Editorial:FGF21 as a therapeutic target for obesity and insulin resistance: from rodent models to humans

Obesity is a global pandemic that requires the urgent development of therapies and prevention strategies. To define new pharmacologic therapies or nutritional approaches it is mandatory to find new targets. Fibroblast growth factor 21 (FGF21) is considered a potential target to treat obesity, due to its favorable metabolic activity, signalling pathways and regulatory mechanisms. It is well-documented that FGF21 is induced by a wide range of biological stress conditions and a key signal that communicates and coordinates the physiologic response to restore the metabolic homeostasis in different tissues (1). FGF21 is elevated in pathological conditions such as obesity, insulin resistance, or fatty liver disease where an impairment of its signalling has been described (2). On the other hand, FGF21 analogues tested in overweight/obese patients with type 2 diabetes or NAFLD/NASH can reduce dyslipidaemia and steatosis, but improvements in glycaemic control or body weight were not globally restored (3). This suggests that pharmacologic effects of FGF21 are different from its physiological effects. In this Research Topic “FGF21 as a therapeutic target for obesity and insulin resistance: from rodent models to humans”, we include publications related to new advances involving FGF21, its signalling pathway, and its potential as a target to treat obesityinfo:eu-repo/semantics/publishedVersio

Supporting self-regulated learning

Self-regulated learning (SRL) competences are crucial for lifelong learning. Their cultivation requires the right balance between freedom and guidance during the learning processes. Current learning systems and approaches, such as personal learning environments, give overwhelming freedom, but also let weak learners alone. Other systems, such as learning management systems or adaptive systems, tend to institutionalise learners too much, which does not support the development of SRL competences. This chapter presents possibilities and approaches to support SRL by the use of technology. After discussing the theoretical background of SRL and related technologies, a formal framework is presented that describes the SRL process, related competences, and guidelines. Furthermore, a variety of methods is presented, how learners can be supported to learn in a self-regulated way

IL-17 signaling accelerates the progression of nonalcoholic fatty liver disease in mice

Inflammation plays a central pathogenic role in the pernicious metabolic and end-organ sequelae of obesity. Among these sequelae, nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease in the developed world. The twinned observations that obesity is associated with increased activation of the interleukin (IL)-17 axis and that this axis can regulate liver damage in diverse contexts prompted us to address the role of IL-17RA signaling in the progression of NAFLD. We further examined whether microbe-driven IL-17A regulated NAFLD development and progression. We show here that IL-17RA−/− mice respond to high-fat diet stress with significantly greater weight gain, visceral adiposity, and hepatic steatosis than wild-type controls. However, obesity-driven lipid accumulation was uncoupled from its end-organ consequences in IL-17RA−/− mice, which exhibited decreased steatohepatitis, nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase enzyme expression, and hepatocellular damage. Neutralization of IL-17A significantly reduced obesity-driven hepatocellular damage in wild-type mice. Further, colonization of mice with segmented filamentous bacteria (SFB), a commensal that induces IL-17A production, exacerbated obesity-induced hepatocellular damage. In contrast, SFB depletion protected from obesity-induced hepatocellular damage. Conclusion: These data indicate that obesity-driven activation of the IL-17 axis is central to the development and progression of NAFLD to steatohepatitis and identify the IL-17 pathway as a novel therapeutic target in this condition. (Hepatology 2014;59:1830–1839

Insulin Concentration Modulates Hepatic Lipid Accumulation in Mice in Part via Transcriptional Regulation of Fatty Acid Transport Proteins

Fatty liver disease (FLD) is commonly associated with insulin resistance and obesity, but interestingly it is also observed at low insulin states, such as prolonged fasting. Thus, we asked whether insulin is an independent modulator of hepatic lipid accumulation.In mice we induced, hypo- and hyperinsulinemia associated FLD by diet induced obesity and streptozotocin treatment, respectively. The mechanism of free fatty acid induced steatosis was studied in cell culture with mouse liver cells under different insulin concentrations, pharmacological phosphoinositol-3-kinase (PI3K) inhibition and siRNA targeted gene knock-down. We found with in vivo and in vitro models that lipid storage is increased, as expected, in both hypo- and hyperinsulinemic states, and that it is mediated by signaling through either insulin receptor substrate (IRS) 1 or 2. As previously reported, IRS-1 was up-regulated at high insulin concentrations, while IRS-2 was increased at low levels of insulin concentration. Relative increase in either of these insulin substrates, was associated with an increase in liver-specific fatty acid transport proteins (FATP) 2&5, and increased lipid storage. Furthermore, utilizing pharmacological PI3K inhibition we found that the IRS-PI3K pathway was necessary for lipogenesis, while FATP responses were mediated via IRS signaling. Data from additional siRNA experiments showed that knock-down of IRSs impacted FATP levels.States of perturbed insulin signaling (low-insulin or high-insulin) both lead to increased hepatic lipid storage via FATP and IRS signaling. These novel findings offer a common mechanism of FLD pathogenesis in states of both inadequate (prolonged fasting) and ineffective (obesity) insulin signaling

Modulation of hepatic inflammation and energy-sensing pathways in the rat liver by high-fructose diet and chronic stress

