Featured Articles

Volume 6 | No. 10 | October 2017

Lorcaserin improves glycemic control via a melanocortin neurocircuit The obesity medication lorcaserin, a 5-hydroxytryptamine 2C receptor (5-HT2CR) agonist, improves glycemic control in association with weight loss in obese patients with type 2 diabetes. Burke and colleagues find that lorcaserin improves glycemic control in mouse models of T2D without altering energy balance or body weight. They reveal brain pro-opiomelanocortin (POMC) peptides as a necessary and sufficient neurochemical mediator of lorcaserin’s glucoregulatory effects.

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Mitochondrial uncoupling in the melanocortin system differentially regulates NPY and POMC neuronsBy using the original weight-loss inducing drug 2,4-dinitrophenol (DNP), Michael et al. demonstrate that chemical uncoupling of the melanocortin system promotes increased energy expenditure and weight loss through differentially regulating excitability of orexigenic neuropeptide Y (NPY) and anorexigenic proopiomelanocortin (POMC) neurons. DNP is known to cross the blood-brain-barrier, and the data presented support a key and novel mechanism by which chemical uncoupling agents targeting the melanocortin system, such as DNP, may offer new insight for future approaches to tackle obesity.

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Peripheral cannabinoid-1 receptor blockade restores hypothalamic leptin signalingAccumulating evidence supports the pathogenic role of an overactive endocannabinoid/CB1 receptor (CB1R) system in obesity and the metabolic syndrome. Tam et al. find that peripheral CB1R blockade in mice with diet-induced obesity restores sensitivity to endogenous leptin, which elicits hypophagia via the re-activation of melanocortin signaling in the arcuate nucleus.

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Dwarfism and insulin resistance in male offspring caused by α1-adrenergic antagonism during pregnancyUsing the α1-adrenergic specific antagonist prazosin, Oelkrug et al. test the long-term consequences of maternal α1-blockade in pregnancy for the endocrine and metabolic phenotype of the adult offspring. They demonstrate that maternal α1-adrenergic blockade can constitute an epigenetic cause for dwarfism and insulin resistance.

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ANGPTL8 promotes the ability of ANGPTL3 to bind and inhibit lipoprotein lipaseLipoprotein lipase (LPL) activity is critically regulated by several interacting proteins, including angiopoietin-like 3 (ANGPTL3). ANGPTL3 is thought to regulate triglyceride clearance by inhibiting LPL. The data of Chi and colleagues indicate that angiopoietin-like protein 8 (ANGPTL8) binds to ANGPTL3 and that this complex is necessary for ANGPTL3 to efficiently bind and inhibit LPL. Their studies provide mechanistic insight into the interactions of ANGPTL3 and ANGPTL8, providing critical information that could be used for development of therapeutics targeting ANGPTL8 or the interactions between ANGPTL8 and ANGPTL3.

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Adipocyte glucocorticoid receptor is important in lipolysis and insulin resistanceGlucocorticoids are produced by the adrenal cortex under the control of the hypothalamus and pituitary gland and have been implicated in multiple aspects of adipose tissue biology. Shen, Roh, et al. demonstrate that adipocyte glucocorticoid receptor (GR) participates in lipolysis but does not contribute to altered glucose homeostasis or insulin resistance in the setting of diet-induced obesity. Administration of dexamethasone, however, causes insulin resistance that depends upon the presence of GR in adipocytes.

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Lipid nanoparticle delivery of glucagon receptor siRNA improves glucose homeostasisLipid nanoparticle (LNP) delivery of small interfering RNA (siRNA) effectively targets the liver and is in clinical trials for the treatment of various diseases. Neumann and colleagues compare the effectiveness of glucagon receptor (Gcgr)-siRNA delivered via LNPs to leptin in two mouse models of diabetes. Their results indicate that Gcgr siRNA encapsulated in LNPs is an effective therapy in mouse models of type 1 and type 2 diabetes.

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Gαs regulates Glucagon-Like Peptide 1 Receptor-mediated cyclic AMP generationAfter activation, G protein coupled receptors associate with heterotrimeric G proteins at the plasma membrane to initiate second messenger signaling. Girada and colleagues suggest that cyclic AMP generation by internalized Glucagon-Like Peptide-1 Receptor takes place at the Rab5 endosomal compartment, where prolonged association of Galpha S subunit (Gαs) with the internalized receptor following orthosteric activation contributes to the sustained endosomal cyclic AMP generation that likely supports glucose stimulated insulin secretion in pancreatic beta cells.

