Featured Articles

Volume 28 | October 2019

Skeletal muscle Akt in the regulation of muscle mass and glucose homeostasisThe serine/threonine kinase Akt (protein kinase B) has been implicated as a central regulator of insulin action in skeletal muscle. A prevailing hypothesis is that a reduction in insulin-stimulated Akt activation decreases glucose uptake leading to hyperglycemia and systemic insulin resistance. To directly assess the role of skeletal muscle Akt on muscle growth and glucose homeostasis, Jaiswal et al. deleted Akt2 or both Akt1 and Akt2 specifically in the skeletal muscles of mice. While mice bearing an Akt2 deletion alone showed no effect on muscle growth and glucose metabolism, congenital deletion of both the Akt isoforms resulted in a drastic reduction in muscle mass and a mild defect in glucose tolerance.

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The GIP receptor in brown adipose tissueInsulinotropic polypeptide (GIP) is a gut-derived hormone that potentiates glucose-dependent insulin secretion via cognate receptors on islet β-cells. It also exerts a wide range of extra-pancreatic actions. Beaudry et al. studied the physiological roles of GIP in brown adipose tissue (BAT) using tissue-specific deletions of the GIP receptor. They found the BAT GIP receptor associated with changes in gene expression, IL-6 expression and secretion, oxygen consumption ex vivo, lipid utilization, the defence of body temperature, and metabolism.

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Dysregulation of PP2A-Akt interaction contributes to SNRK deficiency induced insulin resistance Sucrose non-fermenting related kinase (SNRK) is expressed abundantly in adipose tissues. It is a regulator of adipose inflammation and energy homeostasis in both mice and humans. Li and colleagues hypothesized that SNRK play important roles in adipose glucose metabolism in mice. They show that SNRK ablation is sufficient to inhibit insulin-regulated AKT phosphorylation and glucose uptake in adipose tissues and identify a novel SNRK pathway regulating insulin signaling in adipose tissue.

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cAMP-miR-203-IFN-γ network regulates fat browning and glucose toleranceSeveral miRNAs have recently emerged as important regulators of brown and beige adipocyte differentiation and function. The microRNA miR-203 is enriched in brown fat. Guo et al. studied the role of miR-203 in vivo and found that upregulation of miR-203 could be used for the suppression of the interferon-γ (IFN-γ) signaling pathway. They also provide mechanistic insights that the cAMP-miR-203-IFN-γ network regulates inflammation response and white adipose tissue browning.

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Tbx15 is required for adipocyte browning induced by adrenergic signalingTBX15 (T-box 15) is a transcription factor that plays an important role in the adipogenesis of primary brown and beige adipocyte precursors. To further elucidate its role in adipose tissues, Sun, Zhao, and colleagues generated adipose-specific Tbx15 knockout mice. They demonstrate that Tbx15 is important for adipocyte thermogenesis and browning in adipose tissue in vivo. Interventions that increase TBX15 expression may provide new therapeutic strategies to promote thermogenesis and combat obesity and related metabolic disorders.

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Double bond configuration of palmitoleate is critical for atheroprotectionA significant reduction in cardiovascular disease risk can be achieved by replacing saturated fatty acids with mono- or poly-unsaturated fatty acids. Palmitoleate is a mono-unsaturated fatty acid that has beneficial effects on metabolism and atherosclerosis. However, it is unknown whether the cis and trans isoforms of palmitoleate have the same effect. Cimen and colleagues directly compared the effects of cis- and trans-palmitoleate on inflammation and atherosclerosis in a hypercholesterolemic mouse model and found that positive effects were restricted to the cis form only.

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Short-term cold exposure supports human Treg inductionRegulatory T cells (Tregs) are key in controlling tissue homeostasis and function including local fat depots, where they can suppress inflammatory processes. It has been previously shown that short-term cold exposure can induce Tregs in mice. Becker et al. studied the effect of short-term cold exposure on Tregs in humans and show that cold stimulation supports Treg induction also in humans.

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Temporal expression patterns of the melatoninergic system in the thymus of childrenMelatonin from the pineal gland is best known for its regulation of the circadian rhythm. However, melatonin synthesis also occurs in other organs, one of which is the thymus. Melatonin synthesis changes with age. To assess whether the thymic melatoninergic system shows changes related to development, Cruz-Chamorro et al. studied the enzyme expression required for melatonin synthesis as well as the nuclear and membrane melatonin receptors in normal human thymuses from children of different ages. They found that the thymic melatoninergic system is present and especially active from the first days of human life and its expression is inversely correlated with the age of the human thymus.

