Featured Articles

Volume 6 | No. 11 | November 2017

The autonomic nervous system and GLP-1 receptors control heart rateGlucagon-like peptide-1 (GLP-1) is a gut hormone with pleiotropic effects that, among other actions, also controls heart rate (HR). The data available so far suggest that GLP-1 may control HR indirectly, through modulation of autonomic nervous system activity, as well as directly, through control of pacemaker activity via the atrial GLP-1 receptor (GLP-1R). To elucidate the relative importance of and inter-dependence of these pathways, Baggio, Ussher et al. have now studied the regulation of HR in control and Glp1rCM-/- mice treated with the GLP-1R agonists lixisenatide or liraglutide. Their findings reveal temporally distinct contributions from both the sympathetic nervous system and cardiac GLP-1Rs in the HR response to GLP-1R agonism in vivo.

Abstract | PDF



Acute activation of GLP-1-expressing neurons promotes glucose homeostasis and insulin sensitivityIn response to food intake, glucagon-like peptides (GLP-1/2) are co-released from enteroendocrine L cells in the gut as well as preproglucagon (PPG) neurons in the nucleus of the solitary tract (NTS) of the brainstem, which together constitute the key nutritional signals for the control of energy balance and glucose homeostasis. Shi and colleagues determined whether activation of PPG neurons per se modulates glucose homeostasis and insulin sensitivity in vivo. They show in Gcg-Cre lean mice infected with excitatory hM3Dq virus in the brainstem NTS that acute activation of Gcg neurons (which include the PPG neurons) enhances glucose tolerance, suppresses basal endogenous glucose production, and augments hepatic insulin sensitivity.

Abstract | PDF



Superior reductions in hepatic steatosis and fibrosis with a GLP1R agonist and obeticholic acid The current standard of care for nonalcoholic steatohepatitis (NASH) is limited to ameliorating components of the associated metabolic syndrome. Unfortunately, the long-term effectiveness of these interventions is questionable. Therefore, developing new pharmacological therapies is vital to combating the complex nature of NASH. Jouihan and colleagues investigated the use of long-acting glucagon-like peptide-1 receptor (GLP-1R) agonist IP118 and the farnesoid-X receptor (FXR) agonist obeticholic acid (OCA). They found that their combination is more effective than using either compounds separately in slowing or reversing NASH-associated defects including hepatic steatosis and fibrosis.

Abstract | PDF



Host-microbiota interaction induces inflammation and glucose intoleranceThe gut microbiota has emerged as an important factor regulating host physiology and metabolism, in particular glucose metabolism and adiposity. Molinaro et al. did a time-resolved study on how colonization of germfree (GF) mice affects kinetics of adiposity and glucose metabolism. They found that colonization resulted in a bi-phasic glucose impairment. The first phase, occurring within 3 days of colonization (early phase) co-occurred with an inflammatory response and was independent of adiposity. The second phase, 14-28 days after colonization (delayed phase), was mostly ascribed to adipose tissue expansion and inflammation.

Abstract | PDF



Deletion of hepatic ChREBP impairs glucose homeostasis and insulin sensitivity Carbohydrate response element binding protein (ChREBP) is a key transcription factor involved in coordinating the feeding response. Association studies have linked increased ChREBP expression in liver to hepatic steatosis and insulin resistance. Jois and colleagues sought to clarify the role of hepatic ChREBP in glucose homeostasis and insulin sensitivity using a novel mouse model of hepatic ChREBP deletion. They found that liver ChREBP is vital in maintaining hepatic insulin sensitivity and coordinating the appropriate responses to fasting and feeding through glucose sensing.

Abstract | PDF



FGF21 is robustly induced by ethanol and has a protective role in liver injury Chronic ethanol consumption is known to be lipotoxic and is associated with accumulation of hepatic fat. While alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) have distinct characteristics, they also share similar pathologies. Considering this, Desai, Singhal and colleagues hypothesized that ethanol consumption might also increase expression of fibroblast growth factor 21 (FGF21). They found increased FGF21 expression after binge alcohol consumption in humans and mice. Their data suggest that FGF21 has a dual role in ethanol metabolism. Acutely, FGF21 acts centrally to inhibit ethanol consumption. Chronically, the rise in hepatic FGF21 expression may have anti-inflammatory and anti-fibrotic roles.