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Macrophage alternative activation confers protection against lipotoxicity-induced cell deathIn lean individuals, adipose tissue macrophages (ATMs) have an alternatively activated (M2) phenotype that limits inflammation and sustains homeostasis. Dai et al. find that the signal transducer and activator of transcription 6 (Stat6) - peroxisome proliferator-activated receptor (Ppar) axis plays an important role in protecting macrophages against lipotoxicity-induced cellular dysfunction. This is mediated by transcriptional regulation of cell death/pro-survival genes. Dysregulation of M2 signaling increases susceptibility to palmitic acid-induced cell death, which contributes to the initiation of metabolic inflammation in white adipose tissue.

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Brown adipocytes can display a mammary basal myoepithelial cell phenotype in vivoLi, Li et al. demonstrate that classic brown adipocytes, and probably beige/brite adipocytes, are capable of showing a mammary basal myoepithelium phenotype but not a luminal secretory phenotype in vivo. They show that if cells that express uncoupling protein 1 are killed during lactation, the growth of offspring is reduced, suggesting the conversion of brown/beige adipocytes to mammary cells is functionally significant, even though numerically small.

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Cdkal1 regulates mitochondrial function in adipose tissuePolymorphic variants within the CDKAL1 locus are strongly associated with increased risk of developing type 2 diabetes by genome wide association studies (GWAS) and dozens of replication studies in diverse populations. Palmer and colleagues investigate the biological role of Cdkal1 in adipose tissue in vivo using a mouse model with adipocyte-specific knockout (A-KO) of Cdkal1. Their findings suggest that the type 2 diabetes GWAS candidate gene Cdkal1 has a functional role in regulating mitochondrial function in vivo.

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Activated macrophages control human adipocyte mitochondrial bioenergetics Recent data from mouse studies suggest that macrophages are modifiers of adipocyte energy metabolism and mitochondrial function. Keuper et al. report a direct action of IL10/TGFβ-activated macrophages on decreased mitochondrial gene expression and function of human white adipocytes, which is reflected in whole human white adipose tissue samples by the association of mitochondrial complex III (UQCRC2) and complex I (NDUFB8) gene expression levels with low CD40:CD163 ratio. Their data suggest that human white adipocytes in different inflammatory microenvironments demonstrate differential metabolic profiles.

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Inhibition of cholinergic potentiation of insulin secretion: Protection by casein kinase 2 inhibitorAlthough cholinergic regulation of insulin release has been known for many years, the mechanisms by which acetylcholine stimulates insulin secretion are still debated. Doliba et al. show for the first time glucolipotoxic impairments of cholinergic potentiation of glucose-stimulated insulin secretion in isolated mouse and human islets. An inhibitor of casein kinase 2 (CK2) protects the glucose dependent acetylcholine potentiation of insulin secretion against glucolipotoxicity. The results strengthen the view that phosphorylation of β-cell M3-muscarinic receptors by CK2 is of pathophysiological and potential clinical relevance.

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Elevated hepatic DPP4 activity promotes insulin resistance and non-alcoholic fatty liver diseaseDipeptidyl peptidase 4 (DPP4) is a serine protease that cleaves a variety of substrates including incretin hormones, chemokines, growth factors, and neuropeptides. Baumeier and colleagues analyze the DPP4 activity in plasma of healthy subjects and patients with non-alcoholic fatty liver disease. They elucidate the effect of hepatocyte-specific Dpp4 overexpression on the development of insulin resistance and liver steatosis in mice under obese conditions.

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Intestinal SIRT3 overexpression in mice improves whole body glucose homeostasisThe most efficient treatment for type 2 diabetes and morbid obesity so far is surgical intervention, such as Roux-en-Y gastric bypass. Ramachandran et al. find that on high-fat diet Sirtuin 3 (SIRT3) overexpression protects the mice from developing glucose intolerance and insulin resistance. They suggest that an increase in the metabolic flux of enterocytes is sufficient to improve whole body glucose homeostasis in diet-induced obesity, independent of body weight, body composition, or fat distribution.

