Featured Articles

Volume 30 | December 2019

LDL receptor and cholesterol metabolism play a role in impaired adult hippocampal neurogenesisHypercholesterolemia, especially in its inherited form, is an important risk factor for the development of neurodegenerative diseases. Familial hypercholesterolemia (FH) is caused by genetic abnormalities predominantly in the low-density lipoprotein (LDL) receptor (LDLr) gene, resulting in an ineffective metabolism of LDL particles. However, it remains unclear whether the chronic exposure to high circulating cholesterol levels or the dysfunction of the LDLr as such contributes to the altered central nervous system function. Engel and colleagues explored if adult hippocampal neurogenesis might be involved in cognitive dysfunction associated with FH and found that that impairment in hippocampal neurogenesis might contribute to the behavioral phenotype in LDLr-/- mice.

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A high-resolution 3D modeling system for pancreatic epithelial cell biology Over the past decade, our understanding of human pancreas development has steadily increased. This is partially due to the recent advancements in differentiation of human pluripotent stem cells into pancreatic islet-like clusters. Although this in vitro differentiation system has provided lots of information, it cannot address the impact of tissue morphogenesis on endocrine cell differentiation. Therefore, Bakhti, Scheibner, et al. developed a simple ex vivo 3D cyst culture from pancreatic progenitors, providing a high-resolution modeling system that not only allows for studying pancreas development in a temporal fashion but also enables comparing pancreatic epithelial biology across species and genotypes.

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Sex-specific metabolic functions of adipose Lipocalin-2Lipocalin-2 (LCN2) is a secreted glycoprotein that has been implicated in several cardio-metabolic disease states including obesity, inflammation and insulin resistance, alcoholic and non-alcoholic fatty liver disease, cardiac hypertrophy, heart failure, and atherosclerosis. However, most studies of LCN2 were only conducted in male mice. Krishnan and colleagues examined gene-by-sex interactions and demonstrate that adipose-secreted, and not liver-secreted, LCN2 is causal in developing diet-induced metabolic complications, but only in females.

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PTEN regulates adult adipose tissue homeostasis and redistribution Phosphatase and tensin homologue deleted on chromosome ten (PTEN) is a dual protein and lipid phosphatase that is a a potent regulator of cellular growth, survival, and insulin mediated glucose uptake. Although depleting or overexpressing PTEN demonstrates its influence on adipocyte differentiation, these studies provide few insights into the role of PTEN in the mature adipose remodeling process. Huang, Queen, McMurphy, et al. manipulated PTEN expression in an individual fat depot to investigate how PTEN modulates fat depot distribution in adult mouse and discovered a PTEN-leptin-sympathetic signaling loop that regulates adipose redistribution.

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Circadian clock network desynchrony promotes weight gain and alters glucose homeostasisIn complex organisms such as mammals, circadian energy metabolism is orchestrated by an interplay of central and peripheral clocks, with a master pacemaker being located in the suprachiasmatic nucleus (SCN) and subordinate clocks in non-SCN central and peripheral tissues. Kolbe et al. used SCN pacemaker knockout mice to dissect the role of central and peripheral clock function in metabolic homeostasis. They show that a functional SCN clock is not needed to sustain metabolic health in a rhythmic environment, which is sufficient to drive behavioral and peripheral clock network rhythms. In constant conditions, however, the synchronizing capacity of the master clock becomes key for this synchronization and metabolic homeostasis.

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Increases in LXRα induced by paternal alcohol use enhance offspring adaptation to obesityAlthough maternal exposures to alcohol, cigarettes, and other drugs of abuse have well-established effects on fetal development, the importance of the lifestyle choices of the father have only recently been recognized for their potential to influence offspring health. Chang et al. found that the male offspring of alcohol-exposed sires displayed enhanced metabolic adaptation and slowed weight gain when challenged with a high-fat diet, as well as several of the undesirable side effects of liver X receptor stimulation, including increased hepatic cholesterol efflux and hypertriglyceridemia.

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Loss of FoxOs in muscle reveals sex-based differences in insulin sensitivity but mitigates diet-induced obesityFoxOs are ubiquitously expressed transcription factors that control cellular differentiation, muscle growth, metabolism, and tumor suppression pathways. Their role in muscle glucose metabolism or regulation of obesity-induced insulin resistance has not been fully explored. Penniman, Suarez Beltran, and colleagues found that muscle-specific FoxO 1/3/4 triple knockout (TKO) led to increased muscle size associated with increased energy expenditure, which mitigated fat gain and metabolic complications of a high fat diet. Furthermore, they identified sex-based differences in AKT2 expression that were associated with impaired insulin action in muscle from male, but not female, mice.

