Featured Articles

Volume 6 | No. 7 | July 2017

Transgenerational dietary reprogramming of the unfolded protein response Grandpaternal exposure to altered food availability is associated with a greater risk for obesity and cardiovascular disease in grandchildren. While adipose tissue is one of the major sites of paternal high caloric intake-induced transgenerational reprogramming, less is known about the impact on skeletal muscle physiology and metabolism. Alm, de Castro Barbosa, et al. determined the transgenerational response of paternal diet-induced obesity on the skeletal muscle transcriptome and lipidome. Transcriptomic analysis revealed that grand-offspring of diet-induced obese founders present altered unfolded protein response in skeletal muscle. These findings advance the notion that paternal exposure to environmental factors program whole-body and tissue-specific features, affecting the development and health of successive generations.

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Parental Obesity Leads to Metabolic Changes in the F2 Generation in Drosophila The known genetic risk factors for diabetes account for only about 10% of its heritability. Over the last decade, however, it has become clear that at least some of this risk can be attributed to the epigenetic inheritance of the parental and even grandparental metabolic state. Palu et al. employ a genetic approach to examine the effects of obesity in the parental generation of Drosophila using Adipokinetic Hormone Receptor (AKHR) loss-of-function mutations. AKH functions analogously to the fasting hormone glucagon in mammals. They show that grandpaternal obesity resulting from a loss of AKHR is associated with low triglyceride levels in wild-type F2 offspring of heterozygous F1 mothers.

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Novel inducers of definitive endoderm It is desirable to establish cheap and efficient embryonic stem cell (ESC) differentiation protocols using small molecule compounds with stable and reproducible activity. Korostylev, Mahaddalk, et al. set-up a high-content screen in mouse ESCs and tested 23,406 small molecules. They identified the Rho associated coiled like protein kinase (ROCK) inhibitor Fasudil as a small molecule that efficiently induces definitive endoderm (DE). Based on this finding, they introduce a family of small molecule ROCK inhibitors and a novel mechanism that can robustly induce DE/anterior DE differentiation of pluripotent stem cells in culture, thereby replacing biologics in the differentiation medium.

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Mitochondrial transcription factor B2 is essential in pancreatic β-cells Mitochondrial transcription factor B2 (TFB2M) is required for the transcription of mitochondrial genes. Knowledge about the role of TFB2M in pancreatic β-cells and whether loss of TFB2M leads to mitochondrial dysfunction is lacking. Nicholas, Valtat, et al. examined the functional consequences of Tfb2m-deficiciency in mice with a β-cell specific homozygous and heterozygous knockout of Tfb2m and in rat clonal insulin-producing cells. They found that Tfb2m-deficiency rapidly leads to widespread mitochondrial dysfunction, which gradually overrides cell protective systems. This results in β-cell dysfunction, as well as increased activation of apoptosis via the mitochondrial-dependent pathway and loss of β-cell mass.

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Overexpression of Igf1 counteracts progression to autoimmune diabetes Type 1 diabetes (T1D) results from the progressive autoimmune destruction of β-cells. Insulin-like growth factor 1 (IGF1) is a β-cell mitogen and pro-survival factor that has also been reported to play important roles in β-cell maturation and function. Additionally, IGF1 regulates immune functions. Mallol and colleagues tested the effects of local expression of IGF1 in non-obese diabetic (NOD) mice that spontaneously develop the disease, sharing many genetic and immunopathogenic features with human T1D. Their results show that pancreatic IGF1 expression in adult mice is sufficient to protect against diabetes onset in non-transgenic NOD mice through blockage of the β-cell-directed autoimmune attack.

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The preproglucagon system is not essential for gut growth homeostasis Today, the most effective obesity treatments are glucagon-like peptide 1 (GLP-1) analogs and bariatric surgery. Interestingly, both intervention paradigms have been associated with adaptive growth responses in the gut. Wismann et al. used in situ hybridization to provide a detailed and comparative anatomical map of the local distribution of GLP-1 receptor (Glp1r), GLP-2 receptor (Glp2r), and preproglucagon (Gcg) mRNA expression throughout the mouse gastrointestinal tract. Also, they compared gut development in GLP-1R-, GLP-2R-, or GCG-deficient mice. While mice null for Glp1r or Gcg showed normal intestinal morphology, Glp2r null mice exhibited a slight reduction in small intestinal mucosa volume.

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The human digestive tract has proteases capable of gluten hydrolysisCeliac disease (CD) is a chronic, small intestinal, immune-mediated enteropathy triggered by the exposure to gluten proteins in genetically predisposed individuals. Although 30% of the general population carries a genetic predisposition for CD, only approximately 3% will develop this disease. Gutiérrez et al. identified and characterized the proteins responsible for glutenase activity in human feces and compared the proteolytic profiles involved in degrading gluten peptides between healthy individuals and those with CD. Their results suggest that gluten degradation in feces from patients with CD is caused by the same proteases that are found in non-CD individuals, namely human elastase 3B, elastase 2A, and carboxypeptidase A1.

