Peroxisome proliferator activated receptor-γ in osteoblasts controls bone formation and fat mass by regulating sclerostin expression

•PPARγ in osteoblasts and osteocytes regulates bone fat mass•Mice lacking PPARγ have reduced sclerostin production•Sclerostin contributes to the adipose phenotypes of mutant mice•Sclerostin loss function synergizes with improve metabolism The nuclear receptor peroxisome proliferator activated receptor-γ (PPARγ) is a key contributor metabolic via its adipogenic insulin-sensitizing functions, but it has negative effects on skeletal homeostasis. Here, we questioned whether actions are linked. Ablating Pparg expression produced high mass phenotype, secondary increased osteoblast activity, reduction subcutaneous because fatty acid synthesis oxidation. mutants proceed from regulation production by PPARγ. Mutants exhibited reductions Sost serum levels while increasing normalized both phenotypes. Importantly, disrupting synergized agonist preventing loss. 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Relative littermates, trabecular per 27.5%, significant number, 24.1%, thickness, 16- 24-week-old mice, respectively. Cortical femoral mid-diaphysis age-related changes structure cross-sectional area comparable 8 weeks, significantly ages 16 24 weeks 1H–1K). Histomorphometric performed 16-week 1L–1O), apposition rate rate, decrease osteoclast 1P 1Q). abundance adipocytes 1R). Similar vivo, cultures calvarial differentiation. Compared staining alkaline phosphatase matrix mineralization Runx2, Atf4, Bglap2 S1D). Tnfsf11 (rank ligand) affected Tnfrsf11b (osteoprotegerin) S1E), explain osteoclasts observed vivo. Therefore, maturing development. Assessment organ weights necropsy composition. When compared gonadal pad (gWAT) 2A) inguinal (iWAT) 2B). Histological examination iWAT adipocyte size dramatic multilocular 2D). Intrascapular brown (BAT) morphometry 2C 2D) organs S2A–S2C) controls. detectable change feeding behavior, levels, expenditure 2E, 2F, S2D–S2F). However, suggested ratio synthesis, Acaca Fasn, 2G 2H) oxidation (Acadl, Cpt1a, Ppara, 2I) Furthermore, (Ppargc1a Ucp1, 2I), UCP1 immunostaining 2D), mitochondrial proteins 2J) suggesting induction beiging depot. Except modest, Atp5a1, BAT 2K), consistent Analysis metabolites developed improvements lipid metabolism. Serum triglycerides 2L) free cholesterol 2M 2N). Random pancreatic β-cell islet morphology mutants, lower suggests sensitivity 2O–2R). excursions during tolerance testing dampened relative 2S) greater degree 2T). ability stimulate AKT phosphorylation iWAT, quadriceps, liver littermates 2U). Female S3). depots female Likewise, displayed test. Thus, simultaneously whole further examine effect metabolism, next challenged (HFD, 60% kcal fat) 4 weeks. Surprisingly, HFD PPARγ-deficiency 3A) 3B). Because chow 1E), normalization after represented substantial suppression accrual (% BV/TV −16.21 ± 18.07% versus −34.70 16.36%, p = 0.042, Mean SD). compartment, HFD-fed Tt. Ar 13.70 11.89% −0.92 7.37%, 0.007) likely feeding. contrast, retained During 12-week study, gain 3C) had BAT, 3D–3F S4A). chow-fed histological molecular 3G–3J). except Ucp1 remained elevated considerably than 2I 3K). Adipocyte gWAT (despite synthesis), there marked inflammation S4B–S4E). liver, marker steatosis 3G 3L–3N). contributed maintenance improved mirrored mutants. random 3O 3P) tests 3Q 3R). triglycerides, fatt