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Subcellular metabolic pathway kinetics are revealed by correcting for artifactual post harvest metabolismMetabolites function as fuel for energy production, substrates for biosynthetic processes, and important signaling molecules, but the function of metabolites is highly dependent upon their sub-cellular location. Reliable direct measurement of kinetic parameters in sub-cellular metabolite pools is an important but challenging goal. Although it is recognized that metabolism can take place during biochemical fractionation of cells, a clear understanding of how such post-harvest metabolism impacts the interpretation of subcellular isotope tracing data and methods to correct for this are lacking. Trefely et al. set out to directly assess artifactual metabolism, enabling them to develop and test a post-labeling correction strategy.

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The anti-obesity effect of FGF19 does not require UCP1-dependent thermogenesisThe endocrine hormone fibroblast growth factor 19 (FGF19) has emerged as a potential target for the treatment of obesity and its associated comorbidities. The therapeutic benefits associated with FGF19 administration have also been proposed to be linked to the recruitment of uncoupling protein 1 (UCP1) and other key thermogenic pathways in white and brown adipose tissue. However, Antonellis and colleagues show that while chronic FGF19 administration reduced body weight, it did not increase energy expenditure in UCP1KO mice. This suggests that the anti-obesity action of FGF19 may be driven by its classical role in the regulation of hepatic bile acid synthesis rather than the upregulation of thermogenic pathways in adipose tissue.

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The glutamate receptor GluK2 contributes to the regulation of glucose homeostasis Ionotropic glutamate receptors of the kainate type are present in pancreatic cells. Abarkan, Gaitan, et al. studied the function of the receptor GluK2 in adult and middle-aged mice to elucidate possible roles in islet function and glucose homeostasis. Their observations suggest that kainate receptors are involved in glucose homeostasis, although the main initial mechanism may imply several sites. Moreover, the knockout of GluK2 may avoid the reduction in glucose homeostasis that occurs during aging.

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RGS2 balances brown adipose tissue function and differentiationThe most important regulators of brown adipose tissue (BAT) activity include members of the G protein-coupled receptors (GPCRs) that may signal via Gs, Gq or other G proteins. Regulators of G Protein Signaling (RGS) are important modulators of GPCR activity. Klepac and colleagues elucidated the role of RGS2 in brown adipocyte differentiation and BAT function. RGS2-deficient (RGS2-/-) brown adipocytes exhibited a severe defect in adipogenesis that was caused by increased Gq signaling. Analysis of RGS2-/- mice revealed an unexpected increase in lipolysis and BAT activity due to increased Gs signaling. Thus, RGS2 is a multifunctional inhibitor of Gq that also regulates Gs signaling in BAT.

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The Hepatokine TSK does not affect BAT thermogenic capacity, weight gain, and glucose homeostasisTsukushi (TSK) is a hepatokine, a factor secreted by the liver that may have effects throughout the body. TSK was suggested to be part of a negative feedback mechanism emerging from the liver to repress thermogenesis in brown adipose tissue (BAT) and reduce energy expenditure. In contrast, Mouchiroud et al. found that TSK-null mice are not protected against the development of obesity and do not show improvement in glucose metabolism. The overexpression of TSK also failed to modulate thermogenesis, body weight, and glucose tolerance. Thus, they conclude that TSK in not a significant regulator of BAT thermogenesis and is unlikely to represent an effective target for preventing obesity and improving glucose homeostasis.

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A new path for NAD+ biosynthesis from an orally bioavailable NAD+ precursor Nicotinamide adenine dinucleotide (NAD+) plays critical roles in energy metabolism as an electron transferring agent. Nicotinamide riboside (NR) is an NAD+ precursor that can be used as a dietary supplement, but it has several drawbacks. Giroud-Gerbetant, Joffraud, et al. identified NRH, a reduced form of NR, as a new NAD+ precursor. NRH shows an unprecedented ability to increase NAD+ in cultured cells and mice, as it is more potent and faster than NR. Despite the minor chemical modification, NRH utilizes a different path than NR to synthesize NAD+. The authors also demonstrate that NRH is protected against degradation in the plasma and can be detected in circulation after oral administration. Finally, NRH also demonstrates therapeutic efficacy against cisplatin-induced kidney injury.

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Steroidogenic control of liver metabolism through a nuclear receptor-networkThe cytochrome P450 enzyme Cyp17a1 catalyzes intermediate reactions in the synthesis of all steroid hormones. Metabolic regulation by the liver is under the control of members of the nuclear receptor class of transcription factors, with farnesoid X receptor (FXR) and peroxisome proliferator activated receptor alpha (PPARα) playing important roles. Milona et al. discovered that Cyp17a1 is repressed by FXR action in the liver in the fed state. During starvation, Cyp17a1 is de-repressed and produces a hormone ligand for PPARα. The authors show that hepatic Cyp17a1-dependent PPARα-activity is essential for the maintenance of fasting glucose and ketone levels. This is an important new link between extra-gonadal steroidogenic pathways and a nutrient responsive nuclear receptor network.

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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.



Isa Kolbe, Henrik Oster
University of Lübeck, Germany
Referring article

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