Featured Articles

Volume 8 | February 2018

Differential contribution of POMC and AgRP neurons to the regulation of autonomic nerve activity by leptinLeptin acts in the brain as part of a negative feedback mechanism to control adiposity through stimulation of sympathetic nerve activity (SNA). The arcuate nucleus (ARC) contains multiple unique leptin receptor (LepR) positive neuronal populations including those expressing proopiomelanocortin (POMC) and agouti-related peptide (AgRP). In the present study, Bell et al. show that POMC and AgRP neurons differentially contribute to leptin control of regional activity of the autonomic nervous system. These findings support the notion that leptin engages different neuronal populations in a selective manner to control the activity of the sympathetic and parasympathetic nervous systems.

Abstract | PDF



Leptin transport across brain barriers controls food rewardLeptin is a key hormone controlling body weight by inhibiting food intake and stimulating energy expenditure. In addition, leptin receptor (LepR) regulates food reward. Until now, it was unclear whether leptin has to penetrate brain barriers to exert its central effects. To directly assess the role of LepR in leptin uptake by the brain and to elucidate LepR function in CNS barriers for body weight regulation, Di Spiezio and colleagues deleted all LepR isoforms selectively in brain endothelial cells and the choroid plexus. When deleting LepR in brain endothelial and epithelial cells, the uptake of leptin by the brain was reduced and body weight was increased on a high-fat diet but not on normal chow. Further experiments revealed that LepR in brain barriers inhibits food reward.

Abstract | PDF



Inhibition of ceramide synthesis restores insulin signaling and enhances β-cell function Obesity following a high fat diet (HFD) but also intra-hypothalamic injections of saturated fatty acids (FFAs) have been shown to induce central lipotoxicity. Central lipotoxicity has also been shown to be deleterious for the hypothalamic control of glucose homeostasis. Campana and colleagues deciphered the role of endogenous ceramide synthesis on the deregulation of hypothalamic insulin signaling and its consequences on glucose homeostasis. They found that de novo ceramide synthesis induced a hypothalamic insulin resistance. Interestingly, they also found that inhibition of de novo ceramide synthesis in the hypothalami of obese Zucker rats improved glucose tolerance.

Abstract | PDF



A gut-brain axis regulating glucose metabolism mediated by bile acids and FGFBile acids modulate glucose homeostasis by direct actions on two receptors, G-protein coupled bile acid receptor 1 (GPBAR1) and farnesoid X receptor (FXR). One well known role for FXR is as a bile acid sensor within the enterocyte that increases the production of fibroblast growth factor 15 (FGF15; FGF19 is the human ortholog). Liu et al. provide evidence that bile acid signaling via FXR affects ileal FGF15/19 production, causing activation of FGFR1 on melanocortinergic neurons to significantly improve glucose tolerance. They identified a gut-brain axis wherein bile acid and FGF15/19 can improve glucose handling as well as short FGF-derived peptides that improve glucose homeostasis.

Abstract | PDF



Adropin: A link between the biological clock and cholesterol homeostasisAdropin is a product of the Energy Homeostasis Association (ENHO) gene. It is a secreted peptide implied in metabolic status signaling. Ghoshal et al. report that plasma adropin concentrations are inversely related to plasma levels of low-density lipoprotein cholesterol (LDL-C) in males, but not in females. They also report that the biological clock may be a plausible focal point linking Enho transcription with nutrient intake and cellular metabolic condition.

Abstract | PDF



Cdkn2a deficiency promotes adipose tissue browningGenome-wide association studies have established the CDKN2A/B locus as a hotspot influencing genetic risk for different cardio-metabolic diseases including type 2 diabetes. While rodent and human studies have highlighted the potential role of CDKN2A/B on insulin secretion, the contribution of CDKN2A/B to the control of insulin sensitivity is still elusive. Rabhi, Hannou Gromada et al. demonstrate that the genetic deletion of Cdkn2a promotes energy expenditure and improves insulin sensitivity in diet-induced obesity. Their data suggest that Cdkn2a plays a key role in energy metabolism by regulating a white-to-brown fat transition.

