Featured Articles

Volume 4 | No. 11 | November 2015

Adiporedoxin, an upstream regulator of ER oxidative folding and protein secretion in adipocytesMany proteins are produced and secreted in adipose tissue, most notably adipokines- hormone-like polypeptides that affect energy balance and insulin sensitivity. To understand how such proteins are assembled for secretion, Jedrychowski and colleagues describe the function of a novel endoplasmic reticulum oxidoreductase called adiporedoxin (Adrx).This molecule functions upstream of protein disulfide isomerase and plays an important role in the assembly and secretion of disulfide-bond containing proteins. Proteomic analysis reveals that Adrx over and under expression in vitro enhances and attenuates, repectively, the secretion of several disulfide-bonded proteins including adiponectin and collagen isoforms. Mice lacking Adrx show a complex and mixed phenoptype of lower adipokine secretion and lower adipocyte collagen deposition along with ER stress and hyperinsulinemia.

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Impact of tamoxifen on adipocyte lineage tracingYe and colleagues express concern for tamoxifen usage in adipose studies, especially lineage tracing. Tamoxifen is used for temporal control of genetic manipulations by inducing nuclear translocation of Cre recombinase. The authors demonstrate that in adipose tissue, tamoxifen remains detectable after a washout period of 10 days and its nuclear translocation activity for Cre lasts beyond 2 months. This indicates that an extended period is necessary to completely wash out tamoxifen activity. The authors also identify that tamoxifen has profound effects on adipose physiology, like acute fat loss and de novo adipogenesis in mice.

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Adipocyte Progenitor Cells Initiate MCP-1-Mediated Macrophage Accumulation in Visceral Adipose TissueIn adipose tissue, the chemokine MCP-1 recruits inflammatory macrophages and promotes metabolic dysregulation during obesity. Kaplan and colleagues provide the first in vivo evidence that Adipocyte Progenitor Cells (AdPCs) are the initial source of MCP-1. Their studies on HFD-mice suggest that during disease, the level of the transcription regulator Id3 increases and induces AdPC proliferation, leading to MCP-1 production, macrophage accumulation and metabolic dysfunction.

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TUSC5 regulates insulin-mediated adipose tissue glucose uptake by modulation of GLUT4 recyclingBeaton and colleagues uncover the tumor suppressor candidate 5 (TUSC5) as a novel regulator of prolonged insulin-stimulated GLUT4 trafficking, thereby regulating glucose uptake in adipocytes. With in vitro and in vivo studies, they conclude that TUSC5 facilitates proper protein recycling, linking GLUT4 trafficking to the ubiquitous machinery. This work reveals a tissue-specific key role for TUSC5 to maintain a healthy metabolic phenotype in mice and humans.

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PGC-1 coactivators in β-cells regulate lipid metabolism and are essential for insulin secretionThe PGC-1 coactivators α and β regulate the activity of multiple transcription factors important for nutrient metabolism. Oropeza and colleagues investigate the role between PGC-1 proteins, β-cell function, and energy homeostasis. With in vitro cell models and specific β-cell knockout mice, they demonstrate that β-cell lipid metabolism is disrupted by loss of PGC1s, and they identify a novel role for the coactivators in the potentiation of insulin secretion by fatty acids.

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The calcineurin-NFAT pathway controls activity-dependent circadian gene expressionDyar and colleagues examine the relationship between muscle activity, the circadian regulation of muscle genes, and whether changes in activity can directly affect the muscle clock. They compare the circadian transcriptomes of two mouse hindlimb muscles with vastly different activity patterns and find major differences in gene expression. Denervation changed the expression of muscle circadian genes but did not affect the core clock genes. Around 15% of the skeletal muscle circadian genes are controlled by nerve activity. They identify the Ca2+ - dependent calcineurin-NFAT pathway as an important mediator for the activity-dependent circadian gene expression, showing that circadian locomotor activity rhythms of NFAT nuclear translocation and target gene expression.

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Human skeletal myotubes display a cell-autonomous circadian clock implicated in basal myokine secretionIn addition to its well-described function in mechanical activity, skeletal muscle has also been characterized as a secretory organ, producing and releasing myokines. Perrin and colleagues demonstrate that primary human skeletal myotubes possess circadian rhythms and reveal their critical impact on myokine secretion. They record the basal circadian profile of different myokines and show that the secretion can be downregulated by siClock-mediated clock disruption.

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Enhanced insulin sensitivity in skeletal muscle and liver by physiological overexpression of SIRT6Recent studies have identified sirtuins, enzymes exerting post-translational modifications, as potential therapeutic targets for improving hyper-caloric feeding induced metabolic imbalances. The role of SIRT6, one of the seven mammalian sirtuins, in metabolism is controversial. Anderson and colleagues developed and studied a mouse that overexpresses SIRT6 (Sirt6BAC mice). Compared to control mice, SIRT6 overexpressing mice have enhanced insulin sensitivity in skeletal muscle and liver, what suggests protective actions against diet-induced type 2 diabetes mellitus.

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Sex-dependent changes in metabolism, behavior and anxiety after eliminating ventromedial hypothalamus excitatory output The ventromedial nucleus of the hypothalamus (VMH) regulates energy homeostasis as well as social and emotional behaviors. Cheung and colleagues assess the role of glutamatergic signaling in the VMH responses by knocking out the vesicular glutamate transporter 2 (Vglut2) in SF-1 VMH neurons in mice and carrying out metabolic and neurobehavioral assays. The loss of VMH glutamatergic signaling drives sex-dependent differences: it decreases diet-induced obesity in females, attenuates aggression and learned fear in males, and is anxiolytic in both sexes.

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Ablation of intact hypothalamic and/or hindbrain TrkB signaling leads to perturbations in energy balanceThe brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin receptor kinase B (TrkB) play a paramount role in the central regulation of energy balance. Although they are both distributed broadly throughout the CNS, Ozec and colleagues show that hypothalamic deletion of TrkB is sufficient to cause increased body weight, adiposity and impaired glucose homeostasis. Complete hindbrain deletion of TrkB is lethal, but a reduction in TrkB (in heterozygous mice) results in pronounced hyperphagia without affecting the body weight.

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Leptin potentiates astrogenesis in the developing hypothalamusLeptin is an essential regulator of diverse metabolic processes in adult mammals and plays a key role in hypothalamic neurons and astrocytes. Rottkamp and colleagues examined the effects of leptin on the proliferative capacity of astrocytes in the developing hypothalamus by treating postnatal mice with leptin. Leptin treatment enhanced the proliferation of astrocytes while conditional removal of leptin receptors reduced it. The assumption is that the metabolic effects of leptin on hypothalamic feeding circuits occur in part in the early postnatal period.

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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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