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author:("ree, Karen")
1.  Resistance to Diet-Induced Obesity in Mice with Synthetic Glyoxylate Shunt 
Cell metabolism  2009;9(6):525-536.
Summary
Given the success in engineering synthetic phenotypes in microbes and mammalian cells, constructing non-native pathways in mammals has become increasingly attractive for understanding and identifying potential targets for treating metabolic disorders. Here we introduced the glyoxylate shunt into mouse liver to investigate mammalian fatty acid metabolism. Mice expressing the shunt showed resistance to diet-induced obesity on a high fat diet despite similar food consumption. This was accompanied by a decrease in total fat mass, circulating leptin levels, plasma triglyceride concentration, and a signaling metabolite in liver, malonyl-CoA, that inhibits fatty acid degradation. Contrary to plants and bacteria, in which the glyoxylate shunt prevents the complete oxidation of fatty acids, this pathway when introduced in mice increases fatty acid oxidation such that resistance to diet-induced obesity develops. This work suggests that using non-native pathways in higher organisms to explore and modulate metabolism may be a useful approach.
doi:10.1016/j.cmet.2009.04.008
PMCID: PMC4277884  PMID: 19490907
2.  Insulin Resistance and Altered Systemic Glucose Metabolism in Mice Lacking Nur77 
Diabetes  2009;58(12):2788-2796.
OBJECTIVE
Nur77 is an orphan nuclear receptor with pleotropic functions. Previous studies have identified Nur77 as a transcriptional regulator of glucose utilization genes in skeletal muscle and gluconeogenesis in liver. However, the net functional impact of these pathways is unknown. To examine the consequence of Nur77 signaling for glucose metabolism in vivo, we challenged Nur77 null mice with high-fat feeding.
RESEARCH DESIGN AND METHODS
Wild-type and Nur77 null mice were fed a high-fat diet (60% calories from fat) for 3 months. We determined glucose tolerance, tissue-specific insulin sensitivity, oxygen consumption, muscle and liver lipid content, muscle insulin signaling, and expression of glucose and lipid metabolism genes.
RESULTS
Mice with genetic deletion of Nur77 exhibited increased susceptibility to diet-induced obesity and insulin resistance. Hyperinsulinemic-euglycemic clamp studies revealed greater high-fat diet–induced insulin resistance in both skeletal muscle and liver of Nur77 null mice compared with controls. Loss of Nur77 expression in skeletal muscle impaired insulin signaling and markedly reduced GLUT4 protein expression. Muscles lacking Nur77 also exhibited increased triglyceride content and accumulation of multiple even-chained acylcarnitine species. In the liver, Nur77 deletion led to hepatic steatosis and enhanced expression of lipogenic genes, likely reflecting the lipogenic effect of hyperinsulinemia.
CONCLUSIONS
Collectively, these data demonstrate that loss of Nur77 influences systemic glucose metabolism and highlight the physiological contribution of muscle Nur77 to this regulatory pathway.
doi:10.2337/db09-0763
PMCID: PMC2780886  PMID: 19741162
3.  Phosphatidate degradation: Phosphatidate phosphatases (lipins) and lipid phosphate phosphatases 
Biochimica et biophysica acta  2009;1791(9):956-961.
Summary
Three lipid phosphate phosphatases (LPPs) regulate cell signaling by modifying the concentrations of a variety of lipid phosphates versus their dephosphorylated products. In particular, the LPPs are normally considered to regulate signaling by the phospholipase D (PLD) pathway by converting phosphatidate (PA) to diacylglycerol (DAG). LPP activities do modulate the accumulations of PA and DAG following PLD activation, but this could also involve an effect upstream of PLD activation. The active sites of the LPPs are on the exterior surface of plasma membranes, or on the luminal surface of internal membranes. Consequently, the actions of the LPPs in metabolizing PA formed by PLD1 or PLD2 should depend on the access of this substrate to the active site of the LPPs. Alternatively, PA generated on the cytosolic surface of membranes should be readily accessible to the family of specific phosphatidate phosphatases, namely the lipins. Presently, there is only indirect evidence for the lipins participating in cell signaling following PLD activation. So far, we know relatively little about how individual LPPs and specific phosphatidate phosphatases (lipins) modulate cell signaling through controlling the turnover of bioactive lipids that are formed after PLD activation.
doi:10.1016/j.bbalip.2009.02.007
PMCID: PMC2875194  PMID: 19250975
Diacylglycerol; lysophosphatidate; phosphatidate; phospholipase D; triacylglycerol synthesis
4.  The Lipin Family: Mutations and Metabolism 
Current opinion in lipidology  2009;20(3):165-170.
