scholarly journals Adult mice are unresponsive to AAV8-Gremlin1 gene therapy targeting the liver

PLoS ONE ◽  
2021 ◽  
Vol 16 (2) ◽  
pp. e0247300
Author(s):  
Roxana Khatib Shahidi ◽  
Jenny M. Hoffmann ◽  
Shahram Hedjazifar ◽  
Laurianne Bonnet ◽  
Ritesh K. Baboota ◽  
...  
Keyword(s):  
Body Weight ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Insulin Signalling ◽  
Serum Levels ◽  
Inhibitory Effect ◽  
Liver Cells ◽  
Adult Mice ◽  
Gremlin 1

Objective Gremlin 1 (GREM1) is a secreted BMP2/4 inhibitor which regulates commitment and differentiation of human adipose precursor cells and prevents the browning effect of BMP4. GREM1 is an insulin antagonist and serum levels are high in type 2 diabetes (T2D). We here examined in vivo effects of AAV8 (Adeno-Associated Viral vectors of serotype eight) GREM 1 targeting the liver in mature mice to increase its systemic secretion and also, in a separate study, injected recombinant GREM 1 intraperitoneally. The objective was to characterize systemic effects of GREM 1 on insulin sensitivity, glucose tolerance, body weight, adipose cell browning and other local tissue effects. Methods Adult mice were injected with AAV8 vectors expressing GREM1 in the liver or receiving regular intra-peritoneal injections of recombinant GREM1 protein. The mice were fed with a low fat or high fat diet (HFD) and followed over time. Results Liver-targeted AAV8-GREM1 did not alter body weight, whole-body glucose and insulin tolerance, or adipose tissue gene expression. Although GREM1 protein accumulated in liver cells, GREM1 serum levels were not increased suggesting that it may not have been normally processed for secretion. Hepatic lipid accumulation, inflammation and fibrosis were also not changed. Repeated intraperitoneal rec-GREM1 injections for 5 weeks were also without effects on body weight and insulin sensitivity. UCP1 was slightly but significantly reduced in both white and brown adipose tissue but this was not of sufficient magnitude to alter body weight. We validated that recombinant GREM1 inhibited BMP4-induced pSMAD1/5/9 in murine cells in vitro, but saw no direct inhibitory effect on insulin signalling and pAkt (ser 473 and thr 308) activation. Conclusion GREM1 accumulates intracellularly when overexpressed in the liver cells of mature mice and is apparently not normally processed/secreted. However, also repeated intraperitoneal injections were without effects on body weight and insulin sensitivity and adipose tissue UCP1 levels were only marginally reduced. These results suggest that mature mice do not readily respond to GREMLIN 1 but treatment of murine cells with GREMLIN 1 protein in vitro validated its inhibitory effect on BMP4 signalling while insulin signalling was not altered.

Effects of cortisol and progesterone on insulin binding and lipogenesis in adipocytes from normal and diabetic rats

1985 ◽  
Vol 106 (2) ◽  
pp. 225-231 ◽  
Author(s):  
A.-M. Mendes ◽  
R. J. Madon ◽  
D. J. Flint
Keyword(s):  
Body Weight ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Insulin Receptor ◽  
Body Weight Gain ◽  
Serum Insulin ◽  
Insulin Binding ◽  
Serum Glucose ◽  
Diabetic Rats ◽  
Receptor Concentration

ABSTRACT Cortisol implants in normal and diabetic rats reduced body weight, adiposity, insulin receptor concentration and both basal and insulin-stimulated rates of lipogenesis in isolated adipocytes, whilst insulin sensitivity was unchanged. In normal but not diabetic rats these changes were accompanied by increased serum glucose and insulin concentrations. In contrast, progesterone implants in normal and diabetic rats increased body weight gain, adiposity, insulin receptor concentration and both basal and insulin-stimulated rates of lipogenesis in adipose tissue, again without affecting insulin sensitivity. Progesterone did not affect serum insulin concentrations in normal or diabetic rats but accelerated the decline in serum glucose concentrations which occurred during an overnight fast in diabetic rats. The results suggest that (1) cortisol inhibits lipogenesis in adipose tissue without affecting insulin sensitivity, (2) cortisol reduces insulin binding in adipose tissue without a requirement for hyperinsulinaemia, which might itself indirectly lead to down-regulation of the insulin receptor, and (3) in diabetic rats progesterone stimulates lipogenesis in adipose tissue without any increase in food intake or serum insulin concentrations suggesting that progesterone may have a direct anabolic role in adipose tissue. J. Endocr. (1985) 106, 225–231

scholarly journals Adipocytes as an Important Source of Serum S100B and Possible Roles of This Protein in Adipose Tissue

