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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\n                    <jats:italic>Ksr2<\/jats:italic>\n                    deleted, but whether this affects bone health remains unknown. Here we studied the bones of global\n                    <jats:italic>Ksr2<\/jats:italic>\n                    null mice and found that\n                    <jats:italic>Ksr2<\/jats:italic>\n                    negatively regulates femoral, but not vertebral, bone mass in two genetic backgrounds, while the paralogous gene,\n                    <jats:italic>Ksr1<\/jats:italic>\n                    , 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\n                    <jats:italic>Ksr2<\/jats:italic>\n                    \u2019s known role as a regulator of feeding by its function in the hypothalamus, pair-feeding and osteoblast-specific conditional deletion of\n                    <jats:italic>Ksr2<\/jats:italic>\n                    reveals that\n                    <jats:italic>Ksr2<\/jats:italic>\n                    can regulate bone formation autonomously. Despite the gains in appendicular bone mass observed in the absence of\n                    <jats:italic>Ksr2<\/jats:italic>\n                    , 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\n                    <jats:italic>Ksr2<\/jats:italic>\n                    , an adiposity and diabetic gene, regulates bone metabolism.\n                  <\/jats:p>","DOI":"10.7554\/elife.82810","type":"journal-article","created":{"date-parts":[[2022,10,6]],"date-time":"2022-10-06T07:38:41Z","timestamp":1665041921000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.82810","source":"Crossref","is-referenced-by-count":7,"title":["Contrasting effects of Ksr2, an obesity gene, on trabecular bone volume and bone marrow adiposity"],"prefix":"10.7554","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9294-4276","authenticated-orcid":true,"given":"Gustavo A","family":"Gomez","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03z6z3n38","id-type":"ROR","asserted-by":"publisher"}],"name":"VA Loma Linda Healthcare System","place":["Loma Linda, 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