Publications (3)10 Total impact
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Article: Acute inhibition of central c-Jun N-terminal kinase restores hypothalamic insulin signalling and alleviates glucose intolerance in diabetic mice.
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ABSTRACT: The hypothalamus has been identified to be a main insulin target tissue for regulating normal body weight and glucose metabolism. Recent observations suggest that c- Jun-N-terminal kinase (JNK)-signalling plays a crucial role in the development of obesity and insulin resistance since neuronal JNK-1 ablation in the mouse prevented high fat diet-induced obesity (DIO) and increased energy expenditure as well as insulin sensitivity. Here we investigated whether central JNK inhibition is associated with sensitization of hypothalamic insulin signalling in mice fed a high fat diet for three weeks and in leptin-deficient mice. We determined whether intracerebroventricular (ICV) injection of a pharmacological JNK inhibitor (SP600125) improves impaired glucose homeostasis. By immunohistochemistry, we first observed that JNK activity was increased in the ARC and the VMH in both mouse models, relative to normo-glycemic controls. This suggests that up-regulation of JNK in these regions is associated with glucose intolerance and obesity, independent of leptin levels. Acute ICV injection of SP600125 ameliorates glucose tolerance within 30 minutes in both leptin-deficient and DIO mice. Given the acute nature of ICV injections, these effects cannot be attributed to changes in food intake or energy balance. In a hypothalamic cell line, and in the ARC and VMH of leptin-deficient mice JNK inhibition by SP600125 consistently improved impaired insulin signalling. This was determined by a reduction of phospho-insulin receptor substrate-1 [IRS-1(Ser612)] protein in a hypothalamic cell line and a decline in the number of pIRS-1(Ser612) immunoreactive cells in the ARC and VMH. Serine 612 phosphorylation of IRS-1 is regarded to negatively regulate insulin signalling. In leptin-deficient mice, in both nuclei, central inhibition of JNK increased the number of cells immunoreactive for phospho-AKT (Ser473) and phospho-GSK-3β (Ser9), which are important markers of insulin signalling. Collectively our data suggest that acute inhibition of central JNK improves impaired glucose homeostasis and is associated with sensitization of hypothalamic insulin signalling. © 2013 British Society for Neuroendocrinology.Journal of Neuroendocrinology 01/2013; · 3.14 Impact Factor -
Article: Hypothalamic glycogen synthase kinase 3β has a central role in the regulation of food intake and glucose metabolism.
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ABSTRACT: GSK3β (glycogen synthase kinase 3β) is a ubiquitous kinase that plays a key role in multiple intracellular signalling pathways, and increased GSK3β activity is implicated in disorders ranging from cancer to Alzheimer's disease. In the present study, we provide the first evidence of increased hypothalamic signalling via GSK3β in leptin-deficient Lepob/ob mice and show that intracerebroventricular injection of a GSK3β inhibitor acutely improves glucose tolerance in these mice. The beneficial effect of the GSK3β inhibitor was dependent on hypothalamic signalling via PI3K (phosphoinositide 3-kinase), a key intracellular mediator of both leptin and insulin action. Conversely, neuron-specific overexpression of GSK3β in the mediobasal hypothalamus exacerbated the hyperphagia, obesity and impairment of glucose tolerance induced by a high-fat diet, while having little effect in controls fed standard chow. These results demonstrate that increased hypothalamic GSK3β signalling contributes to deleterious effects of leptin deficiency and exacerbates high-fat diet-induced weight gain and glucose intolerance.Biochemical Journal 08/2012; 447(1):175-84. · 4.90 Impact Factor -
Article: Effect of central and peripheral leucine on energy metabolism in the Djungarian hamster (Phodopus sungorus).
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ABSTRACT: Branched-chain amino acids, particularly leucine, are thought to activate nutrient sensing pathways in the hypothalamus that regulate food intake and energy homeostasis. In the light of recent controversial findings of leucine's effect on energy homeostasis further clarification of the metabolic impact of dietary leucine supplementation is required. We examined the pharmacological and dietary effects of leucine on energy metabolism in the Djungarian hamster (Phodopus sungorus), a well-established model for studies of alterations in leptin sensitivity and energy metabolism. We acutely administered leucine into the lateral ventricle (1.1 μg) of hamsters to characterize whether leucine exhibits anorexigenic properties in this species as has been described in other rodents. Next the catabolic effect of dietary administered leucine via supplemented rodent diet (15 % leucine), drinking water (17 g/L leucine) and oral gavages (10 mg/day); as well as the effect of subcutaneously (0.1 and 3 mg/day) and intraperitoneally (0.1, 3 and 6 mg/day) injected leucine which avoids the gastrointestinal-track was analyzed. Centrally administered leucine reduced 24 h food intake (by 32 %) and body weight. Both parameters were also reduced in hamsters with leucine supplemented diet, but this catabolic response was based on a pronounced taste aversion to the leucine-diet. In all other experiments, dietary leucine and peripheral injections of leucine had no effect on food intake, body weight and basal blood glucose levels. Our data suggest that in the Djungarian hamster dietary leucine fails to exhibit catabolic effects that would override the evolutionary conserved adaptations of the species which is critical for its survival.Journal of Comparative Physiology B 07/2012; · 1.97 Impact Factor
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Institutions
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2012–2013
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Philipps-Universität Marburg
- Fachbereich Biologie
Marburg an der Lahn, Hesse, Germany
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