Featured Articles

Volume 18 | December 2018

LY3298176, a dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetesTreatment of type 2 diabetes mellitus (T2DM) with glucagon-like peptide-1 receptor agonists (GLP-1RAs) leads to several improvements. However, there are still opportunities to enhance the existing GLP-1RA class. Coskun et al. describe a novel, single-peptide, dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonist, LY3298176. The dual functionality of the peptide is described in preclinical in vitro and in vivo models and in clinical trials. In the latter, LY3298176 led to decreased glucose levels and decreased body weight in healthy individuals during a multiple ascending dose study, and in a randomized, 4-week, Phase 1b trial in T2DM patients.

Abstract | PDF



Control of hepatic gluconeogenesis by Argonaute2During fasting, the liver engages several mechanisms to facilitate hepatic glucose production. Recent studies have identified post-transcriptional regulators of liver function including non-coding RNAs and inhibition of abundant microRNAs. Yan, Wang, Bishop, et al. show that Argonaute2 (Ago2) expression in the liver is modulated according to changes in extracellular glucose concentrations and conditional deletion in the hepatocyte diminishes adaptive glucose production during fasting. Together these results identify Ago2 as an essential regulator of the fasting response.

Abstract | PDF



Switching obese mothers to a healthy diet improves fetal hypoxemia, hepatic metabolites, and lipotoxicity Infants born to mothers with obesity show increased intrahepatocellular lipid storage. These offspring are at a higher risk of progressing toward obesity, non-alcoholic fatty liver disease, cardiovascular disease, and hepatic carcinoma later in life. Wesolowski and colleagues tested switching obese female non-human primates to a healthy diet prior to pregnancy and found improved fetal hypoxemia, hepatic metabolites, and lipotoxicity.

Abstract | PDF



Glucose tolerance and insulin sensitivity define adipocyte transcriptional programs in human obesityObese individuals are at high risk of developing life-threatening co-morbidities. However, 10-25 % of obese people stay healthy. These individuals remain glucose tolerant and insulin sensitive, with normal blood pressure and a favorable lipid profile. Gerlini, Berti, and colleagues analyzed primary subcutaneous adipocytes from morbidly obese individuals discordant for metabolic health. They discovered that instead of insulin resistance, impaired glucose homeostasis is a major determinant of adipocyte transcriptional response. Furthermore, they identified 19 genetic associations with phenotypes of glucose homeostasis and/or body weight and composition.

Abstract | PDF



Activation of estrogen receptor alpha induces beiging of adipocytesThe recent discovery that beige adipose tissues exist in adult humans has led to the concept that increasing their activity is a therapeutic strategy to reduce body weight and improve insulin sensitivity. Most of the approaches for inducing beiging of white adipose tissue rely on activation of the sympathetic nervous system. However, adrenergic activation cannot be used therapeutically in humans because of its adverse effects on other tissues. Santos et al. found that activation of adipocyte estrogen receptor alpha increases markers of beiging. This could be a novel therapeutic target to promote beiging of adipose tissues to improve metabolic homeostasis.

Abstract | PDF



TRPV1 neurons regulate β-cell function in a sex-dependent mannerThe pancreas is innervated by sensory neurons originating from the vagus and the spinal nerves. A large proportion of these sensory neurons express the transient receptor potential vanilloid 1 (TRPV1), a non-selective cation channel. Karam et al. used a combination of chemical and surgical models to address whether TRPV1 sensory neurons directly modulate functional β-cell mass and consequently alter glucose homeostasis. Their data suggest that TRPV1 sensory neurons directly modulate, at least in part, pancreatic β-cell function in a sex-dependent manner.

Abstract | PDF



AF-1 of estrogen receptor alpha controls obesity through enhancement of energy expenditureEstrogen Receptor alpha (ERα) is a ligand dependent transcription regulator, and its activity is modulated by estrogenic compounds. Estrogenic compounds bind to the ligand binding domain and control the functionality of the transcriptional activation domains of ERα, named AF-1 and AF-2. Understanding of the precise functions of AF-1 and AF-2 in ERα in metabolic regulation may lead to generation of precise therapeutic interventions for controlling ERα function appropriately in pre- and post-menopausal women. Arao et al. suggest that the specific activation of ERα AF-1 can enhance energy expenditure without changing feeding and locomotion behavior.

