Glucose regulates RMI1 expression through the E2F pathways in adipose cells.

RecQ-mediated genome instability 1 (RMI1) has been identified as a novel energy homeostasis-related molecule. While recent studies have suggested that change in RMI1 expression levels in adipose tissue may affect the body's energy balance, no reports have identified the mechanism behind this expression regulation. In the present study, we found that RMI1 expression increased on differentiation of 3T3-L1 fibroblasts to adipocytes. In addition, glucose stimulation induced RMI1 expression to approximately eight times the baseline level. Further, knockdown of either E2F5 or E2F8 mRNA using siRNA suppressed this glucose-induced up-regulation of RMI1 expression. These results suggest that RMI1 expression may be regulated by glucose, at least in part, via E2F expression.

Adipocyte hyperplasia and RMI1 in the treatment of obesity.

The escalating prevalence of obesity is one of the most pressing health concerns of the modern era, yet existing medicines to combat this global pandemic are disappointingly limited in terms of safety and effectiveness. The inadequacy of currently available therapies for obesity has made new drug development crucial. In the past several decades, however, major progress has been achieved in understanding adipocyte hyperplasia associated with the pathogenesis of obesity, and consequently new potential targets for the medical treatment of obesity have been identified. We primarily review recent progress in the regulation of adipocyte hyperplasia as a novel emerging nontraditional approach. In this minireview, we focus on recQ-mediated genome instability 1 (RMI1), a recently identified novel molecular target for obesity treatment. RMI1-deficient mice have been found to be resistant to high-fat diet- and genetics-related obesity. Expression of this protein is regulated by E2F transcription factors, and recent studies have suggested that RMI1 plays an important role in the control of energy homeostasis during the development of obesity, with a mode of action based on the regulation of adipocyte hyperplasia.

SHIP2 and its involvement in various diseases.

IMPORTANCE OF THE FIELD: Inositol polyphosphate 5-phosphatase (SHIP2) is an important negative regulator of intracellular phosphatidylinositol phosphate, a key second messenger of various intracellular signaling pathways. The functional upregulation of SHIP2 results in signaling blockade, leading to related disorders. AREAS COVERED IN THIS REVIEW: We first summarize the role of SHIP2 in the regulation of insulin signaling and type 2 diabetes, including remarkable advances in pharmacological approaches. In addition, this review highlights new findings regarding the involvement of SHIP2 in a number of diseases, including cancer, neurodegenerative diseases, and atherosclerosis. WHAT THE READER WILL GAIN: Recently identified small-molecule inhibitors of SHIP2 phosphatase activity emphasize the potential therapeutic value of SHIP2. In addition, currently available evidence demonstrates the importance of the scaffolding-type protein function of SHIP2. Understanding this interesting function will help clarify the complicated involvement of SHIP2 in various disorders. TAKE HOME MESSAGE: Recent studies have demonstrated that SHIP2 is a promising therapeutic target for not only type 2 diabetes, but also cancer, neurodegenerative diseases, and atherosclerosis. Targeting SHIP2 through specific small-molecule inhibitors will have beneficial effects on these diseases.

Glucose metabolism activation by SHIP2 inhibitors via up-regulation of GLUT1 gene in L6 myotubes.

Lipid phosphatase SH2 domain-containing inositol 5'-phosphatase 2 (SHIP2) plays an important role in the regulation of insulin signaling. In this report, we identified AS1938909, a novel small-molecule SHIP2 inhibitor. AS1938909 showed potent inhibition of SHIP2 (Ki=0.44 microuM) and significant selectivity over other related phosphatases. Further, AS1938909 increased Akt phosphorylation, glucose consumption, and glucose uptake in L6 myotubes. Treatment of L6 myotubes with SHIP2 inhibitors for 48 h significantly induced expression of GLUT1 mRNA, but not that of GLUT4. These results suggest that pharmacological inhibition of SHIP2 activates glucose metabolism due, at least in part, to up-regulation of GLUT1 gene expression.

RMI1 deficiency in mice protects from diet and genetic-induced obesity.