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How CGRP maintains the stability of neuromuscular junctionα-Calcitonin gene-related peptide (CGRP) is a 37-amino-acid neuropeptide that is released at neuro-muscular junctions (NMJ) and stabilizes nicotinic acetylcholine receptors as well as muscle structure. However, the mechanism of this action has remained unclear. Machado and colleagues found that the increased NMJ stability is mediated by mechanistic target of rapamycin complex 1 and the suppression of autophagy. In addition, the present data show that the calcium-dependent proteolytic system is also inhibited by CGRP, a mechanism that could also be important for the maintenance of the synapse.

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Cognitive dysfunction in diabetic rats is prevented by pyridoxamineIt is increasingly evident that people with diabetes have a higher risk of developing Alzheimer’s disease or other central nervous system disorders related to cognitive decline. Pyridoxamine is one of the three interconvertible members of vitamin B6, an essential cofactor in several processes including synthesis of neurotransmitters. Protective effects of pyridoxamine from several secondary complications of diabetes have previously been described. Kassab et al. demonstrate that robust recognition memory deficits in diabetic rats are correlated with dysfunction in brain metabolism. Pyridoxamine treatment prevented these recognition memory deficits.

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Direct and indirect effects of liraglutide on hypothalamic neurons Glucagon-like peptide 1 (GLP-1) is a gut derived hormone that plays a key role in regulation of glucose metabolism. In addition, GLP-1 suppresses feeding. The acute effects of GLP-1 receptor activation in melanocortin neurons mirrors that of the description of leptin. Liraglutide is a GLP-1 receptor agonist. He et al. find that leptin and GLP-1 directly modulate neuronal excitability of melanocortin neurons in an additive manner. They also describe a melanocortin pre-synaptic network altered in response to GLP-1.

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HSP70 induces liver X receptor pathway and cholesterol reduction Heat shock protein 70 (HSP70) is a chaperone that facilitates protein folding and transport, with essential roles in maintaining cell homeostasis and survival. In addition to its chaperone function in proteostasis, HSP70 can act as a signaling molecule. Gungor, Vanharanta, et al. studied the effects of rHSP70 on human primary monocyte-derived macrophage foam cells that accumulate cholesterol, which leads to artherosclerosis. They found that HSP70 exerts atheroprotective effects and that this can be mechanistically explained by HSP70 mediated stimulation of the liver X receptor, the master regulator of cholesterol removal.

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Temporal plasticity of insulin and incretin secretion and insulin sensitivity following sleeve gastrectomy Bariatric procedures like vertical sleeve gastrectomy (VSG) alleviate diabetic hyperglycemia in 40-50% of patients. To further study the changes of key glucoregulatory factors after VSG over time, Douros et al. assessed glycemic regulation, incretin secretion, insulin sensitivity, and islet function over 90 days in mice with VSG and sham-operated controls pair-fed to match caloric intake. They found that an acute postoperative enhancement of intrinsic islet function persists over time. This surgical effect is superior to that seen with caloric restriction or weight loss alone. Critically, the early enhancements to incretin secretion and islet function diminish over time as insulin sensitivity increases, indicating modulation of these factors after surgery.

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mTORC1 and CB1 signaling regulate inputs onto the hypothalamic PVN in response to energy availabilityThe paraventricular nucleus (PVN) of the hypothalamus plays key roles in the regulation of energy balance. However, whether excitatory glutamatergic transmission from pro-opiomelanocortin (POMC) neurons affects the activity of PVN parvocellular neurons is not known. Mechanistic target of rapamycin complex 1 (mTORC1) controls intracellular energy availability. Cannabinoid receptor type 1 (CB1R) can affect the mTOR pathway. Mazier et al. show that mTORC1 activity in POMC neurons regulates glutamatergic inputs to PVN parvocellular neurons and that this function is exerted via control of pre-synaptic CB1R.

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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.



Daniela Cota
INSERM, Bordeaux, France
Referring article

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October
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2019
Nature Conference: Advances in Metabolic Communication
Rio de Janeiro, Brasil
October
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2019
13th European Nutrition Conference
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27 − 31
2019
Metabolism in Action
Hillerod, Denmark
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6 − 8
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Cachexia, Sarcopenia and Muscle Wasting
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