Abstract | PDF



Islet-enriched long non-coding RNAs contributing to β-cell failure in type 2 diabetes Long non-coding RNAs (lncRNAs) participate in diverse gene-regulatory mechanisms and their dysregulation has been implicated in many human diseases. Recently, lncRNAs were found to contribute to β-cell development and glucose homeostasis. Motterle et al. identified novel islet lncRNAs and investigated their role in the regulation of β-cell functions. They show that lncRNAs are modulated in islets from obese diabetic mice and individuals with type 2 diabetes (T2D) and may contribute to β-cell failure during T2D development.

Abstract | PDF



Disruption of orthopedia homeobox (Otp) is associated with obesity and anxiety The development of neuroendocrine cell lineages in the hypothalamus requires a number of transcription factors including orthopedia homeobox (OTP). Moir, Bochukova and colleagues have carried out a high throughput dominant N-ethyl-N-nitrosourea (ENU) mutagenesis screen in mice with the objective of identifying novel obesity models. They report an obese model with a novel hypomorphic mutation in the orthopedia homeobox (Otp) gene.

Abstract | PDF



Four microRNAs are regulators of skeletal muscle mitochondrial metabolism MicroRNAs (miRNAs) are small non-coding RNA strands of approximately 20-22 nucleotides regulate the stability and translation of conventional messenger RNAs. Dahlmans et al. performed an unbiased, hypothesis-free screening approach in C2C12 myoblasts, using specific miRNA inhibitors, leading to the identification of 19 specific miRNAs as positive modulators of mitochondrial metabolism when silenced. The expression of four of these miRNAs showed a strong relationship with in vivo mitochondrial function in humans.

Abstract | PDF



Absence of the kinase S6k1 mimics the effect of chronic endurance exercise Physical exercise training is associated with increased insulin sensitivity, improved glycemic control, and reduced risk for developing type 2 diabetes mellitus. However, the regulatory network responsible for the diabetes-protective effect of exercise is not well understood. Activation of the mammalian target of rapamycin complex 1(mTORC1)/ Ribosomal protein S6 Kinase-1 (S6k1) pathway may play an important role in metabolic adaptation to endurance exercise training that relates to improvements in glucose homeostasis. Binsch, Jelenik et al. report that the absence of S6k1 upregulates ketogenesis and improves oxidative substrate utilization and conservation of carbohydrate reserves under a high fat diet consumption, thus mimicking the condition of chronic endurance exercise.

Abstract | PDF



FGF21 mimetic antibody stimulates UCP1-independent brown fat thermogenesis Fibroblast Growth Factor 21 (FGF21) is an endocrine member of the FGF super family that has been identified as a regulator of brown adipose tissue (BAT) thermogenesis and nutrient metabolism. Although pre-clinical and clinical studies suggest that FGF21 analogs may become an effective therapy for obesity related disorders, the mechanism that leads to BAT thermogenesis remains elusive. Chen et al. demonstrate that uncoupling protein 1 is not essential for the antibody bFKB1 to stimulate BAT thermogenesis in obese mice. They show that bFKB1 acts as an FGF21 mimetic protein whose in vivo metabolic activity originates outside of the adipocytes.

Abstract | PDF



The mitochondrial pyruvate carrier mediates increases in hepatic TCA cycle capacity Hepatocyte mitochondria provide energy for the whole body by supporting the synthesis of new glucose during fasting Hepatocyte mitochondrial pyruvate carrier (MPC) activity may play a fundamental role in the aberrant metabolism underlying type 2 diabetes (T2D). Rauckhorst, Gray, and colleagues demonstrate that high-fat diet increases TCA cycle capacity and that this increase is MPC-dependent. Thus, by contributing to chronic hyperglycemia, fibrosis, and TCA cycle expansion, the hepatocyte MPC is a key mediator of the pathophysiology induced in the HFD model of T2D.

Abstract | PDF



Amino acid sensing in hypothalamic tanycytes via umami taste receptors One population of hypothalamic cells that is potentially a key player in energy homeostasis is the tanycyte. As amino acids are important signals of satiety, determination of the ability of tanycytes to detect amino acids would be an important advance in understanding the possible functions of these cells. Lazutkaite et al. show that hypothalamic tanycytes are directly sensitive to a range of amino acids. Amino acids act on tanycytes via two receptors. These data warrant investigation as to whether tanycytes may be physiological mediators of satiety signals and act to reduce food intake.

Abstract | PDF



The FGF21 response to fructose predicts metabolic health Concerns about the consumption of fructose have been raised as high fructose intake may contribute to the current epidemics of obesity and its metabolic complications. Fructose is preferentially metabolized by the liver and can increase hepatic expression of fibroblast growth factor 21 (FGF21). ter Horst, Gilijamse et al. find that fructose-FGF21 responsiveness is exaggerated in subjects with poor metabolic health as reflected by the associations with elevated endogenous glucose production, increased lipolysis, and insulin resistance. They also demonstrate that the FGF21 response to fructose persists in post-bariatric subjects.

