Featured Articles

Volume 6 | No. 12 | December 2017

Cranberry extract reverses insulin resistance and hepatic steatosis The use of polyphenol-rich fruit extracts or isolated polyphenols to alleviate obesity-linked diseases has been demonstrated in humans and in animal models, but the mechanisms of action are not yet fully elucidated. Anhê and colleagues investigated the potential of a polyphenol-rich cranberry extract (CE) to reverse an already established obesity, insulin resistance, and non-alcoholic fatty liver disease (NAFLD) in mice. They demonstrate that CE polyphenols strongly improve liver homeostasis. This was associated with improvements in glucose tolerance and full restoration of insulin sensitivity despite the maintenance of obesity. Their data also put forward potential microbial contributors to the effect of CE.

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Knockout of GCN5 does not enhance mitochondrial adaptationPeroxisome proliferator activated receptor-γ coactivator-1α (PGC-1α) is an important contributor to mitochondrial biogenesis and function in skeletal muscle. Combined data from several studies implicate general control of amino acid synthesis 5 (GCN5) as an important negative regulator of PGC-1α transcriptional activity in skeletal muscle and, by extension, mitochondrial biogenesis. Dent and colleagues have now directly investigated the contribution of GCN5 to skeletal muscle metabolism and mitochondrial function in vivo. Their results suggest that loss of GCN5 in muscle does not enhance in vivo basal or endurance exercise-induced metabolic adaptation.

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Discovery of agonists for the succinate receptor GPR91 Succinate functions not only as an energy source and building block but also as an extracellular messenger, signaling via the G-protein coupled receptor (GPCR) GPR91. Metabolic stress conditions cause the levels of succinate to rise, enabling activation of GPR91. The physiological role of GPR91 on whole body metabolism, however, is still unclear. Trauelsen and colleagues developed drug-like non-metabolite GPR91 agonists as potential pharmacological tools by using a receptor structure-based approach. The compounds they identified should make it possible to study effects of selective GPR91 activation in an in vivo setting after oral administration.

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Muscle autophagy in endurance-trained runners before and after a high-fat meal Metabolic inflexibility has been implicated in the pathogenesis of obesity and the development of insulin resistance. Tarpey et al. observed elevated markers of mitophagy activity in skeletal muscle of endurance-trained runners (ET) compared with sedentary (SED) males, without a discernible difference in markers of autophagy. However, the greater content of mitophagy markers in skeletal muscle of ET individuals was not associated with a corresponding higher level of metabolic flexibility. Still, skeletal muscle metabolic flexibility increased following a high-fat meal in the ET but not SED individuals.

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Modulation of cognition and anxiety-like behavior by bone remodelingOsteocalcin is a bone-derived hormone that regulates a growing number of physiological functions. Osteocalcin-/- mice have increased anxiety-like behavior and depression, decreased exploratory behavior, and impaired learning and memory. Given that osteocalcin is produced only by osteoblasts, Khrimian et al. asked whether an impairment in osteoblast differentiation and function, as may occur in various skeletal dysplasias or with aging, could affect cognition or anxiety. Their results suggest that a decrease in osteocalcin is indeed the cause for these cognitive impairments.

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Induction of FGF21 does not require activation of the hepatic XBP1Fibroblast growth factor 21 (FGF21) has emerged as a key regulator of the metabolic response to fasting. Endoplasmic reticulum (ER) stress is a well-established inducer of hepatic FGF21 expression. X-box binding protein 1 (XBP1) has been strongly implicated in regulating hepatic lipid and glucose metabolism, making it an intriguing candidate for mediating the effect of ER stress on FGF21 expression. To directly determine whether hepatic Xbp1 is required for induction of hepatic Fgf21 in vivo, Olivares and Henkel subjected mice bearing a hepatocyte-specific deletion of Xbp1 to fasting, a ketogenic diet, or pharmacologic ER stress, all potent stimuli of Fgf21 expression. By this, they provide definitive evidence that hepatic Xbp1 is not required for induction of hepatic Fgf21.

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AMPK activation protects against hepatic steatosis in MCT1 haploinsufficient mice Hepatic steatosis can evolve into non-alcoholic fatty liver disease (NAFLD). Monocarboxylate transporter isoform 1 (MCT1) haploinsufficient mice (MCT1+/-) exhibit resistance to high-fat diet-induced obesity and associated NAFLD. Carneiro et al. reinforce the concept that AMP-activated protein kinase (AMPK) activation mediates this effect and promotes a protection against hepatic steatosis by inhibiting Sterol Regulatory Element Binding Protein 1 (SREBP1). They also reveal an unexpected regulatory role of circulating lactate in the regulation of hepatic lipid metabolism.

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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.



Luc Pellerin
Université de Lausanne, Switzerland
Referring article

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