Featured Articles

Volume 4 | No. 12 | December 2015

Bioenergetic cues shift FXR splicing towards FXRα2Farnesoid X receptor (FXR) consists of four distinct proteins and is a promising target for the treatment of non-alcoholic fatty liver disease (NAFLD). Correia and colleagues show that FXR variants regulate hepatic lipid metabolism in an isoform-dependent manner. This constitutes a novel mechanism by which alternative FXR splicing in the liver integrates systemic energetic demands with a gene program of enhanced lipid handling/utilization and ketogenesis that positively impacts hepatic steatosis and insulin sensitivity.

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High intensity interval training improves liver and adipose tissue insulin sensitivityMarcinko and colleagues show that high intensity interval training (HIIT) improves exercise capacity and whole-body glucose homeostasis by enhancing liver and adipose tissue insulin sensitivity. These effects are independent of reductions in adiposity/adipose tissue cell size. Improved insulin sensitivity is also independent of adipose tissue inflammation, macrophage infiltration/inflammation or reductions in liver lipid content, indicating dissociation between these parameters and insulin resistance. They demonstrate that HIIT exercise training improves insulin sensitivity independently of the AMPK-ACC signaling pathway.

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A human beta cell line with drug inducible excision of immortalizing transgenesAccess to human beta cells is crucial to progress in understanding human-specific beta cell function. Benazra and colleagues have produced a novel human beta cell line derived from EndoC-βH2 cells that contains floxed immortalizing transgenes and an integrated Tamoxifen inducible form of CRE recombinase. This new line offers a simple and efficient procedure to mass produce non-proliferative human beta cells that can maintain a stable phenotype for 5 weeks in culture.

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Accumulation of 3-hydroxytetradecenoic acid: Cause or corollary of glucolipotoxic impairment of bioenergetics?One of the processes implicated in fatty acid-induced pancreatic beta cell dysfunction is impairment of bioenergetics. Doliba and colleagues show that islets cultured under glucolipotoxic conditions suffer a marked perturbation of energy metabolism. They propose defective bioenergetics as main cause of glucolipotoxicity.

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α/β-Hydrolase domain-6 and saturated long chain monoacylglycerol regulate insulin secretionGlucose stimulated insulin secretion (GSIS) is a biphasic process with a rapid first phase followed by a sustained second phase. Zhao and colleagues provide evidence that α/β-hydrolase domain-6 (ABHD6) accessible monoacylglycerol (MAG), which is produced during nutrient metabolism, synergizes with other cellular signals arising from fuel and some non-fuel stimuli to potentiate insulin secretion and that MAG activates the KATP-independent pathway and second phase of secretion. The data highlight the importance of ABHD6 and MAG in regulating insulin secretion in response to all stimuli to control glucose homeostasis.

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Hepatocyte TRAF3 promotes insulin resistance and type 2 diabetesChen and colleagues have identified hepatic TNF receptor-associated factor 3 (TRAF3) as a new metabolic regulator in obese mice. Liver TRAF3 levels are abnormally higher in obesity. Hepatocyte-specific deletion of TRAF3 attenuates insulin resistance, glucose intolerance, and hepatic steatosis in obese mice. Obesity-associated factors trigger and/or amplify a glucose-TRAF3 reinforcement loop in the liver, which is likely to drive type 2 diabetes and nonalcoholic fatty liver disease (NAFLD) progression. Disrupting this glucose-TRAF3 positive feedback loop may serve as a new strategy to treat type 2 diabetes and NAFLD.

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Hypothalamic CaMKKβ mediates glucagon anorectic effect and its diet-induced resistanceGlucagon counteracts hypoglycemia and opposes insulin actions by stimulating hepatic glucose synthesis and mobilization. Quiñones and colleagues show that glucagon causes a rapid and transient decrease in food intake through a mechanism involving the glucagon receptor, protein kinase A, Ca2+ -calmodulin-dependent protein kinase kinase β (CaMKKβ) and AMPK within the arcuate nucleus (ARC). This functional pathway is blunted in diet-induced obese rats, suggesting a high fat diet-induced resistance to the anorectic action of central glucagon. The data describe the molecular underpinnings by which glucagon controls feeding that may lead to a better understanding of anorexia and cachexia.

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GLP-1 sensitivity despite insulin resistance in obese humansThe data of Heni and colleagues support a model in which GLP-1 is secreted after food intake, and subsequently reaches the brain where it regulates food-related activity of the orbitofrontal cortex, independently of insulin. While obese persons seem to be insulin-resistant in this brain area, they might remain sensitive to GLP-1. The orbitofrontal GLP-1 response might regulate reward and reduce hunger, which could help individuals to stop eating and prevent further food intake.

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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.



Randy J. Seeley, Henriette Frikke-Schmidt
University of Michigan Health System, Ann Arbor, USA
Referring article

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