Abstract | PDF



Maternal obesity alters fatty acid oxidation, AMPK activity, and associated DNA methylation Epidemiological data indicate that obesity during pregnancy is an important contributor to adiposity and metabolic disease risk in the offspring. Boyle et al. investigated cellular lipid metabolism and AMP-activated protein kinase (AMPK) activity in infant mesenchymal stem cells (MSCs) undergoing myogenesis in vitro. They identified maternal obesity-associated reductions in offspring MSC lipid metabolism and AMPK activity. The authors will continue to follow these children longitudinally to be better able to address whether umbilical cord MSC metabolism is predictive of future weight gain or adiposity patterns.

Abstract | PDF



Decreasing CB1 receptor signaling improves insulin sensitivity Liver resident macrophages, called Kupffer cells (KCs), are thought to be the major source of hepatic inflammation. Cannabinoid 1 receptor (CB1R) has a proinflammatory function in macrophages and CB1R signaling is strongly involved in the development of fatty liver and insulin resistance. Jourdan et al. demonstrate that knock-down of CB1R in Kupffer cells leads to improved global insulin sensitivity by reducing inflammation and reactive oxygen species production and by promoting mitochondria uncoupling through an increase in uncoupling protein 2 activity.

Abstract | PDF



KLK5 induces shedding of DPP4 from circulatory Th17 cells Increasing plasma levels and activity of dipeptidyl peptidase-4 DPP4 are associated with rapid progression of metabolic syndrome to overt type 2 diabetes mellitus (T2DM). While DPP4 inhibitors are increasingly used as anti-hyperglycemic agents, the reason for the increase in plasma DPP4 activity in T2DM patients remains elusive. Nargis and colleagues show that in T2DM patients, circulating CD4+ T cells, specifically cells having the Th17 phenotype, shed cleaved DPP4 protein into plasma due to the enzymatic action of kallikrein-related peptidase (KLK5). Thus, they uncovered a hitherto unknown link between T cell inflammation and aberrant plasma DPP4 abundance in T2DM.

Abstract | PDF



Bombesin-like receptor 3 expression in glutamatergic neurons is required for regulation of energy metabolismBombesin-like receptor 3 (BRS-3) is an orphan G protein-coupled receptor. Insights into the function of BRS-3 come from a Brs3 knockout (KO) mouse. The null phenotype includes obesity, increased food intake and meal size, and reductions in metabolic rate, resting body temperature, and resting heart rate. Xiao and colleagues developed mice that allow selective, conditional deletion or re-expression of Brs3. They used these mice to investigate the necessity and sufficiency of Brs3 in glutamatergic and GABAergic neurons for regulation of energy homeostasis and identified a role for Brs3 in glutamatergic but not GABAergic neurons.

Abstract | PDF



Adult neural stem cell fate is determined by activation of mitochondrial metabolismNeurogenesis persists in the brain of adult mammals in two well-defined niches, the hippocampus and the sub-ventricular zone. Neural stem cells (NSCs) principally rely on aerobic glycolysis before differentiation, contrasting with mature cells, in which metabolism is mainly based on mitochondrial oxidative phosphorylation (OXPHOS). Gothié et al. hypothesized that thyroid hormone (TH) determination of NSC fate could implicate modulation of the glycolysis to OXPHOS metabolism transition. Their data show that TH signaling increases mitochondrial dynamics and activates mitochondrial respiration during NSC differentiation, thus directing adult NSC determination to a neuronal fate.

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.



Amna Khamis
University of Lille, CNRS, Institute Pasteur de Lille, Lille, France
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
June 30 −
July 1
2019
ATLAS Symposium 2019
Middelfart, Denmark
August
25 − 30
2019
Epigenomics, Nuclear Receptors and Disease
Spetses Island, Greece
September
9 − 12
2019
Ageing and Regeneration
Innsbruck, Austria
September
23 − 25
2019
7th Helmholtz Diabetes Conference
Munich, Germany
October
15 − 18
2019
Nature Conference: Advances in Metabolic Communication
Rio de Janeiro, Brasil
October
15 − 18
2019
13th European Nutrition Conference
Dublin, Ireland
October
27 − 31
2019
Metabolism in Action
Hillerod, Denmark
December
6 − 8
2019
Cachexia, Sarcopenia and Muscle Wasting
Berlin, Germany
Media Coverage
Supported by