Abstract | PDF



Overexpression of melanocortin 2 receptor accessory protein 2 regulates energy intake and expenditureMelanocortin 2 receptor accessory protein 2 (MRAP2) has a critical role in energy homeostasis, which has been linked to action on Melanocortin 4 receptor (MC4R) signaling. However, the mechanism by which MRAP2 knockout animals become obese is still unclear. Bruschetta and colleagues assessed the effect of postnatal overexpression of MRAP2 in MC4R neurons of the hypothalamic paraventricular nucleus (PVN). They found that MRAP2 acts postnatally, in a sex-specific manner, in the regulation of food intake and energy expenditure through the enhancement of MC4R neuronal signaling in the PVN.

Abstract | PDF



Ghrelin transport across the blood-brain barrier can occur independently of the growth hormone secretagogue receptorGhrelin is a 28-amino acid peptide mainly produced in the stomach and small intestines. Its receptor is the growth hormone secretagogue receptor (GHSR) 1a. Rhea et al. investigated whether ghrelin transport across the blood-brain barrier (BBB) is GHSR dependent by using a Ghsr null mouse model. They show for the first time that the GHSR is not solely responsible for ghrelin transport across the BBB.

Abstract | PDF



Neuronatin deletion causes growth restriction and obesity Neuronatin (Nnat) is a paternally expressed, imprinted gene found in neuroendocrine systems. Single nucleotide polymorphisms in the human NNAT locus are associated with extreme childhood obesity and reduced expression of NNAT is found in human adipose tissue in obese children. Millership et al. found that deletion of Nnat led to a transient postnatal growth restriction, followed by decreased energy expenditure, blunted leptin sensitivity, and hyperphagia in adulthood, resulting in obesity under high fat diet-feeding or associated with aging.

Abstract | PDF



Cellular and synaptic reorganization of arcuate NPY/AgRP and POMC neurons after exerciseExercise increases insulin sensitivity. Recent observations support a rapid and constitutive plasticity of melanocortin synaptic organization which responds and contributes to metabolic homeostasis, particularly for neuropeptide Y (NPY) and proopiomelanocortin (POMC) positive neurons. He and colleagues hypothesized that such changes could underlie the positive effects of exercise. They found multiple mechanisms in the remodeling of synaptic and cellular properties of NPY and POMC neurons of the arcuate nucleus in response to exercise.

Abstract | PDF



Endocannabinoid and nitric oxide systems mediate effects of NPY on energy expenditureNeuropeptide Y (NPY) is a key peptide in the central regulation of energy homeostasis. One of the main brain regions where NPY exerts its effects on food intake and energy expenditure is the hypothalamic paraventricular nucleus (PVN). Péterfi, Farkas, Denis, Farkas, et al. describe that NPY seems to exert rapid action on parvocellular PVN neurons by gating both inhibitory and excitatory inputs to these neurons via activation of endocannabinoid and nitric oxide retrograde signaling systems.

Abstract | PDF



Large extracellular vesicles are conveyors of Macrophage Migration Inhibitory FactorWhite adipose tissue (WAT) is recognized as an endocrine organ that secretes many factors. Recent evidence has highlighted the potential role of extracellular vesicles (EVs) in the development of metabolic diseases. Amosse, Durcin, and colleagues identified large EVs as specific conveyors of functional Macrophage Migration Inhibitory Factor (MIF) cytokine. Although MIF enzymatic activity is not well defined, its importance has been underlined in multiple disease states.

Abstract | PDF



Compensatory mechanisms for methylglyoxal detoxification in diabetesMethylglyoxal (MG) is a highly potent glycating agent that is an indirect cause for complications in diabetes. The Glyoxalase system is considered to be the major pathway by which MG is detoxified. Schumacher, Morgenstern, et al. studied the effects of a glyoxalase 1 knockout and found that aldo-keto reductases can compensate for the loss of glyoxalase 1. They conclude that the combination of metabolic, enzymatic, and genetic factors rather than glyoxalase 1 deficiency only may provide a better means of identifying patients who are at risk of developing late complications caused by elevated levels of MG.

Abstract | PDF



Insulin receptor-mediated signaling regulates pluripotency markers and lineage differentiationThe insulin/insulin-like growth factor (IGF) family regulates the pre- and postnatal development and maintenance of optimum metabolic functioning of virtually all mammalian cells. Previous studies demonstrated the importance of IGFII/IGF1R and ERBB2 receptor signaling in the maintenance of self-renewal of human embryonic stem cells. Gupta, De Jesus, and colleagues explored the direct role of insulin receptor-mediated signaling in pluripotency maintenance and in lineage development by reprogramming insulin receptor global knockout mouse embryonic fibroblasts into induced pluripotent stem cells. Together, these studies underscore the importance of insulin-mediated signaling for maintenance of pluripotency and lineage development.

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.



Abdelfattah El Ouaamari
Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, USA
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
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