, with enhanced osteoblastogenesis and osteoclastogenesis. Marrow adipocyte is diminished in the bone marrow of Ddr2Adipo mice, due to activation of lipolysis. Fatty acid in the bone marrow was reduced in Ddr2Adipo mice. RNA-Seq analysis identified adenylate cyclase 5 (Adcy5) as downstream molecule of Ddr2. Mechanically, adipocytic Ddr2 modulates Adcy5-cAMP-PKA signaling, and Ddr2 deficiency stimulates lipolysis and supplies fatty acid for oxidation in osteoblasts, leading to the enhanced osteoblast differentiation and bone mass. Treatment of Adcy5 specific inhibitor abolishes the increased bone mass gain in Ddr2Adipo mice. These observations establish, for the first time, that Ddr2 plays an essential role in the crosstalk between fat and bone. Targeting adipocytic Ddr2 may be a potential strategy for treating obesity and pathological bone loss simultaneously.

Highlights

  • Obesity is one of the most important health problems facing modern society worldwide

  • Discoidin domain receptor 2 (Ddr2) gene is exclusively deleted in adipocytes (Fig. S1)

  • WT and Ddr2Adipo mice were fed with high-fat diet (HFD) for 24 weeks

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Summary

Introduction

Obesity is one of the most important health problems facing modern society worldwide. More than 1.9 billion adults (18 years and older) are overweight, more than 650 million adults are obesity. This means that 39% of adults are overweight and 13% are obese. Obesity is closely associated with chronic diseases, such as high blood pressure, coronary heart disease, type 2 diabetes, and low-bone-mass disorders. Many obesity patients have osteoporosis symptom including decreased bone mass, changed microstructure, and increased bone fragility. Osteoporosis leads to increased risk of fracture and dramatically affects the life qualities of patients. Finding out a target that both regulates fat metabolism and bone mass is of great importance

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