Abstract | PDF



Degradation of brown adipocyte purine nucleotides regulates UCP1 activityMitochondrial uncoupling protein 1 (UCP1) is essential for the thermogenic process in brown adipocytes and a target of the crucial regulatory signals. In the resting state, UCP1 is inhibited by the binding purine di- and triphosphate nucleotides (GDP, ADP, GTP, ATP). The concentration of purine nucleotides can be assumed to be well in a range in which their degradation may actively contribute to activation of UCP1. Fromme and colleagues found a decrease in purine nucleotide di- and triphosphate concentration upon adrenergic stimulation of primary brown adipocytes and present evidence that alterations in purine nucleotide metabolism are involved in the activation of UCP1-mediated thermogenesis.

Abstract | PDF



Elevating eosinophils in obese mice does not rescue metabolic impairmentsA recently identified role for eosinophils is their potential influence on whole-body metabolic fitness by regulating adipose tissue (AT) health. To date, interventional studies have targeted eosinophils via nonspecific means which increase eosinophils but also alter a cascade of upstream or off-target immune reactions, making it difficult to definitively conclude eosinophils are responsible for the observed improvements in metabolic fitness. Bolus et al. aimed to determine whether directly normalizing AT eosinophil numbers via rIL5 injections in obese mice would improve metabolic fitness. They found that AT eosinophils of obese mice were successfully restored to levels of lean mice, but none of the metabolic improvements seen in other hypereosinophilic models were observed.

Abstract | PDF



Stard13 controls insulin secretion through F-actin remodelingActin cytoskeleton remodeling is regulated by the Rho-family of small GTPases in different cell types, including the pancreatic β-cells. The actin cytoskeleton plays a complex role in regulating insulin release: it acts as a physical barrier, impeding the access of insulin granules to the cell periphery, but it also actively participates in it by providing a cytoskeletal track for insulin granule transport. To gain insight into how actin cytoskeleton regulates insulin secretion, Naumann et al. visualized F-actin in β-cells. Their results suggest a previously unappreciated role of the Rho GTPase activating protein Stard13 as a key component of the insulin secretion machinery through actin cytoskeletal remodeling.

Abstract | PDF



Hepatocyte estrogen receptor α promotes reverse cholesterol transportObese, premenopausal women are more insulin sensitive than body mass index-matched men and have lower risk of coronary heart disease (CHD) with a less atherogenic plasma lipid profile. After menopause, CHD risk in women approaches that of men of the same age, suggesting that sex differences in CHD risk are in part influenced by estrogen signaling pathways. Zhu et al. investigated whether hepatic estrogen signaling regulates reverse cholesterol transport (RCT) and is protective against early stages of atherosclerosis. They show that hepatocyte estrogen receptor α plays an important role in RCT to protect against lipid retention in the artery wall at early stages of atherosclerosis during Western diet feeding in female mice.

Abstract | PDF



Hepatic regulation of VLDL receptor modulates NAFLDNon-alcoholic fatty liver disease (NAFLD) is currently the most common liver disorder. Recently, it has been reported that very low-density lipoprotein receptor (VLDLR) plays an important role in the development of hepatic steatosis. VLDLR is regulated by several transcription factors, including Peroxisome Proliferator-Activated Receptor (PPAR) γ. However, little is known about the effects of PPARβ/δ on VLDLR regulation in the liver. Zarei and colleagues show that Pparβ/δ deficiency regulates VLDLR levels, whereas fibroblast growth factor 21 (FGF21) deficiency exacerbates ER stress-induced VLDLR levels, contributing to the progression of hepatic steatosis.

Abstract | PDF



Pharmacological stimulation of p53 ameliorates NAFLD p53 is an intensively studied protein, primarily as a tumor suppressor. Although there is a large body of evidence showing that p53 promotes fatty acid catabolism while it inhibits anabolism, the possible contribution of p53 to the pathogenesis of nonalcoholic fatty liver disease (NAFLD) has only recently begun to be understood. Porteiro et al. demonstrate that chronic pharmacological stimulation of p53 with a low dose of doxorubicin improves liver injury in different models of diet-induced steatosis and steatohepatitis through stimulation of fatty acid oxidation and decrease of lipogenesis, inflammation, and ER stress.

