Targeting adipocytic discoidin domain receptor 2 impedes fat gain while increasing bone mass

Area of Science:

• Metabolic research
• Bone biology
• Adipocyte research

Background:

• Obesity is linked to low bone mass disorders.
• Discoidin domain receptor 2 (DDR2) is implicated in skeletal and fat metabolism.
• The role of DDR2 in fat-bone crosstalk is not well understood.

Purpose of the Study:

• To investigate the role of DDR2 in adipocytes regarding fat metabolism and bone health.
• To elucidate the molecular mechanisms underlying DDR2's influence on fat-bone crosstalk.

Main Methods:

• Generation of Ddr2 conditional knockout mice (Ddr2^Adipo) with Ddr2 deletion specifically in adipocytes.
• High-fat diet feeding to assess diet-induced obesity and bone parameters.
• Analysis of adipocyte size, bone mass, mechanical properties, osteoblastogenesis, and osteoclastogenesis.
• RNA-sequencing (RNA-Seq) to identify downstream molecular targets.
• Pharmacological inhibition of identified signaling pathways.

Main Results:

• Ddr2^Adipo mice were protected from high-fat diet-induced weight gain and showed reduced adipocyte size.
• These mice exhibited significantly increased bone mass and improved mechanical properties.
• Bone marrow showed diminished adipocytes due to enhanced lipolysis and reduced fatty acid levels.
• RNA-Seq identified adenylate cyclase 5 (Adcy5) as a downstream target of DDR2.
• Adipocytic DDR2 was found to modulate the Adcy5-cAMP-PKA signaling pathway, influencing lipolysis and osteoblast differentiation.

Conclusions:

• DDR2 in adipocytes plays a critical role in regulating fat metabolism and bone mass.
• DDR2 deficiency in fat cells promotes lipolysis, providing fatty acids for osteoblast activity, thus enhancing bone formation.
• Targeting adipocyte DDR2 presents a potential dual therapeutic strategy for obesity and bone loss disorders.