Purpose High-fructose consumption and chronic stress are both associated with metabolic inflammation and insulin resistance. Recently, disturbed activity of energy sensor AMP-activated protein kinase (AMPK) was recognized as mediator between nutrient-induced stress and inflammation. Thus, we analyzed the effects of high-fructose diet, alone or in combination with chronic stress, on glucose homeostasis, inflammation and expression of energy sensing proteins in the rat liver. Methods In male Wistar rats exposed to 9-week 20% fructose diet and/or 4-week chronic unpredictable stress we measured plasma and hepatic corticosterone level, indicators of glucose homeostasis and lipid metabolism, hepatic inflammation (pro- and anti-inflammatory cytokine levels, Toll-like receptor 4, NLRP3, activation of NF kappa B, JNK and ERK pathways) and levels of energy-sensing proteins AMPK, SIRT1 and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha). Results High-fructose diet led to glucose intolerance, activation of NF kappa B and JNK pathways and increased intrahepatic IL-1 beta, TNF alpha and inhibitory phosphorylation of insulin receptor substrate 1 on Ser(307). It also decreased phospho-AMPK/AMPK ratio and increased SIRT1 expression. Stress alone increased plasma and hepatic corticosterone but did not influence glucose tolerance, nor hepatic inflammatory or energy-sensing proteins. After the combined treatment, hepatic corticosterone was increased, glucose tolerance remained preserved, while hepatic inflammation was partially prevented despite decreased AMPK activity. Conclusion High-fructose diet resulted in glucose intolerance, hepatic inflammation, decreased AMPK activity and reduced insulin sensitivity. Chronic stress alone did not exert such effects, but when applied together with high-fructose diet it could partially prevent fructose-induced inflammation, presumably due to increased hepatic glucocorticoids

Risk factors for human cutaneous anthrax outbreaks in the hot-spot districts of Northern Tanzania: an unmatched case control study

Royal Society of Open Science, 2018; 5: 180479Bacillus anthracis is an aerobic, Gram-positive and sporeforming bacterium, which causes anthrax in herbivores. Humans get infected after coming into contact with infected animals’ products. An unmatched case–control study was conducted to identify the importance of demographic, biological and/or behavioural factors associated with human cutaneous anthrax outbreaks in the hotspot areas of Northern Tanzania. A semi-structured questionnaire was administered to both cases and controls. The age range of participants was 1–80 years with a median age of 32 years. In the younger group (1–20 years), the odds of being infected were 25 times higher in the exposed group compared to the unexposed group (OR¼ 25, 95% CI ¼ 1.5–410). By contrast, the odds of exposure in the old group ( 20 years) were three times lower in the exposed group compared to the unexposed group (OR ¼ 3.2, 95% CI ¼ 1.28–8.00). Demographic characteristics, sleeping on animal’s skins, contacting with infected carcasses through skinning and butchering, and not having formal education were linked to exposure for anthrax infection. Hence, a One Health approach is inevitable for the prevention and control of anthrax outbreaks in the hotspot areas of Northern Tanzania.The World Ban

Preservation of allograft bone using a glycerol solution: a compilation of original preclinical research

Abstract Background Bone allografts are used in many orthopedic procedures to provide structural stability as well as an osteoconductive matrix for bone ingrowth and fusion. Traditionally, bone allografts have been preserved by either freezing or freeze-drying. Each of these preservation methods has some disadvantages: Frozen grafts require special shipping and storage conditions, and freeze-drying requires special lyophilization equipment and procedures that may impact biomechanical integrity. This report describes an alternate type of preservation using glycerol, which allows storage of fully-hydrated tissues at ambient temperature avoiding the potential complications from freeze-drying. Methods In the in vitro three-point bend test, cortical bone was processed and frozen, freeze-dried, or treated with glycerol-based preservation (GBP). Load was applied to each graft at a rate of 2.71 mm/min. The flexural strain, flexural strength, and flexural modulus were then calculated. In the in vitro axial compression test, iliac crest wedges, fibular segments, and Cloward dowels were processed and either freeze-dried or GBP treated. The compressive strength of the grafts were tested at time zero and after real time aging of 1, 4, and 5 years. In the in vivo rat calvarial defect assessment, freeze-dried, frozen, and GBP bone implants were compared after being implanted into a critical sized defect. Samples underwent histological and biomechanical evaluation. Results Bone grafts subjected to GBP were found to be at least biomechanically equivalent to frozen bone while also being significantly less brittle than freeze-dried bone. GBP-preserved bone demonstrated significantly greater compressive strength than freeze-dried at multiple time points. Preclinical research performed in calvaric defect models found that GBP-preserved bone had similar osteoconductivity and biocompatibility to frozen and freeze-dried samples. Conclusion Preclinical research demonstrated that glycerol–preservation of bone yields a material that maintains biomechanical strength while eliminating the need for extensive rehydration or thaw periods if used clinically. Additionally, in vivo evidence suggests no negative impact of glycerol-preservation on the ability of bone grafts to successfully participate in new bone formation and fusion

Risk factors for human cutaneous anthrax outbreaks in the hot-spot districts of Northern Tanzania: an unmatched case control study

Royal Society of Open Science, 2018; 5: 180479Bacillus anthracis is an aerobic, Gram-positive and sporeforming bacterium, which causes anthrax in herbivores. Humans get infected after coming into contact with infected animals’ products. An unmatched case–control study was conducted to identify the importance of demographic, biological and/or behavioural factors associated with human cutaneous anthrax outbreaks in the hotspot areas of Northern Tanzania. A semi-structured questionnaire was administered to both cases and controls. The age range of participants was 1–80 years with a median age of 32 years. In the younger group (1–20 years), the odds of being infected were 25 times higher in the exposed group compared to the unexposed group (OR¼ 25, 95% CI ¼ 1.5–410). By contrast, the odds of exposure in the old group ( 20 years) were three times lower in the exposed group compared to the unexposed group (OR ¼ 3.2, 95% CI ¼ 1.28–8.00). Demographic characteristics, sleeping on animal’s skins, contacting with infected carcasses through skinning and butchering, and not having formal education were linked to exposure for anthrax infection. Hence, a One Health approach is inevitable for the prevention and control of anthrax outbreaks in the hotspot areas of Northern Tanzania.The World Ban