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Rev-Erb co-regulates muscle regeneration via tethered interaction with the NF-Y cistrome Skeletal muscle’s high capacity for regeneration is typically sufficient for dynamically maintaining skeletal muscle mass and functions in response to minor injuries and normal wear and tear. Rev-Erbs are nuclear receptors that act as transcriptional repressors and seem to be both inhibitors of muscle differentiation and promoters of mitochondrial function. This apparent paradox suggests that there is a need to explore the regulatory mechanisms underlying Rev-Erb’s activity in skeletal muscle in more detail. Welch and colleagues observed that silencing and pharmacologically disrupting Rev-Erb activity significantly increased the rate of cultured myoblast differentiation. This suggests that Rev-Erb may be an interesting therapeutic target for the treatment of diverse muscular diseases.

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Loss of ADAMTS5 enhances brown adipose tissue massThe metzincin superfamily of zinc-dependent metalloproteinases is involved in remodeling the extracellular matrix and comprises the MMP (matrix metalloproteinases), ADAM (A Disintesgrin and Metalloproteinase), and ADAMTS (ADAM with a Thrombospondin type-1 motif) subfamilies. For several of these proteinases, a role in development of adipose tissue has been documented, but little information is available on the ADAMTS group. Using a diet-induced obesity model in mice, Bauters and colleagues show that ADAMTS5 deficiency promotes brown adipose tissue development as well as browning of white adipose tissue.

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ASK1 is transcriptionally upregulated in obesity, defining a dys-metabolic obese phenotype Obese sub-phenotypes associated with increased cardio-metabolic risk are characterized by metabolically and endocrinologically dysfunctional adipose tissue (AT). In human-AT in obesity, one stress-responsive pathway activated particularly in the intraabdominal visceral fat is a mitogen-activated protein kinase (MAP kinase) signaling cascade involving ASK1. Haim and colleagues test the hypothesis that ASK1 expression and its downstream signals are regulated by the transcription factor E2F1 in human-AT in obesity. They found that both clinically and mechanistically, the E2F1-ASK1 network molecularly defines an obese sub-phenotype characterized by AT stress and metabolic dysfunction.

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Metformin causes a futile intestinal-hepatic cycle which increases energy expenditure Metformin-treatment of Type 2 diabetes mellitus (T2DM) results in lowering of elevated blood glucose levels and significant weight loss. Surprisingly, the mechanisms responsible for lowering body weight are unknown. Schommers, Thurau, Bultmann-Mellin, et al. continuously fed metformin in a therapeutically relevant dose to mice on a high fat diet in order to investigate how the drug slows down the development of T2DM and weight gain, the other well described mode of action in patients. They found that metformin causes a futile intestinal-hepatic cycle which increases energy expenditure.

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Neonatal GLP1R activation limits adult adiposityMany of the central circuits that regulate energy balance, specifically those of hypothalamic origin, originate during the first few weeks of life in rodents. Administration of the Glucagon-like peptide 1 receptor (GLP1R) agonist Exendin-4 (Ex-4) during the neonatal period prevents the development of adult-onset diabetes in IUGR rats and attenuates age related weight gain in both IUGR and sham controls. Rozo, Babu, and colleagues show that many of these effects are abrogated by the deletion of GLP1R in the Sim1 expression domain that includes the paraventricular hypothalamic nucleus (PVH), suggesting that this novel role of neonatal GLP1R activation is mediated, in part, through a central mechanism involving the PVH.

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Uncoupling protein 2 regulates daily rhythms of insulin secretion capacity Uncoupling protein 2 (UCP2) is a member of the mitochondrial anion carrier superfamily that, when activated, can partially uncouple aerobic respiration from ATP synthesis. In pancreatic β-cells, there is a negative relationship between UCP2 and glucose-stimulated insulin secretion (GSIS). Seshadri et al. asked why β-cells express Ucp2 if its activity is detrimental to insulin secretion and metabolic health. They found that that Ucp2 mRNA is dynamically expressed in healthy β-cells over the course of a 24 h daily cycle such that Ucp2 expression is low in the fed/active phase to promote maximal GSIS capacity and upregulation of Ucp2 in the fasted/inactive phase suppresses GSIS capacity.

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Dysregulation of a novel miR-23b/27b-p53 axis impairs muscle stem cell differentiation of humans with type 2 diabetes MicroRNAs (miRNAs) are increasingly recognized as fine-tuning regulators of metabolism, and are dysregulated in several disease conditions. There is a decline in muscle mass and function in Type 2 diabetes mellitus (T2DM) patients compared with healthy control subjects. Henriksen and colleagues studied miRNA regulation and differentiation of muscle stem cells derived from humans with T2DM or from healthy controls. They present a novel miR-23b/27b-p53/Rb pathway that is dysregulated in muscle stem cells of non-obese humans with T2DM, resulting in compromised muscle cell differentiation in vitro and possibly contributing to the impaired muscular phenotype of T2DM in humans.

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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.



Andrea Rozo, Doris Stoffers
Perelman School of Medicine at the University of Pennsylvania, Philadelphia, USA
Referring article

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Conferences & Events
September
17 − 19
2017
5th Helmholtz-Nature Medicine Diabetes Conference
Munich, Germany
October
1 − 5
2017
Lifetime Influence of Genes and Environment
Copenhagen, Denmark
October
15 − 17
2017
Cell Symposia: Metabolic Disease Therapies
San Diego, USA
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