The maintenance of glucose homeostasis requires that organisms respond to changing environmental conditions by balancing pancreatic insulin secretion with the ability of tissues, particularly liver, muscle, and fat, to respond to hormone-induced signaling by importing or secreting glucose 
. Obesity and other insults that promote diabetes do so by causing inflammation and insulin resistance, which is characterized by the inability of tissues to transduce insulin/insulin receptor interactions into elevated glucose uptake in muscle and adipose tissue and/or efficient insulin-mediated suppression of gluconeogenesis in liver. In peripheral tissues such as those noted above, insulin association with the insulin receptor (InsR; NM_010568.2) induces insulin receptor substrates (IRS1/2; NM_010570/NM_001081212.1) tyrosine phosphorylation, which through activated PI3-kinase, promotes the phosphorylation of phosphatidylinositol 4,5-bisphosphate (PIP2) to yield phosphatidylinositol (3,4,5)-trisphosphate (PIP3). This process is inhibited by the phosphatase PTEN (NM_008960.2). PIP3 promotes the membrane localization of PDK1 (NM_008960.2) and Akt1 (NM_011062.4), where PDK1 and PDK2 phosphorylate Akt1, resulting in glucose uptake and metabolism. In addition to PTEN, a number of factors can regulate these events. For example, inflammatory pathways have a profound negative impact on insulin signaling; in one instance, Stat3 activation induces Socs3 transcription, which in turn indirectly represses InsR and IRS1/2 activities 
CPEB (NM_007755.4) is an mRNA binding protein that controls cytoplasmic polyadenylation-induced translation by interacting with the 3′ UTR cis-acting cytoplasmic polyadenylation element (CPE) and three regulatory proteins including Gld2 (NM_001094423.1), a poly(A) polymerase; PARN (NM_001087674.1), a deadenylating enzyme, and Maskin (NM_001088495.1), which also associates with eIF4E (NM_001090548.1), the cap-binding factor 
. Initial CPEB-repression occurs because Maskin binding to eIF4E precludes the eIF4E-eIF4G interaction that is necessary to recruit the 40S ribosomal unit to the 5′ end of the mRNA. Because Maskin is tethered to CPE, only CPE-containing RNAs are repressed. CPEB-induced stimulated (i.e., deprepressed) translation is initiated when CPEB is phosphorylated on S174 or T171 (species-dependent), which expels PARN from the ribonucleoprotein complex. This event allows Gld2 to polyadenylate the RNA by default. The newly elongated poly(A) tail is then bound by poly(A) binding protein (PABP), which also binds eIF4G; the PABP/eIF4G complex displaces Maskin from eIF4E, allowing for formation of the initiation complex on the 5′ cap structure.
By regulating mRNA-specific translation, CPEB profoundly influences gametogenesis and early development 
, neuronal synaptic plasticity 
, and cell-cycle progression 
. CPEB also regulates translation during cellular senescence; fibroblasts derived from Cpeb1
knockout (KO) mice do not senesce as do wild type (WT) cells, but are immortal 
. Similarly, human cells depleted of CPEB bypass senescence and have a three-fold extended lifespan 
. In the mouse cells, aberrant over-expression of myc (NM_001177353.1) mRNA is at least one event that mediates the senescence response 
, while in human cells, reduced p53 (NM_000546.4) mRNA translation accounts for the senescence bypass 
To identify additional mRNAs that are translationally regulated by CPEB during senescence, we used sucrose density gradient centrifugation to prepare polysomes from WT and Cpeb1 KO mouse embryo fibroblasts (MEFs) followed by microarray analysis. Unexpectedly, several mRNAs encoding insulin-signaling molecules (see below) were found to be excessively polysomal in the KO versus WT MEFs. Consequently, we investigated the involvement of CPEB in insulin signaling and glucose homeostasis. In Cpeb1 KO liver, muscle, and fat, there was a dramatic and widespread mis-expression of insulin-signaling proteins. Increased expression of two major negative regulators of insulin signaling, PTEN and Stat3 (NM_213659.2), was associated with reduced Akt phosphorylation in both Cpeb1 KO liver and in CPEB-depleted HepG2 human liver cells. When fed on a high fat diet, WT and Cpeb1 KO mice were both obese, but only the KO animals displayed liver insulin resistance. These and other data demonstrate that CPEB control of PTEN and Stat3 mRNA translation is essential for liver insulin signaling and glucose homeostasis.