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Reduced renal sympathetic nerve activity contributes to improved glucose tolerance in Pomc knockout miceHypothalamic pro-opiomelanocortin (POMC) is a precursor polypeptide that is synthesized in the pituitary gland as well as the arcuate nucleus (Arc) of the hypothalamus. Chhabra et al. report that ArcPOMC is essential in maintaining basal renal sympathetic nerve activity (RSNA) in mice. They also demonstrate the critical function of RSNA in glucose reabsorption. Reduced RSNA in ArcPomc-/- mice as well as renal denervation in wildtype and diabetic db/db mice improves their glucose tolerance by elevating glycosuria via reduced proximal tubular GLUT2 levels. Elevated glycosuria is likely a mechanism for improving glucose tolerance after renal denervation in drug resistant hypertensive patients.

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Angiopoietin-like protein 4 is an exercise-induced hepatokine, regulated by glucagon and cAMPAngiopoietin-like protein-4 (ANGPTL4) is a secreted plasma protein expressed in adipose tissue and liver. Ingerslev, Hansen, and colleagues show that ANGPTL4 is released from the hepato-splanchnic bed but not the leg during exercise. The glucagon-to-insulin ratio is identified as an important regulator of ANGPTL4 plasma in humans, probably involving cAMP-PKA-driven hepatic ANGPTL4 expression.

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Single-cell RNA-sequencing reveals a distinct population of proglucagon-expressing cellsEnteroendocrine preproglucagon-expressing PPG-cells secrete the gut hormones glucagon-like peptide 1 (GLP-1) and peptideYY (PYY) and are important regulators of glucose metabolism. Glass et al. find that upper small intestinal PPG-cells can be separated into at least 3 major clusters that exhibit differential expression of Gcg, Cck, Pyy, Gip, and Tph1. Receptor and ion channel expression profiles differ across the clusters, suggesting that these PPG-cell sub-populations likely contribute to the differential responsiveness of gut hormones to nutritional and local signals.

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Point mutation of Ffar1 abrogates fatty acid-dependent insulin secretionFree fatty acid receptor-1 (FFAR1) promotes long chain fatty acid-mediated augmentation of glucose-induced insulin secretion. Sabrautzki, Kaiser, Przemeck, and colleagues introduce a mouse model carrying the point mutation R258W in Ffar1, which abolishes the stimulation of insulin secretion in response to long chain fatty acids. They find that high fat diet feeding induces glucose intolerance in wild-type mice while mutant mice with dysfunctional FFAR1 remain glucose tolerant.

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Bidirectional manipulation of gene expression in adipocytes using CRISPRa and siRNAFunctional investigation of novel gene/protein targets associated with adipocyte differentiation or function heavily relies on efficient tools to manipulate gene expression in adipocytes in vitro. Lundh and colleagues report a detailed in vitro protocol using easily accessible tools to manipulate gene expression in adipocytes. The major advantage of this model is that once the core components of the CRISPRa SAM system are established, it is easy to use and allows for concurrent expression and silencing of virtually any gene of interest - either alone or in combination - in both pre- and mature adipocytes.

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Evaluation of a melanocortin-4 receptor (MC4R) agonist (Setmelanotide) in MC4R deficiencyThe Melanocortin 4 receptor (MC4R), which is a seven-transmembrane domain G-protein coupled receptor (GPCR), has been considered as a potential drug target for the treatment of obesity. Setmelanotide is a synthetic cyclic peptide that binds to human MC4R with high affinity. Collet, Dubern, Mokrosinski, Connors, et al. report the comprehensive classification of all known human mutations in MC4R and show that individuals with MC4R deficiency as well as those expressing the wild type MC4R lose weight following Setmelanotide treatment.

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Neonatal pancreatic pericytes support β-cell proliferationβ-cell proliferation rates decline with age and are significantly higher during the neonatal period than during adulthood. Epshtein and colleagues find that neonatal pancreatic pericytes secrete factors that promote β-cell proliferation. This finding could aid in developing improved protocols for β-cell expansion as a potential cure for diabetes.

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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.



Brandon L Roberts, Baylin Bennett
Oregon National Primate Research Center, Beaverton, Oregon, USA
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