Purpose of review
The family of three lipin proteins act as phosphatidate phosphatase (PAP) enzymes required for glycerolipid biosynthesis, and also as transcriptional coactivators that regulate expression of lipid metabolism genes. The genes for lipin-1, lipin-2 and lipin-3 are expressed in key metabolic tissues, including adipose tissue, skeletal muscle, and liver, but the physiological functions of each member of the family have not been fully elucidated. Here we examine the most recent studies that provide information about the roles of lipin proteins in metabolism and human disease.
Recent findings
Recent studies have identified mutations that cause lipin-1 or lipin-2 deficiency in humans, leading to acute myoglobinuria in childhood or the inflammatory disorder Majeed syndrome, respectively. The effects of lipin-1 deficiency appear to include both the loss of glycerolipid building blocks and the accumulation of lipid intermediates that disrupt cellular function. Several studies have demonstrated that polymorphisms in the LPIN1 and LPIN2 genes are associated with metabolic disease traits, including insulin sensitivity, diabetes, blood pressure, and response to thiazolidinedione drugs. Furthermore, lipin-1 expression levels in adipose tissue and/or liver are positively correlated with insulin sensitivity. Studies of lipin-1 in adipocytes have shed some light on its relationship with insulin sensitivity.
Summary
Lipin-1 and lipin-2 are required for normal lipid homeostasis, and have unique physiological roles. Future studies, for example using engineered mouse models, will be required to fully elucidate their specific roles in normal physiology and disease.
doi:10.1097/MOL.0b013e32832adee5
PMCID: PMC2875192  PMID: 19369868
triglyceride; phosphatidic acid phosphatase; transcriptional coactivator; lipodystrophy; obesity; insulin resistance; myopathy
5.  Adipose tissue dysfunction tracks disease progression in two Huntington's disease mouse models 
Human Molecular Genetics  2009;18(6):1006-1016.
In addition to the hallmark neurological manifestations of Huntington's disease (HD), weight loss with metabolic dysfunction is often observed in the later stages of disease progression and is associated with poor prognosis. The mechanism for weight loss in HD is unknown. Using two mouse models of HD, the R6/2 transgenic and CAG140 knock-in mouse strains, we demonstrate that adipose tissue dysfunction is detectable at early ages and becomes more pronounced as the disease progresses. Adipocytes acquire a ‘de-differentiated’ phenotype characterized by impaired expression of fat storage genes. In addition, HD mice exhibit reduced levels of leptin and adiponectin, adipose tissue-derived hormones that regulate food intake and glucose metabolism. Importantly, some of these changes occur prior to weight loss and development of some of the characteristic neurological symptoms. We demonstrate that impaired gene expression and lipid accumulation in adipocytes can be recapitulated by expression of an inducible mutant huntingtin transgene in an adipocyte cell line and that mutant huntingtin inhibits transcriptional activity of the PGC-1α co-activator in adipocytes, which may contribute to aberrant gene expression. Thus, our findings indicate that mutant huntingtin has direct detrimental effects in cell types other than neurons. The results also indicate that circulating adipose-tissue-derived hormones may be accessible markers for HD prognosis and progression and suggest that adipose tissue may be a useful therapeutic target to improve standard of life for HD patients.
doi:10.1093/hmg/ddn428
PMCID: PMC2649017  PMID: 19124532
6.  Hoofbeats, zebras, and insights into insulin resistance 
In this issue of the JCI, Semple and colleagues report phenotypic evaluation of patients with a germline mutation in the gene encoding serine/threonine kinase AKT2 (see the related article beginning on page 315). Their findings support the idea that the postreceptor actions of insulin in the liver — suppression of gluconeogenesis and stimulation of lipogenesis — are mediated through divergent pathways that can be uncoupled. The results appear to refine the arrangement of crucial steps along these pathways and show how comprehensive study of the phenotype, “deep phenotyping,” of patients who carry rare mutations might complement other types of experiments to elucidate complex pathways and mechanisms.
doi:10.1172/JCI38420
PMCID: PMC2631308  PMID: 19244606

Results 1-6 (6)