title: The transcription factor ATF4 regulates glucose metabolism in mice through its expression in osteoblasts.
abstract: The recent demonstration that osteoblasts have a role in controlling energy metabolism suggests that they express cell-specific regulatory genes involved in this process. Activating transcription factor 4 (ATF4) is a transcription factor that accumulates predominantly in osteoblasts, where it regulates virtually all functions linked to the maintenance of bone mass. Since Atf4-/- mice have smaller fat pads than littermate controls, we investigated whether ATF4 also influences energy metabolism. Here, we have shown, through analysis of Atf4-/- mice, that ATF4 inhibits insulin secretion and decreases insulin sensitivity in liver, fat, and muscle. Several lines of evidence indicated that this function of ATF4 occurred through its osteoblastic expression. First, insulin sensitivity is enhanced in the liver of Atf4-/- mice, but not in cultured hepatocytes from these mice. Second, mice overexpressing ATF4 in osteoblasts only [termed here alpha1(I)Collagen-Atf4 mice] displayed a decrease in insulin secretion and were insulin insensitive. Third, the alpha1(I)Collagen-Atf4 transgene corrected the energy metabolism phenotype of Atf4-/- mice. Fourth, and more definitely, mice lacking ATF4 only in osteoblasts presented the same metabolic abnormalities as Atf4-/- mice. Molecularly, ATF4 favored expression in osteoblasts of Esp, which encodes a product that decreases the bioactivity of osteocalcin, an osteoblast-specific secreted molecule that enhances secretion of and sensitivity to insulin. These results provide a transcriptional basis to the observation that osteoblasts fulfill endocrine functions and identify ATF4 as a regulator of most functions of osteoblasts.
authors.affiliation: Department of Genetics and Development, Columbia University College of Physicians and Surgeons, New York, New York, USA.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Yoshizawa
authors.forename: Eiichi
authors.initials: E
authors.lastname: Hinoi
authors.forename: Dae Young
authors.initials: DY
authors.lastname: Jung
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kajimura
authors.forename: Mathieu
authors.initials: M
authors.lastname: Ferron
authors.forename: Jin
authors.initials: J
authors.lastname: Seo
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Graff
authors.forename: Jason K
authors.initials: JK
authors.lastname: Kim
authors.forename: Gerard
authors.initials: G
authors.lastname: Karsenty
mesh_terms: D051701:Activating Transcription Factor 4 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015870:Gene Expression; D005947:Glucose / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D008954:Models, Biological; D010006:Osteoblasts / Q000378:metabolism*; D015675:Osteocalcin / Q000378:metabolism; D010641:Phenotype
chemical_list: C081452:Atf4 protein, mouse; D007328:Insulin; D015675:Osteocalcin; D051701:Activating Transcription Factor 4; D005947:Glucose