2010 ◽  
Vol 2010 ◽  
pp. 1-7 ◽  
Author(s):  
Carlos Alberto Gonçalves ◽  
Marina Concli Leite ◽  
Maria Cristina Guerra
Keyword(s):  
Adipose Tissue ◽  
Brain Injury ◽  
Brain Damage ◽  
Current Knowledge ◽  
Biological Significance ◽  
Serum Levels ◽  
Serum S100b ◽  
Definitive Evidence ◽  
Astroglial Activation

Adipocytes contain high levels of S100B and in vitro assays indicate a modulated secretion of this protein by hormones that regulate lipolysis, such as glucagon, adrenaline, and insulin. A connection between lipolysis and S100B release has been proposed but definitive evidence is lacking. Although the biological significance of extracellular S100B from adipose tissue is still unclear, it is likely that this tissue might be an important source of serum S100B in situations related, or not, to brain damage. Current knowledge does not preclude the use of this protein in serum as a marker of brain injury or astroglial activation, but caution is recommended when discussing the significance of changes in serum levels where S100B may function as an adipokine, a neurotrophic cytokine, or an alarmin.

α1-Antitrypsin A treatment attenuates neutrophil elastase accumulation and enhances insulin sensitivity in adipose tissue of mice fed a high-fat diet.

2021 ◽  
Author(s):  
Randall F. D'Souza ◽  
Stewart W.C. Masson ◽  
Jonathan S. T. Woodhead ◽  
Samuel L James ◽  
Caitlin MacRae ◽  
...  
Keyword(s):  
Body Weight ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Glucose Uptake ◽  
Neutrophil Elastase ◽  
High Fat Diet ◽  
Tolerance Test ◽  
Metabolic Dysfunction ◽  
High Fat ◽  
Insulin Tolerance

Neutrophils accumulate in insulin sensitive tissues during obesity and may play a role in impairing insulin sensitivity. The major serine protease expressed by neutrophils is neutrophil elastase (NE), which is inhibited endogenously by α1-antitrypsin A (A1AT). We investigated the effect of exogenous (A1AT) treatment on diet induced metabolic dysfunction. Male C57Bl/6j mice fed a chow or a high fat diet (HFD) were randomized to receive 3x weekly i.p injections of either Prolastin (human A1AT; 2mg) or vehicle (PBS) for 10 weeks. Prolastin treatment did not affect plasma NE concentration, body weight, glucose tolerance or insulin sensitivity in chow fed mice. In contrast, Prolastin treatment attenuated HFD induced increases in plasma and white adipose tissue (WAT) NE without affecting circulatory neutrophil levels or increases in body weight. Prolastin-treated mice fed a HFD had improved insulin sensitivity, as assessed by insulin tolerance test, and this was associated with higher insulin-dependent IRS-1 (insulin receptor substrate) and AktSer473phosphorylation, and reduced inflammation markers in WAT but not liver or muscle. In 3T3-L1 adipocytes, Prolastin reversed recombinant NE-induced impairment of insulin-stimulated glucose uptake and IRS-1 phosphorylation. Furthermore, PDGF mediated p-AktSer473 activation and glucose uptake (which is independent of IRS-1) was not affected by recombinant NE treatment. Collectively, our findings suggest that NE infiltration of WAT during metabolic overload contributes to insulin-resistance by impairing insulin-induced IRS-1 signaling.

Cardiac-specific VEGFB overexpression reduces lipoprotein lipase activity and improves insulin action in rat heart

2021 ◽  
Author(s):  
Rui Shang ◽  
Nathaniel Lal ◽  
ChaeSyng Lee ◽  
Yajie Zhai ◽  
Karanjit Puri ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
Lipoprotein Lipase ◽  
Insulin Action ◽  
Insulin Signalling ◽  
Isolated Heart ◽  
Cardiac Metabolism ◽  
Metabolic Reprogramming ◽  
Flux Analysis

Cardiac muscle utilizes multiple sources of energy including glucose and fatty acid (FA). The heart cannot synthesize FA and relies on obtaining it from other sources, with lipoprotein lipase (LPL) breakdown of lipoproteins suggested to be a key source of FA for cardiac use. Recent work has indicated that cardiac vascular endothelial growth factor B (VEGFB) overexpression expands the coronary vasculature and facilitates metabolic reprogramming that favours glucose utilization. We wanted to explore whether this influence of VEGFB on cardiac metabolism involves regulation of LPL activity with consequent effects on lipotoxicity and insulin signalling. The transcriptomes of rats with and without cardiomyocyte-specific overexpression of human VEGFB were compared by using RNA-sequencing. Isolated perfused hearts or cardiomyocytes incubated with heparin were used to enable measurement of LPL activity. Untargeted metabolomic analysis was performed for quantification of cardiac lipid metabolites. Cardiac insulin sensitivity was evaluated using fast-acting insulin. Isolated heart and cardiomyocytes were used to determine transgene-encoded VEGFB isoform secretion patterns and mitochondrial oxidative capacity using high-resolution respirometry and extracellular flux analysis. In vitro, primary transgenic cardiomyocytes incubated overnight and thus exposed to abundantly secreted VEGFB isoforms in the absence of any in vivo confounding regulators of cardiac metabolism demonstrated higher basal oxygen consumption. In the whole heart, VEGFB overexpression induced an angiogenic response that was accompanied by limited cardiac LPL activity through multiple mechanisms. This was associated with a lowered accumulation of lipid intermediates, diacylglycerols and lysophosphatidylcholine, that are known to influence insulin action. In response to exogenous insulin, transgenic hearts demonstrated increased insulin sensitivity. In conclusion, the interrogation of VEGFB function on cardiac metabolism uncovered an intriguing and previously unappreciated effect to lower LPL activity and prevent lipid metabolite accumulation to improve insulin action. VEGFB could be a potential cardioprotective therapy to treat metabolic disorders, for example diabetes.