Abstract | PDF



The EndoC-βH1 cell line is a valid model of human beta cellsThe insulin producing beta cell is central in the etiology of human diabetes as beta cell failure is the major determining factor for progression from impaired glucose tolerance to overt diabetes. New potent antidiabetic drugs are needed, and analyses using human beta cells are a necessity as the majority of in vitro research so far has been done on islets and cell lines from rodents with only sporadic follow-up using human islets. Tsonkova and colleagues performed a thorough phenotypic validation of the human beta cell line EndoC-βH1. They conclude that it is a valid cell line model of human beta cells that can be successfully used as a screening platform for early drug discovery.

Abstract | PDF



Androgen receptor overexpression in prostate cancer in type 2 diabetes In contrast to numerous other malignancies, the incidence of prostate cancer is not increased in case of concurrent type 2 diabetes mellitus. Nevertheless, prostate cancer survival is clearly reduced when type 2 diabetes is present. One of the crucial drivers for prostate cell growth is androgen signaling. To better understand why prostate cancer survival is reduced in type 2 diabetes, Lutz et al. performed gene expression analysis of key proteins involved in androgen signaling and steroid modulators thereof using prostate tissue samples of men with and without diabetes. They report enhanced expression of androgen receptor in prostate cancer and stronger activation of androgen signaling in men with type 2 diabetes.

Abstract | PDF



Adiponectin release and insulin receptor targeting share endosomal trafficking routes The adipose tissue releases a variety of bioactive molecules into the circulation, such as adipokines, cytokines, and lipid metabolites. The precise intracellular trafficking pathways and particular molecular components mediating the targeting and release of bioactive molecules are still largely elusive. To explore the impact of ADP-ribosylation factor related protein 1 (ARFRP1) as part of the vesicle trafficking machinery on the secretory capacity of mature adipocytes, Rödiger and colleagues generated a mouse model with an inducible fat-specific disruption of Arfrp1. They demonstrate that the loss of Arfrp1 from differentiated adipocytes diminishes adiponectin secretion and plasma membrane localization of the insulin receptor, which is associated with detrimental effects on adipocyte metabolism and glucose homeostasis.

Abstract | PDF



Cadm2 regulates body weight and energy homeostasisCadm2 is an immunoglobulin domain-containing adhesion protein that mediates the assembly of pre-synaptic specializations in neurons in the brain to direct interactions across the nascent and mature synaptic cleft. Recently, it has been shown that the closely related Cadm1 regulates body weight and energy homeostasis via its expression within the hippocampus and hypothalamus. Here, Yan and colleagues illustrate that loss of Cadm2 protects mice from obesity and hyperglycemia by regulating locomotor activity and thermogenesis, further underlining the functional role of this gene family in systemic energy homeostasis via the brain.

Abstract | PDF



Targeting erythropoietin protects against proteinuria Erythropoietin (EPO) is a glycoprotein hormone traditionally considered essential for erythropoiesis. Recent studies revealed a relationship between EPO and the progression of diabetic complications, such as diabetic nephropathy (DN), a common diabetes microvascular complication. DN ranks first as the cause of end-stage renal disease (ESRD). She et al. provide evidence that EPO is a clinically-protective factor in the progression of diabetic complications. They identify EPO as an active renal antiapoptotic factor, protecting kidney from hyperglycemia-induced damage and proteinuria in an EPO receptor-dependent manner both in zebrafish and in type 2 diabetic patients.

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.



Jean-Sébastien Annicotte
Lille University, 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.molmetab.com/user/alerts
Conferences & Events
Feb. 25 −
March 1
2018
Reducing Diabetes-Related End-Organ Injury
Santa Fe, USA
Feb. 25 −
March 1
2018
Aging, Inflammation and Immunity
Austin, USA
March
4 − 8
2018
Manipulation of the Gut Microbiota for Met. Health
Banff, Canada
March
4 − 8
2018
Microbiome, Host Resistance and Disease
Banff, Canada
June
24 − 26
2018
Cell: Translational Immunometabolism
Basel, Switzerland
Media Coverage
Supported by