Featured Articles

Volume 17 | November 2018

Sex dependent impact of gestational stress on predisposition to eating disorders and metabolic diseaseEating disorders (EDs) are damaging mental and metabolic illnesses. Recent evidence suggests that epigenetic mechanisms may be involved in initiating and maintaining EDs. Schroeder et al. explored the effects of chronic variable stress during the whole period of gestation, response to food restriction, and susceptibility to develop activity based-anorexia, binge eating, and metabolic syndrome in male and female offspring. They report that chronic prenatal stress induces sexually dimorphic effects on placental function, affecting fetal hypothalamic programming and subsequent basal metabolism and the response to a variety of metabolic challenges.

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Reductions in glucokinase activity increase responses to hypoglycemiaMaintaining blood glucose within an appropriate range is crucial for survival. To defend against falling blood glucose, a series of robust counter-regulatory responses normally prevent hypoglycemia from occurring. The glucose-sensing apparatus in pancreatic β-cells includes the low affinity hexokinase glucokinase (GCK), which controls glycolytic flux into downstream metabolic sensing. Chakera, Hurst, Spyer, Ogunnowo-Bada, et al. examined the role of GCK in the hormonal protection against hypoglycemia. Their data identify a GCK-dependent glucose-sensing mechanism that boosts responses to falling glucose, augmenting reduction in insulin secretion and the release of glucagon and epinephrine.

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Deletion of the glucagon receptor gene before and after experimental diabetes reveals differential protection from hyperglycemiaGlucagon receptor (GCGR) signaling helps maintain glucose homeostasis by stimulating hepatic glucose production. Interestingly, in rodent models of type-1 diabetes, hyperglycemia is almost completely mitigated by deletion of Gcgr. Rivero-Gutierrez et al. created an inducible Gcgr knockout mouse model to compare acute and chronic loss of the GCGR during insulinopenic diabetes. Their results demonstrate that engagement of compensatory signals, specifically GLP-1 receptor signaling, rather than loss of GCGR activation per se, attenuates the development of hyperglycemia during insulinopenic conditions.

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A PDX1-ATF transcriptional complex governs β cell survivalDiabetes results from the failure of insulin producing β cells to compensate for increased metabolic demand and stress. The homeodomain protein PDX1 is important for the function and survival of β cells. Juliana et al. identify previously undiscovered stress responsive transcriptional complexes containing PDX1, activating transcription factor 4 (ATF4), and ATF5 that regulate expression of stress and apoptosis genes to influence β cell fate decisions during stress.

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microRNA-205-5p is a modulator of insulin sensitivity that inhibits FOXO functionmiRNAs regulate gene expression in physiologic and disease conditions, including type 2 diabetes (T2D). Genome-wide association studies for T2D susceptibility loci indicate that most of the diabetes-associated variants localize to noncoding regions, raising the possibility that miRNAs transcribed from these regions contribute to disease development. Given the role of the transcription factor Forkhead Box Protein O (FOXO) in insulin action, Langlet et al. undertook a systematic search for FOXO-regulated hepatic miRNAs and identified miR-205-5p as an endogenous regulator of insulin sensitivity that coordinately targets components of the insulin signaling cascade, including FOXO itself.

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l-Alanine activates hepatic AMPK and modulates systemic glucose metabolismPlasma amino acids are dysregulated in obesity. While increased branched chain amino acids may reflect inadequate insulin action, it has also been suggested that amino acids can directly modulate insulin action and may contribute to the pathophysiology of insulin resistance. However, the molecular mechanisms responsible for these effects remain uncertain. Adachi and colleagues report that l-alanine uniquely increases phosphorylation of the nutrient sensor AMP kinase (AMPK) and, in parallel, improves glucose tolerance in vivo in mice.

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Lipid droplet characteristics and distribution unmask the athlete’s paradoxIndividuals with type 2 diabetes present with increased storage of intramyocellular lipid (IMCL). Paradoxically, IMCL levels are also elevated in endurance trained athletes, who are very insulin sensitive. This phenomenon is known as the athlete’s paradox. Daemen, Gemmink, et al. examined the athlete’s paradox in individuals with similar levels of IMCL but over a wide range of insulin sensitivity. They found that insulin sensitive, trained individuals possess high levels of muscle fat that is dispersed in small lipid droplets in oxidative type I muscle fibers. On the other hand, in the insulin resistant type 2 diabetic state, most of the muscle fat is found in large lipid droplets in the subsarcolemmal space of type II muscle fibers. Therefore, the athlete’s paradox can be explained from a physiological perspective

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Quantitative mass spectrometry suggests prominent roles for β-MSH and desacetyl-α-MSH in energy homeostasisThe pro-opiomelanocortin (POMC) protein undergoes extensive proteolytic cleavage to produce neuropeptides that regulate food intake and energy expenditure. Since mice are unable to produce β-melanocyte stimulating hormone (β-MSH) from the POMC precursor, their utility as a model system for studying human-specific aspects of POMC processing is limited. Kirwan and colleagues analyzed POMC processing from hypothalamic neuron cell cultures as well as primary human brain samples via liquid chromatography tandem mass spectrometry (LC-MS/MS). They found that β-MSH and desacetyl-α-MSH were present at high concentrations, suggesting important roles for these peptides.

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Glucose sensing in the upper intestine potentiates glucose absorptionOur understanding of how gastrointestinal tract tissues and pathways coordinate the regulation of glucose metabolism after consumption of glucose is still limited. Using a knockout model of the sweet taste receptor (STR) compound Taste receptor type 1 member 2 (T1R2), Smith, Azari, et al. demonstrate that STR-mediated glucose sensing in the upper intestine is required for the potentiation of glucose absorption. Their findings reveal a mechanism where regulation of STR signaling in L-cells controls glucose absorption in enterocytes to limit postprandial hyperglycemia in response to high consumption of dietary sugars.

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Periodized low protein-high carbohydrate diet confers potent, but transient, metabolic improvementsChronic caloric restriction (CR) extends health and lifespan in experimental models and likely also in humans. However, long-term adherence to this ascetic regimen is difficult, and chronic CR is not feasible to implement broadly as a lifestyle intervention in humans. Since recent studies suggest that protein restriction rather than calorie restriction per se might underlie the anti-aging effects of CR diets, Li and colleagues tested a periodized low protein high carbohydrate diet regimen. They found some potent metabolic improvements, but these reversed within 14 days of returning to the control diet.

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Hepatic leptin receptors can compensate for IL-6Rα deficiency in hepatocellular carcinomaHepatocellular carcinoma (HCC) is a type of cancer that is inflammation-driven. Deficiency of interleukin 6 (IL-6) ameliorates HCC in mice. However, deficiency of the IL-6 receptor α (IL-6Rα) reduces tumor burden only in lean mice and not in obese mice. Mittenbühler et al. show that in obese mice, leptin receptor signaling compensates for the IL-6Rα deficiency and promotes HCC progression.

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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.



Florian Merkle
University of Cambridge, UK
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