Featured Articles

Volume 13 | July 2018

CoDE-seq enables the accurate detection of CNVs and mutations in Mendelian obesity and intellectual disabilitySome rare and severe forms of obesity can be due to only one genetic event, which includes point mutations and copy number variations (CNV). A molecular diagnosis of these extreme forms of obesity is crucial for the optimal care of the patients and genetic counseling for their families. However, CNVs are hard to detect by whole-exome sequencing (WES). Montagne, Derhourhi, and colleagues aimed to develop a new next-generation sequencing strategy, named ‘CoDE-seq’ for Copy number variation Detection and Exome sequencing, enabling the accurate detection of both CNVs and point mutations in only one step. Using this method, they analyzed 82 subjects with suspected Mendelian obesity and/or intellectual disability and achieved a molecular diagnosis in more than 30% of the cases.

Abstract | PDF



A disease-associated Aifm1 variant induces severe myopathy in knockin mice Apoptosis-inducing factor (AIF) was originally described as a pro-death molecule that is released from mitochondria during cell death. Apart from that, AIF has a fundamental housekeeping role in mitochondrial bioenergetics. Over the past few years, several pathogenic mutations in the AIFM1 locus have been causally implicated in a set of X-linked recessive human disorders. Wischhof et al. developed an Aifm1 (R200 del) knockin mouse model, providing the first unequivocal evidence that a disease-associated mutation in the Aifm1 gene causes mitochondrial dysfunction in vivo in mice.

Abstract | PDF



Surplus fat rapidly increases fat oxidation and insulin resistance in lipodystrophic miceOne hypothesis for the tight association of obesity and its metabolic consequences hinges on the notion that the ability to increase the size and number of adipocytes is ultimately ‘limited’ and that, in such circumstances, lipid accumulates in other, less well-adapted tissues. Lipodystrophy (LD), a state defined by reduced adipose tissue mass and function, provides a unique opportunity to directly assess the immediate consequences of surplus fat ingestion in a situation where the capacity of adipose tissue to expand is constrained. Girousse and colleagues tested the effects of surplus fat on a mouse model of LD. Their results suggest that in circumstances in which high fat energy intake exceeds the capacity of adipose storage depots, excess fat induces an increase in fat oxidation, and this results in competition between lipid and carbohydrate oxidative substrates and can contribute to insulin resistance.

Abstract | PDF



Osteoglycin, a novel coordinator of bone and glucose homeostasisWhere positive energy balance precedes an increase in weight, bone must increase its strength to match the increasing mechanical demand. Bone is regulated by neuropeptide Y (NPY) signaling via Y1 receptors. However, local NPY signaling via osteoblastic Y1 receptors not only controls bone mass but also contributes significantly to the control of whole body insulin secretion and glucose homeostasis. Lee et al. identify osteoglycin as a down-stream mediator of Y1 receptor signaling in early osteoblasts. They find novel actions for osteoglycin in the control of bone production, as well as in the modulation of whole body energy balance through the control of food intake and glucose uptake.

Abstract | PDF



Molecular elements in FGF19 and FGF21 defining KLB/FGFR activity and specificityFibroblast growth factors 19 and 21 (FGF19 and FGF21) effectively correct metabolic abnormalities in rodents. They both require transmembrane β-Klotho (KLB) as a co-factor to facilitate signaling through various FGF receptors (FGFRs). Agrawal et al. determined the basis to KLB binding for the C-terminal segments of FGF19 and FGF21 by alanine scanning. Their results map the KLB binding elements in FGF19 and FGF21 at single amino acid resolution and specify a common functional signature by which these endocrine hormones signal via FGFR/KLB complexes, despite the appreciable difference in their native sequences.

Abstract | PDF



Deficiency of FGF21 promotes hepatocellular carcinoma Fibroblast growth factor 21 (FGF21) plays an important role in liver metabolism and is known to be hepatoprotective in the context of several short term hepatic stresses. Singhal et al. show that mice lacking FGF21 and consuming a high fat, high sugar diet develop severe steatosis. With ongoing consumption of this diet, non-alcoholic fatty liver disease ultimately progresses to hepatocellular carcinoma in a high percentage of FGF21 deficient, but not wildtype, mice. Thus, they show that FGF21 is also required to protect the liver in the long term.

Abstract | PDF



Altered pancreatic islet morphology and function in SGLT1 knockout miceThe Na+-D-glucose cotransporter 1 (SGLT1) is predominantly expressed in the small intestine but also in other tissues. Inhibitors of SGLT1 that block small intestinal glucose absorption have been proposed recently as a therapeutic intervention strategy for type 2 diabetes patients. Mühlemann, Zdzieblo, et al. have investigated possible side effects on pancreatic islets when SGLT1 is lost. Loss or impairment of SGLT1 resulted in abnormal pancreatic islet morphology and disturbed islet function in the context of insulin or glucagon secretion. These findings propose a new role for SGLT1 in maintaining proper islet structure and function.

Abstract | PDF



Time-resolved hypothalamic open flow microperfusion reveals normal leptin transport in leptin resistant miceLeptin is a 16 kDa hormone that is secreted from white adipocytes to signal satiety in the brain. Obesity is associated with increased leptin levels and treatment with additional leptin has limited efficacy to lower body-weight. One prevailing theory is that impaired transport of leptin across the blood-brain barrier (BBB) plays a central role in leptin resistance. Kleinert and colleagues used Cerebral Open Flow Microperfusion (cOFM), a new in vivo technique that allows for continuous sampling of the interstitial fluid in brain tissue, to monitor transport of leptin across the BBB over time. Their data demonstrate that leptin transport into the hypothalamus is normal in high fat diet-induced leptin resistance.

Abstract | PDF



Differential effects of glutamate and MCH neuropeptide in MCH neuronsMelanin-concentrating hormone expressing (MCH) neurons of the lateral hypothalamus play an important role in the regulation of metabolism. Previous studies have revealed differences between the effects of MCH neural ablation and MCH knockout, raising the possibility that additional transmitters besides MCH mediate the effects of these neurons. In the present study, Schneeberger, Tan, et al. found that the great majority of MCH neurons are glutamatergic. They compared the physiologic effects of ablating glutamate signaling in these neurons to either an MCH knockout or MCH neural ablation. They found that the effects of knocking out the glutamate transporter and MCH were different, suggesting that the function of MCH neurons is a composite of the function of MCH and glutamate.

Abstract | PDF



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.



Florian Merkle
University of Cambridge, UK
Referring article

Other Scientists...
Issue Alert
If you want to be alerted via email when new content that matches your interests is available, please login or register at www.sciencedirect.com/journal/molecular-metabolism
Conferences & Events
December
9 − 11
2018
Cell Symposia: Metabolites as Signaling Molecules
Seattle, USA
January
13 − 17
2019
Mitochondrial Biology in Heart and Skeletal Muscle
Keystone, USA
February
10 − 14
2019
Obesity and Adipose Tissue Biology
Banff, Canada
February
10 − 14
2019
Functional Neurocircuitry of Feeding and Feeding Disorders
Banff, Canada
February
24 − 28
2019
Tumor Metabolism
Keystone, USA
March
3 − 7
2019
Diabetes: Innovations, Out­comes, Personalized Therapies
Whistler, Canada
March
10 − 14
2019
Microbiome: Mechanisms and Consequences
Montreal, Canada
March
15 − 19
2019
Cancer Metastasis
Florence, Italy
Media Coverage
Supported by