The aim of this study is to discover and characterize novel energy homeostasis-related molecules. We screened stock mouse embryonic stem cells established using the exchangeable gene trap method, and examined the effects of deficiency of the target gene on diet and genetic-induced obesity. The mutant strain 0283, which has an insertion at the recQ-mediated genome instability 1 (RMI1) locus, possesses a number of striking features that allow it to resist metabolic abnormalities. Reduced RMI1 expression, lower fasting-blood glucose and a reduced body weight (normal diet) were observed in the mutant mice. When fed a high-fat diet, the mutant mice were resistant to obesity, and also showed improved glucose intolerance and reduced abdominal fat tissue mass and food intake. In addition, the mutants were also resistant to obesity induced by the lethal yellow agouti (A(y)) gene. Endogenous RMI1 genes were found to be up-regulated in the liver and adipose tissue of KK-A(y) mice. RMI1 is a component of the Bloom's syndrome gene helicase complex that maintains genome integrity and activates cell-cycle checkpoint machinery. Interestingly, diet-induced expression of E2F8 mRNA, which is an important cell cycle-related molecule, was suppressed in the mutant mice. These results suggest that the regulation of energy balance by RMI1 is attributable to the regulation of food intake and E2F8 expression in adipose tissue. Taken together, these findings demonstrate that RMI1 is a novel molecule that regulates energy homeostasis.

Brain-specific carnitine palmitoyl-transferase-1c: role in CNS fatty acid metabolism, food intake, and body weight.

While the brain does not utilize fatty acids as a primary energy source, recent evidence shows that intermediates of fatty acid metabolism serve as hypothalamic sensors of energy status. Increased hypothalamic malonyl-CoA, an intermediate in fatty acid synthesis, is indicative of energy surplus and leads to the suppression of food intake and increased energy expenditure. Malonyl-CoA functions as an inhibitor of carnitine palmitoyl-transferase 1 (CPT1), a mitochondrial outer membrane enzyme that initiates translocation of fatty acids into mitochondria for oxidation. The mammalian brain expresses a unique homologous CPT1, CPT1c, that binds malonyl-CoA tightly but does not support fatty acid oxidation in vivo, in hypothalamic explants or in heterologous cell culture systems. CPT1c knockout (KO) mice under fasted or refed conditions do not exhibit an altered CNS transcriptome of genes known to be involved in fatty acid metabolism. CPT1c KO mice exhibit normal levels of metabolites and of hypothalamic malonyl-CoA and fatty acyl-CoA levels either in the fasted or refed states. However, CPT1c KO mice exhibit decreased food intake and lower body weight than wild-type littermates. In contrast, CPT1c KO mice gain excessive body weight and body fat when fed a high-fat diet while maintaining lower or equivalent food intake. Heterozygous mice display an intermediate phenotype. These findings provide further evidence that CPT1c plays a role in maintaining energy homeostasis, but not through altered fatty acid oxidation.

The brain-specific carnitine palmitoyltransferase-1c regulates energy homeostasis.

Fatty acid synthesis in the central nervous system is implicated in the control of food intake and energy expenditure. An intermediate in this pathway, malonyl-CoA, mediates these effects. Malonyl-CoA is an established inhibitor of carnitine palmitoyltransferase-1 (CPT1), an outer mitochondrial membrane enzyme that controls entry of fatty acids into mitochondria and, thereby, fatty acid oxidation. CPT1c, a brain-specific enzyme with high sequence similarity to CPT1a (liver) and CPT1b (muscle) was recently discovered. All three CPTs bind malonyl-CoA, and CPT1a and CPT1b catalyze acyl transfer from various fatty acyl-CoAs to carnitine, whereas CPT1c does not. These findings suggest that CPT1c has a unique function or activation mechanism. We produced a targeted mouse knockout (KO) of CPT1c to investigate its role in energy homeostasis. CPT1c KO mice have lower body weight and food intake, which is consistent with a role as an energy-sensing malonyl-CoA target. Paradoxically, CPT1c KO mice fed a high-fat diet are more susceptible to obesity, suggesting that CPT1c is protective against the effects of fat feeding. CPT1c KO mice also exhibit decreased rates of fatty acid oxidation, which may contribute to their increased susceptibility to diet-induced obesity. These findings indicate that CPT1c is necessary for the regulation of energy homeostasis.