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Articles by Per Bo Jensen in JoVE
JoVE General
الطاقة البيولوجية التجربة الملف باستخدام الخلايا Myoblast C2C12
1Buck Institute for Age Research, Novato, CA, 2Department of Pathology, Center for Free Radical Biology, University of Alabama at Birmingham - UAB, 3Seahorse Bioscience, North Billerica, MA
وتقدم وصفا لطريقة لتوصيف وظيفة الميتوكوندريا في الخلايا. ملف الميتوكوندريا ولدت يوفر أربعة معلمات وظيفة الميتوكوندريا التي يمكن قياسها في تجربة واحدة : القاعدية معدل التنفس ، والتنفس ATP المرتبطة ، تسرب بروتون ، وقدرة احتياطية.
Other articles by Per Bo Jensen on PubMed
Ups and Downs for Neuropeptides in Body Weight Homeostasis: Pharmacological Potential of Cocaine Amphetamine Regulated Transcript and Pre-proglucagon-derived Peptides
Although most humans experience an underlying upwards drift of the body-weight set-point, body weight appears tightly regulated throughout life. The present review describes the structural basis of the adipostat and hypothesise, which components may constitute available targets for pharmacotherapy of excess body weight. Hypothalamic neurones constitute the major components of the body weight homeostasis maintaining device. Together with neurones of the nucleus of the solitary tract, neurones of the hypothalamic arcuate nucleus constitute the sensory components of the adipostat. The arcuate nucleus neurones respond to circulating levels of leptin and insulin, both of which reflect the levels of energy stored as triacylglycerol in adipocytes. The arcuate nucleus projects heavily to the hypothalamic paraventricular nucleus. Neurones of the hypothalamic paraventricular nucleus are hypothesised to constitute, at least partly, the adipostat motor pattern generator, which upon stimulation activates either net anabolic or catabolic physiological responses. The overall sensitivity of the adipostat is influenced by gain setting neurones hypothesised to be located in the dorsomedial hypothalamic nucleus and lateral hypothalamic area. Cocaine amphetamine regulated transcript (CART) peptides and pre-proglucagon derived peptides, glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2) are catabolic neurotransmitters synthesised in neurones of the arcuate nucleus and the nucleus of the solitary tract, respectively. The present review summarises the available evidence that both families of peptides constitute endogenous transmitters mediating satiety and touch upon potential pharmacological exploitation of this knowledge.
PPARalpha /gamma Ragaglitazar Eliminates Fatty Liver and Enhances Insulin Action in Fat-fed Rats in the Absence of Hepatomegaly
Peroxisome proliferator-activated receptor (PPAR)alpha and PPARgamma agonists lower lipid accumulation in muscle and liver by different mechanisms. We investigated whether benefits could be achieved on insulin sensitivity and lipid metabolism by the dual PPARalpha/gamma agonist ragaglitazar in high fat-fed rats. Ragaglitazar completely eliminated high-fat feeding-induced liver triglyceride accumulation and visceral adiposity, like the PPARalpha agonist Wy-14643 but without causing hepatomegaly. In contrast, the PPARgamma agonist rosiglitazone only slightly lessened liver triglyceride without affecting visceral adiposity. Compared with rosiglitazone or Wy-14643, ragaglitazar showed a much greater effect (79%, P < 0.05) to enhance insulin's suppression of hepatic glucose output. Whereas all three PPAR agonists lowered plasma triglyceride levels and lessened muscle long-chain acyl-CoAs, ragaglitazar and rosiglitazone had greater insulin-sensitizing action in muscle than Wy-14643, associated with a threefold increase in plasma adiponectin levels. There was a significant correlation of lipid content and insulin action in liver and particularly muscle with adiponectin levels (P < 0.01). We conclude that the PPARalpha/gamma agonist ragaglitazar has a therapeutic potential for insulin-resistant states as a PPARgamma ligand, with possible involvement of adiponectin. Additionally, it can counteract fatty liver, hepatic insulin resistance, and visceral adiposity generally associated with PPARalpha activation, but without hepatomegaly.
Differential Influences of Peroxisome Proliferator-activated Receptors Gamma and -alpha on Food Intake and Energy Homeostasis
Chronic treatment with compounds activating peroxisome proliferator-activated receptor (PPAR)gamma and -alpha influences body energy stores, but the underlying mechanisms are only partially known. In a chronic-dosing study, equiefficacious antihyperglycemic doses of the PPAR gamma agonist pioglitazone and PPAR alpha/gamma dual activator ragaglitazar were administered to obesity-prone male rats. The PPAR alpha agonist fenofibrate had no effect on insulin sensitivity. Pioglitazone transiently increased and fenofibrate transiently decreased food intake, whereas ragaglitazar had no impact on feeding. As a result, body adiposity increased in pioglitazone-treated rats and decreased in fenofibrate-treated rats. PPAR gamma compounds markedly increased feed efficiency, whereas PPAR alpha agonist treatment decreased feed efficiency. In fenofibrate-treated rats, plasma acetoacetate was significantly elevated. Plasma levels of this potentially anorectic ketone body were unaffected in pioglitazone- and ragaglitazar-treated rats. High-fat feeding markedly increased visceral fat pads, and this was prevented by pioglitazone and ragaglitazar treatment. Pioglitazone treatment enlarged subcutaneous adiposity in high-fat-fed rats. In conclusion, PPAR gamma activation increases both food intake and feed efficiency, resulting in net accumulation of subcutaneous body fat. The impact of PPAR gamma activation on feeding and feed efficiency appears to be partially independent because the PPAR alpha component of ragaglitazar completely counteracts the orexigenic actions of PPAR gamma activation without marked impact on feed efficiency.
