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Pathological obesity and its complications are associated with an increased propensity for bone fractures. Humans with certain genetic polymorphisms at the kinase suppressor of ras2 (KSR2) locus develop severe early-onset obesity and type 2 diabetes. Both conditions are phenocopied in mice with  Ksr2  deleted, but whether this affects bone health remains unknown. Here we studied the bones of global  Ksr2  null mice and found that  Ksr2  negatively regulates femoral, but not vertebral, bone mass in two genetic backgrounds, while the paralogous gene,  Ksr1 , was dispensable for bone homeostasis. Mechanistically, KSR2 regulates bone formation by influencing adipocyte differentiation at the expense of osteoblasts in the bone marrow. Compared with  Ksr2 ’s known role as a regulator of feeding by its function in the hypothalamus, pair-feeding and osteoblast-specific conditional deletion of  Ksr2  reveals that  Ksr2  can regulate bone formation autonomously. Despite the gains in appendicular bone mass observed in the absence of  Ksr2 , bone strength, as well as fracture healing response, remains compromised in these mice. This study highlights the interrelationship between adiposity and bone health and provides mechanistic insights into how  Ksr2 , an adiposity and diabetic gene, regulates bone metabolism.

Contrasting effects of Ksr2 , an obesity gene, on trabecular bone volume and bone marrow adiposity