Featured Articles

Volume 6 | No. 3 | March 2017

Glucagon-CreER Mouse Line Generated by CRISPR-Cas9Pancreatic α-cells secrete glucagon to increase plasma glucose levels in times of fasting and in opposition to insulin action. α-cell dysfunction contributes to dysglycemia in type 1 and type 2 diabetes mellitus. Here, Ackermann et al. describe a novel Glucagon-CreERT2 gene-addition mouse line that was generated via CRISPR-Cas9 assisted gene targeting, does not disrupt glucagon expression from the targeted allele, and recapitulates endogenous glucagon and glucagon-like peptide 1 expression. This will be a useful tool to perform specific genetic manipulations in murine α-cells. This system allows for time-controlled and cell type-specific gene ablation, gene mutation, or gene activation, depending on the design of the loxP-modified gene of interest.

Abstract | PDF



Glucagon-like peptide-2 controls intestinal amino acid transport Enteroendocrine cells (EECs) have evolved in part to control the efficiency of nutrient absorption through secretion of specialized peptide hormones. Lee and colleagues examined whether and how acute glucagon-like peptide 2 (GLP-2) signaling augments intestinal amino acid (AA) absorption in mice. They identified candidate AA transporters transducing GLP-2 action and demonstrate that loss of GLP-2 receptor signaling in Glp2r-/- mice leads to reduced AA absorption. They show that GLP-2 robustly activates the mTORC1 pathway in the murine small intestine. Collectively, these findings demonstrate that GLP-2 controls energy and AA absorption through pathways engaging AA uptake, linking L cell GLP-2 to physiological mechanisms controlling intestinal AA sensing and absorption in vivo.

Abstract | PDF



Bezafibrate ameliorates diabetes in TallyHo mice Bezafibrate (BEZ) is a member of the fibrate group that possesses the unique feature of activating all known peroxisome proliferator-activated receptors (PPARs). PPARs are transcription factors regulating crucial genes involved in fatty acid metabolism and insulin sensitivity. To study whether BEZ could also ameliorate conditions associated with fatty liver and type 2 diabetes, Franko et al. used the TallyHo mouse model, which is characterized by elevated plasma lipid levels and body weight, high fat mass, steatosis, and intermediate to severe diabetes. Their data demonstrated that BEZ ameliorates impaired glucose metabolism in TallyHo mice via decreased hepatic fat content and suppressed hepatic gluconeogenesis in association with increased mitochondrial mass and elevated metabolic flexibility.

Abstract | PDF



The Roles of Adiponectin-Induced Ceramidase Signaling in Lipid and Glucose HomeostasisAdiponectin is capable of inducing ceramidase activity through its receptors AdipoR1 and AdipoR2. To gain further insights into the local physiological consequences of adiponectin and AdipoR-induced ceramidase activation, Holland, Xia, and colleagues have generated models that inducibly express AdipoR1 or AdipoR2. They used these models to determine which adiponectin receptor may have the most beneficial effects on glucose tolerance. Their data suggest that the lowering of ceramides is a critical player in adiponectin-induced improvements in non-alcoholic fatty liver disease and hepatic insulin resistance in mice with diet-induced obesity.

Abstract | PDF



Effects of a natriuretic peptide in the regulation of adipose tissue and metabolismNatriuretic peptides (NPs) have metabolic effects like promotion of lipolysis in human adipocytes. Importantly, obesity, diabetes, and the metabolic syndrome are all characterized by reduced levels of circulating NP. In the present study, Glöde and colleagues used an optimized designer NP (CD-NP, or Cenderitide) and analyzed the effect of long-term CD-NP in the context of diet-induced obesity. Their findings indicate that the positive effects of NPs on metabolism are only transient and that long-term treatment with NPs might even exacerbate obesity in overweight or obese subjects when accompanied with excessive calorie intake.

Abstract | PDF



Attenuated secretion of GIP does not alleviate hyperphagic obesity and insulin resistance Glucose-dependent insulinotropic polypeptide (GIP) promotes adipogenesis and lipid accumulation in adipocytes. Therefore, there has been some debate over whether GIP agonists used to improve glucose homeostasis may increase adiposity while GIP antagonists could promote weight loss. In the present study, Shimazu-Kuwahara et al. examined whether complete ablation of GIP production could reduce weight gain in the absence of the adipocyte hormone leptin, a condition that results in extreme hyperphagia, obesity, hyperinsulinemia, and insulin resistance, in both mice and humans. They found that Lepob/ob mice became equally obese and insulin resistant whether or not GIP was present, suggesting that GIP antagonism is unlikely to be effective at improving metabolism in extreme obesity associated with defective leptin action.

Abstract | PDF



Relevance of PCSK1 variants for childhood obesity and glucose metabolismVariants in the proprotein convertase subtilisin kexin type 1 (PCSK1) gene encoding proprotein convertase 1/3 (PC1/3) contribute to polygenic obesity risk. Löffler, Behrendt, and colleagues identify two new variants and investigate their clinical relevance together with eight known variants with regard to obesity and glucose metabolism. Their findings of a novel heterozygous loss of function PCSK1 variant in a subject with severe early onset obesity, polycystic ovary syndrome, hypertension, and increased proinsulin levels, and associations of PCSK1 single nucleotide polymorphisms with obesity and insulin resistance in a large pediatric cohort, support the role of PCSK1 variants contributing to obesity in children.

Abstract | PDF



Cholinergic neurons in the hypothalamus regulate food intakeDespite evidence for the physiological roles of the cholinoceptive system in the control of food intake, the origin of cholinergic neurons remains elusive. Jeong et al. examined whether stimulation of the cholingeric pathway from the dorsomedial hypothalamus (DMH) to the arcuate nucleus (ARC) is able to regulate food intake. They found that increased cholinergic neuron activity promoted food intake. Direct stimulation of cholinergic axon terminals in the ARC also increased food intake. This orexigenic effect was completely abolished by a muscarinic receptor antagonist. Hence, the DMH-ARC pathway may play a key role in regulating energy intake.

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.



Ursula Neumann
University of British Columbia, Vancouver, Canada
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
Media Coverage
Supported by