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 α1(I)Collagen-Atf4 mice] displayed a decrease in insulin secretion and were insulin insensitive. Third, the α1(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.

ATF4 is directly recruited by TLR4 signaling and positively regulates TLR4-trigged cytokine production in human monocytes

“…35,36 ATF4 acts as a transcription activator and inhibitor. 35,[37][38][39][40] The results of our cytokine array assay revealed that ATF4 positively regulated the secretion of RANTES, sICAM-1, IL-6, IL-8 and IFN-c, all of which are proinflammatory cytokines. RANTES, a representative chemotactic factor, mediates T cell differentiation and cytokine release, and it is also a chemoattractant for blood monocytes, memory Thelper cells, mast leukocyte and eosinophils.…”

Osteocalcin, energy and glucose metabolism

“…Osteoprotegerin is the receptor that binds to RANKL on osteoblast/stromal cells, blocking the RANKL-RANK interaction and the osteoclast precursors, with a consequent reduction of osteoclasts production and bone resorption (17,18). As a consequence of low osteoprotegerin production, osteoclasts are stimulated, enhancing the acidification of the bone mineral matrix in the reabsorption lacunae and increasing the undercarboxylated osteocalcin release.…”

The osteoblast: An insulin target cell controlling glucose homeostasis

“…(5,6) In accordance with this concept, treatment of wild-type mice with warfarin decreased blood glucose levels. (7) In an unexpected turn of events, the osteoblast was found to express the Esp gene, which encodes a protein tyrosine phosphatase that hampers glucose metabolism by inhibiting osteocalcin endocrine functions. (5) This finding was unexpected because this intracellular protein tyrosine phosphatase is not involved directly in the carboxylation of osteocalcin.…”