RNA-Binding Protein PTB and MicroRNA-221 Coregulate AdipoR1 Translation and Adiponectin Signaling

Abstract

Adiponectin receptor 1 (AdipoR1) mediates adiponectin's pleiotropic effects in muscle and liver and plays an important role in the regulation of insulin resistance and diabetes. Here, we demonstrate a pivotal role for microRNA-221 (miR-221) and the RNA-binding protein polypyrimidine tract-binding protein (PTB) in posttranscriptional regulation of AdipoR1 during muscle differentiation and in obesity. RNA-immunoprecipitation and luciferase reporter assays illustrated that both PTB and miR-221 bind AdipoR1-39UTR and cooperatively inhibit AdipoR1 translation. Depletion of PTB or miR-221 increased, while overexpression of these factors decreased, AdipoR1 protein synthesis in both muscle and liver cells. During myogenesis, downregulation of PTB and miR-221 robustly induced AdipoR1 translation, providing a mechanism for enhanced AdipoR1 protein expression and activation in differentiated muscle cells. In addition, since both PTB and miR-221 are upregulated in liver and muscle of genetic and dietary mouse models of obesity, this novel translational mechanism may be at least partly responsible for the reduction in AdipoR1 protein levels in obesity. These findings highlight the importance of translational control in regulating AdipoR1 protein expression and adiponectin signaling. Given that adiponectin is reduced in obesity, induction of AdipoR1 could potentially enhance adiponectin beneficial effects and ameliorate insulin resistance and diabetes. Adiponectin, an adipocyte-derived abundant plasma protein (1-4) with insulin-sensitizing and antiinflammatory properties, gained recognition as a potential mediator between obesity, insulin resistance, and diabetes (5): Adiponectin levels are reduced in obesity (1), and mice lacking adiponectin develop insulin resistance, glucose intolerance, hyperglycemia, and hypertension-all characteristics of the metabolic syndrome (5,6). Adiponectin's biological effects depend not only on the relative circulating concentrations of the hormone but also on the expression level and function of its receptors (5,7-9). To date, two receptors for adiponectin have been identified (AdipoR1 and AdipoR2), which mediate adiponectin pleoitropic effects (10). Downregulation of the receptors in obesity is involved in the development of insulin resistance and diabetes (11).Skeletal muscle and liver are important targets of adiponectin and its receptors in the regulation of energy metabolism (12). Adiponectin, through AdipoR1, METABOLISMactivates AMP-activated protein kinase (AMPK) in vivo and in vitro, which increases fatty acid oxidation and glucose utilization and leads to an improvement in insulin sensitivity (10,11,(13)(14)(15). Recently, overexpression of AdipoR1 in rat skeletal muscle was shown to enhance insulin sensitivity in vivo through phosphatidylinositol 3-kinase-and AMPK-signaling pathways (16). In addition, specific deletion of AdipoR1 in mouse skeletal muscle demonstrated that AdipoR1 is involved in the regulation of Ca 2+ signaling, peroxisome proliferator-activated receptor g coactivat...

Orally Active Osteoanabolic Agent GTDF Binds to Adiponectin Receptors, With a Preference for AdipoR1, Induces Adiponectin-Associated Signaling, and Improves Metabolic Health in a Rodent Model of Diabetes

“…Interestingly, a recent report characterized a developmentally regulated alternate splice variant of AdipoR1 in human subjects that was strongly enhanced during skeletal muscle differentiation and was decreased in diabetic patients, and the protein level of AdipoR1 accurately represented these changes but not total mRNA levels that accounted for all AdipoR1 splice variants (34). Our data gains further support from another recent report, which describes that microRNA-221 and the RNA binding protein polypyrimidine tract binding protein regulate AdipoR1 protein expression and are induced in genetic and diet-induced mouse models of obesity (35).…”

Pathophysiological Mechanism of Bone Loss in Type 2 Diabetes Involves Inverse Regulation of Osteoblast Function by PGC-1α and Skeletal Muscle Atrogenes: AdipoR1 as a Potential Target for Reversing Diabetes-Induced Osteopenia

“…To decipher intact AdipoR1 expression in bones from its depletion in db skeletal muscle, we assessed microRNA-221 (miR-221) and RNA binding protein polypyrimidine tract binding protein (PTB) levels because they negatively regulate AdipoR1 expression (49). miR-221 level in bone and muscle across all ages was significantly higher in both diabetic strains than wt, although compared with bone, differences in muscle was higher (two-to threefold in bone vs. three-to sixfold in muscle) (Fig.…”

hnRNP I regulates neonatal immune adaptation and prevents colitis and colorectal cancer

“…Thus, it is also possible that hnRNPI may regulate the expression of proteins that alter IRAK1 protein turnover. Of note, hnRNPI is capable of modulating the activity of microRNAs in disease pathogenesis and many important biological processes [30,39–42]. It has been reported that miR-146a controls both translation and degradation of epithelial IRAK1 in the neonatal intestine [19].…”