Featured Articles

Volume 5 | No. 7 | July 2016

Autonomous interconversion between adult pancreatic α-cells and β-cellsYe and colleagues establish an efficient and adaptable lineage tracing system for pancreatic cells. The authors quantitatively identify the sources of adult β-cells under multiple metabolic conditions, and propose a kinetic model of cell conversion. Their data also reconcile the discrepant findings generated by the tamoxifen-inducible system.

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Comprehensive alpha, beta and delta cell transcriptomes reveal that ghrelin selectively activates delta cells DiGruccio et al. offer an alternate mechanistic explanation how ghrelin achieves its insulinostatic actions. Their observations underscore that delta cells play an underappreciated but important physiological role in controlling insulin output by local feedback within pancreatic islets. The high quality transcriptomes from delta, beta, and alpha cells that were instrumental in this discovery will be invaluable to unravel the complex crosstalk that tightly balances insulin and glucagon release from healthy islets and breaks down in diabetes.

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PI3 kinases p110α and PI3K-C2β negatively regulate cAMP via PDE3/8 to control insulin secretionThe preservation of nutrient-stimulated insulin secretion is essential for proper glycaemic control, particularly in the face of insulin resistance. Kolic et al. provide new insight into the basis for phosphatidylinositol-3-OH kinase (PI3K)-mediated regulation of insulin secretion in mouse and human islets. PI3K-C2β limits glucose-stimulated insulin secretion (GSIS) by suppressing cAMP responses in a manner that requires phosphodiesterase (PDE) 3 (in humans and mice) and PDE8B (in mice). PI3K inhibition does not augment GSIS in islets from type-2 diabetic donors.

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Lack of AKT in adipocytes causes severe lipodystrophyLipodystrophy is a disease characterized by lack of adipose tissue accompanied by metabolic derangements. Shearin and colleagues delete Akt1 and Akt2 selectively in adipocytes of mice, thus interrupting a critical insulin-signalling pathway. The authors find that loss of these AKT isoforms in adipocytes causes profound lipodystrophy, associated with fatty liver and systemic insulin resistance.

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Lipodystrophy in mice with adipose tissue-specific insulin receptor ablationAdipose tissue is a complex organ, playing an active role in whole-body energy and metabolic homeostasis. Qiang and colleagues generate and phenotype a new adipose tissue-specific IR mouse model using the adipose tissue-specific Adipoq-Cre line. They find that Adipoq-Cre-mediated insulin receptor (IR) knockout (KO) leads to severe lipodystrophy rather than simply reduced fat mass. The lipodystrophic IR KO mice have profound insulin resistance, hyperglycemia, organomegaly (liver, heart, pancreas, kidney, spleen), and impaired adipokine secretion.

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AGPAT2 is essential for postnatal development and maintenance of white and brown adipose tissue Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder characterized by a lack of adipose tissue (AT). Mutations in the AGPAT2 gene, encoding 1-acylglycerol-3-phosphate O-acyltransferase 2, cause the most common form of CGL. Cautivo et al. show that Agpat2-/- mice are born with AT, which undergoes a rapid degenerative process that leads to the total destruction of AT during the first week after birth. Adipocyte-like cells from differentiated Agpat2-/- mouse embryonic fibroblasts recapitulate the abnormal phenotype observed in subcutaneous white adipose tissue of Agpat2-/- new-born mice. Based on their in vivo and in vitro findings, the authors propose AGPAT2 deficient adipocytes have an impaired capacity to adapt to the massive lipid availability associated with postnatal feeding, leading to cellular stress, death and inflammatory destruction of adipose tissue.

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Metabolic reprogramming through fatty acid transport protein 1 (FATP1) regulates macrophage inflammatory potentialChronic over-nutrition results in low-grade inflammation in metabolically sensitive tissues that contributes to systemic metabolic dysregulation. Johnson, Qin and colleagues report that FATP1 plays a critical role in suppressing inflammation in vitro and reducing Macrophage infiltration and inflammation in vivo through modulation of lipid mediators and oxidative stress. The authors demonstrate for the first time that FATP1 provides a unique mechanism by which the metabolic and inflammatory tone of adipose and systemic metabolism may be regulated.

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G0/G1 Switch Gene 2 controls adipose triglyceride lipase activity and lipid metabolism in skeletal muscleThe first and rate-limiting step of skeletal muscle lipolysis is catalysed by adipose triglyceride lipase (ATGL). The data of Laurens and colleagues show that the protein G0/G1 Switch Gene 2 (G0S2) inhibits ATGL activity in mouse and human skeletal muscle and plays a central role in regulating lipid metabolism and substrate oxidation. These results also suggest that changes in G0S2 expression may cause accumulation of lipotoxic species in skeletal muscle and subsequent impairment of insulin action.

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Branched-chain amino acid restriction in Zucker-fatty rats improves muscle insulin sensitivityAberrant amino acid metabolism has long been recognized as a feature of obesity and accompanying metabolic disease. White, Lapworth et al. describe the results of a nutritional intervention study in which they restricted branched-chain amino acid (BCAA) dietary supply in Zucker-lean and Zucker-fatty rats, the latter being a model of insulin resistance and impaired BCAA metabolism. Their findings demonstrate a clear cause and effect relationship between BCAA supply and insulin sensitivity and highlight underlying biochemical mechanisms.

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Limiting glucocorticoid secretion increases the anorexigenic property of Exendin-4Glucagon-like peptide-1 (GLP-1) based drugs are one of the leading treatment options for obesity and diabetes. Lee and colleagues propose that glucocorticoid counteracts the anorexigenic effects of GLP-1R agonist treatment. Their findings with low dose dexamethasone and lesion approaches support the novel concept that the potency of Exendin-4 as an anorexigenic drug is inversely related to glucocorticoid secretion. Therefore, manipulating glucocorticoid receptor mechanisms will be of interest for the future design of GLP-1-based therapies.

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Melanocortin-3 receptors in the limbic system mediate feeding-related motivational responsesThe melanocortin-3 receptor (MC3R) is expressed in hypothalamic and limbic structures controlling autonomic function and complex ingestive behaviours. Mavrikaki and colleagues find that MC3Rs are required for the full expression of feeding-related motivational responses, but only in situations of caloric insufficiency. The authors also report that rescuing MC3Rs in the mesolimbic dopaminergic system enhances some feeding-related motivational responses during situations of caloric insufficiency, but has no impact on the obese phenotype.

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PGC-1α expression in murine AgRP neurons regulates food intake and energy balanceThe transcriptional coactivator PGC-1α is one of the key regulators of cellular energy homeostasis and strongly affects mitochondrial biogenesis and oxidative metabolism. Gill et al. demonstrate that PGC-1α is directly involved in the regulation of feeding, activity, and body temperature by modulating the activity of agouti-related protein (AgRP) neurons. These changes are associated with an increase in fat and a decrease in lean mass. Importantly, for the first time, the role of PGC-1α in the regulation of appetite can be dissociated from confounding effects of knockout of PGC-1α in peripheral tissues and in other areas of the brain.

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The 60 Second Metabolist
In this section authors briefly report on their work recently published in Molecular Metabolism.

Watch the most recent interview by clicking the video still. The link "referring article" directs you to this author's publication.



Giles Yeo
University of Cambridge, UK
Referring article

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