The Nkx6.1 Homeodomain Transcription Factor Suppresses Glucagon Expression and Regulates Glucose-stimulated Insulin Secretion in Islet Beta Cells
We have previously described rat insulinoma INS-1-derived cell lines with robust or poor glucose-stimulated insulin secretion (GSIS). In the current study, we have further resolved these lines into three classes: class 1, glucose-unresponsive/glucagon-expressing; class 2, glucose-unresponsive/glucagon-negative; and class 3, glucose-responsive/glucagon-negative. The transcription factor Nkx2.2 was expressed with relative abundance of 3.3, 1.0, and 1.0 in class 1, class 2, and class 3 cells, respectively, whereas Nkx6.1 expression had the opposite trend: 1.0, 2.6, and 6.4 in class 1, class 2, and class 3 cells, respectively. In class 1 cells, overexpressed Nkx6.1 suppressed glucagon expression but did not affect the levels of several other prominent beta cell transcription factors. RNA interference (RNAi)-mediated suppression of Nkx6.1 in class 3 cells resulted in a doubling of glucagon mRNA, with no effect on Pdx1 levels, whereas suppression of Pdx1 in class 3 cells caused a 12-fold increase in glucagon transcript levels, demonstrating independent effects of Nkx6.1 and Pdx1 on glucagon expression in beta cell lines. RNAi-mediated suppression of Nkx6.1 expression in class 3 cells also caused a decrease in GSIS from 13.9- to 3.7-fold, whereas suppression of Pdx1 reduced absolute amounts of insulin secretion without affecting fold response. Finally, RNAi-mediated suppression of Nkx6.1 mRNA in primary rat islets was accompanied by a significant decrease in GSIS relative to control cells. In sum, our studies have revealed roles for Nkx6.1 in suppression of glucagon expression and control of GSIS in islet beta cells.
Biological Effects of Fruit and Vegetables
A strong and persistent effect of plant-derived foods on the prevention of lifestyle diseases has emerged from observational studies. Several groups of constituents in plants have been identified as potentially health promoting in animal studies, including cholesterol-lowering factors, antioxidants, enzyme inducers, apoptosis inducers etc. In human intervention studies the dose levels achieved tend to be lower than the levels found to be effective in animals and sampling from target organs is often not possible. A controlled dietary human intervention study was performed with forty-three volunteers, providing 600 g fruit and vegetables/d or in the controls a carbohydrate-rich drink to balance energy intake. Surrogate markers of oxidative damage to DNA, protein and lipids, enzymic defence and lipid metabolism were determined in blood and urine. It was found that a high intake of fruit and vegetables tends to increase the stability of lipids towards oxidative damage. Markers of oxidative enzymes indicate a steady increase in glutathione peroxidase (GPX1) activity in erythrocytes during intervention with fruit and vegetables but there is no effect on GPX1 transcription levels in leucocytes. No change occurs in glutathione-conjugating or -reducing enzyme activities in erythrocytes or plasma, and there are no effects on the transcription of genes involved in phase 2 enzyme induction or DNA repair in leucocytes. Fruit and vegetable intake decreases the level of total cholesterol and LDL-cholesterol, but does not affect sex hormones. In conclusion, it has been shown that total cholesterol and LDL-cholesterol, markers of peripheral lipid oxidation, and erythrocyte GPX1 activity are affected by high intakes of fruit and vegetables. This finding provides support for a protective role of dietary fruit and vegetables against CVD.
Upregulation of the Brainstem Preproglucagon System in the Obese Zucker Rat
A group of neurons in the caudal nucleus of the solitary tract (NTS) processes preproglucagon to glucagon-like peptide 1 (GLP-1), GLP-2 and oxyntomodulin. Whereas the anorectic capacity of all three neuropeptides has been demonstrated, only relatively little is known of preproglucagon mRNA regulation in the brain stem. Using in situ hybridization and fluorescence immunohistochemistry, we examined hindbrain preproglucagon expression in lean and obese Zucker rats under different metabolic perturbations. First, the effect of an acute 48-h fast was examined in male Sprague-Dawley as well as in lean and obese Zucker rats. Whereas fasting had no effect on preproglucagon expression in either genotype, mRNA levels were strongly up regulated in obese Zucker rats. Using a direct immunostaining procedure and a monoclonal GLP-2 antibody, we found a doubling of the immunofluorescence signal emanating from the preproglucagon neurons in caudal brainstem suggesting that indeed the high mRNA levels observed using in situ hybridization histochemistry also reflect a higher translational activity. To investigate the effects of long-term body weight perturbations, lean and obese Zucker rats were either free-fed, voluntarily overfed (chocolate spread enriched chow) or food restricted for 35 days. Preproglucagon levels remained high in the obese Zucker rats irrespective of diet. Finally, in order to functionally validate the apparent hyperactivity in the preproglucagon system in the Zucker rat, we examined the effect of central GLP-1 receptor blockade. ICV administration of 20 microg of the GLP-1 receptor antagonist Des-His-Exendin-9-39 in the morning increased 4-h food intake in obese but not in lean Zucker rats, pointing to an increased activity in central preproglucagon containing pathways in leptin receptor deficient rats. Our data suggest that the preproglucagon neurons in the brainstem are influenced by leptin signaling and point to a role of preproglucagon neurons in the integration of metabolic signals that occurs in the nucleus of the solitary tract.
