FoxO1 Protein Cooperates with ATF4 Protein in Osteoblasts to Control Glucose Homeostasis

Abstract

Background:The skeleton regulates glucose metabolism and energy expenditure. Results: Two transcription factors interact to regulate the activity of an osteoblast-secreted hormone favoring energy metabolism. Conclusion:The skeleton utilizes an intricate transcriptional machinery to maintain energy homeostasis. Significance: Transcription factor-mediated regulation of energy metabolism by the skeleton has potential applications in diseases of abnormal glucose metabolism.

ATF4 Protein Deficiency Protects against High Fructose-induced Hypertriglyceridemia in Mice

“…Implicit in this assertion is that ATF4 exudes a direct impact on glucose metabolism via osteocalcin, a bone hormone that is secreted specifically from osteoblasts (22). ATF4 acts in cooperation with the forkhead transcription factor FoxO1 to stimulate osteoblast expression of embryonic stem cell phosphatase (Esp), an enzyme that catalyzes osteocalcin carboxylation, resulting in inactivation of osteocalcin (22,45). As a result, ATF4 loss-of-function is asso-FIGURE 7.…”

“…Although ATF4 acts in concert with C/EBP to enhance the transcription of target genes (13,55), it is unknown how ATF4 cooperates with C/EBP for binding at the cognate site and for trans-activating promoter activity, nor is it clear whether C/EBP binding facilitates the recruitment of ATF4 at the CARE site or whether the occupancy of the CARE by both ATF4 and C/EBP is necessary for enhancing promoter activity. A recent study shows that ATF4 interacts with the forkhead transcription factor FoxO1 in regulating osteocalcin expression in osteoblasts (45). Further studies are needed to determine the molecular interplay of ATF4 with C/EBP or FoxO1 in regulating hepatic lipid metabolism.…”

Physiological/pathological ramifications of transcription factors in the unfolded protein response

“…Although Atf4 −/− mice did not exhibit an obvious defect in pancreatic β cells (Back et al 2009), ATF4 seems to regulate glucose metabolism in mice by regulating osteoblast function (Kode et al 2012). Atf4 deletion in mice improved glucose and insulin sensitivity, which was abolished by overexpression of ATF4 in osteoblasts through cooperation with FoxO1 (Kode et al 2012).…”

“…Although Atf4 −/− mice did not exhibit an obvious defect in pancreatic β cells (Back et al 2009), ATF4 seems to regulate glucose metabolism in mice by regulating osteoblast function (Kode et al 2012). Atf4 deletion in mice improved glucose and insulin sensitivity, which was abolished by overexpression of ATF4 in osteoblasts through cooperation with FoxO1 (Kode et al 2012). Furthermore, Atf4 deletion specifically in murine osteoblasts causes the same metabolic phenotypes as Atf4 −/− mice, suggesting a requirement of ATF4 in osteoblast-mediated glucose homeostasis (Yoshizawa et al 2009).…”

IGF-1 regulation of key signaling pathways in bone

“…Subsequent activation can signal bcells in the pancreas leading to an increase in proliferation and greater secretion of insulin. Mechanistically, further characterization has shown the following: (1) FoxO1 through its negative regulation of Runx2 52 downregulates Bglap2, (2) FoxO1 and ATF4 synergistically activating Esp, a negative regulator of insulin signaling, 53 affects glucose homeostasis. Another recent study examined an osteoblast-specific knockout of PDK1, a kinase that phosphorylates and partially activates AKT.…”