Phytochemical Screening and Anti-Diabetic Efficacy of O. Sanctum Seed Extract on Streptozotocin Induced Diabetic Rats

2017 ◽  
Vol 54 (3) ◽  
pp. 336
Author(s):  
Kavitha K. ◽  
Ponne S.
Keyword(s):  
Body Weight ◽  
Digestive Enzymes ◽  
Fasting Blood Glucose ◽  
Inhibitory Effect ◽  
Diabetic Rats ◽  
Seed Extract ◽  
Phytochemical Screening ◽  
Weight Changes

The present study was designed to assess the in vitro and in vivo anti-diabetic efficacy of <em>O. sanctum</em> seed and its phytochemical screening. In vitro inhibitory effect on carbohydrate digestive enzymes like α-amylase and α-glucosidase and in vivo parameters such as fasting blood glucose and body weight changes were studied, a potent inhibitory effect was observed on activities of digestive enzymes and a marked decrease in the glucose level in the <em>O. sanctum</em> seed extract treated streptozotocin induced diabetic rats was noted. Further a marked reduction in body weight was also observed.

Adiponectin is required to mediate rimonabant-induced improvement of insulin sensitivity but not body weight loss in diet-induced obese mice

2009 ◽  
Vol 296 (4) ◽  
pp. R929-R935 ◽  
Author(s):  
Stéphanie Migrenne ◽  
Amélie Lacombe ◽  
Anne-Laure Lefèvre ◽  
Marie-Pierre Pruniaux ◽  
Etienne Guillot ◽  
...  
Keyword(s):  
Body Weight ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Energy Homeostasis ◽  
Hepatic Glucose Production ◽  
Body Weight Loss ◽  
Metabolic Effects ◽  
Wild Type ◽  
High Fat ◽  
Wild Type Littermate

The increase in adiponectin levels in obese patients with untreated dyslipidemia and its mRNA expression in adipose tissue of obese animals are one of the most interesting consequences of rimonabant treatment. Thus, part of rimonabant's metabolic effects could be related to an enhancement of adiponectin secretion and its consequence on the modulation of insulin action, as well as energy homeostasis. The present study investigated the effects of rimonabant in adiponectin knockout mice (Ad−/−) exposed to diet-induced obesity conditions. Six-week-old Ad−/− male mice and their wild-type littermate controls (Ad+/+) were fed a high-fat diet for 7 mo. During the last month, animals were administered daily either with vehicle or rimonabant by mouth (10 mg/kg). High-fat feeding induced weight gain by about 130% in both wild-type and Ad−/− mice. Obesity was associated with hyperinsulinemia and insulin resistance. Treatment with rimonabant led to a significant and similar decrease in body weight in both Ad+/+ and Ad−/− mice compared with vehicle-treated animals. In addition, rimonabant significantly improved insulin sensitivity in Ad+/+ mice compared with Ad+/+ vehicle-treated mice by decreasing hepatic glucose production and increasing glucose utilization index in both visceral and subcutaneous adipose tissue. In contrast, rimonabant failed to improve insulin sensitivity in Ad−/− mice, despite the loss in body weight. Rimonabant's effect on body weight appeared independent of the adiponectin pathway, whereas adiponectin seems required to mediate rimonabant-induced improvement of insulin sensitivity in rodents.

scholarly journals Decrease of Obesity by Allantoin via Imidazoline I1-Receptor Activation in High Fat Diet-Fed Mice

2013 ◽  
Vol 2013 ◽  
pp. 1-7 ◽  
Author(s):  
Hsien-Hui Chung ◽  
Kung Shing Lee ◽  
Juei-Tang Cheng
Keyword(s):  
Body Weight ◽  
Adipose Tissue ◽  
Energy Intake ◽  
High Fat Diet ◽  
Chronic Administration ◽  
Receptor Activation ◽  
Inhibitory Effect ◽  
High Fat ◽  
Epididymal White Adipose Tissue ◽  
The Brain

The activation of the imidazoline I1-receptor (I1R) is known to regulate appetite. Allantoin, an active ingredient in the yam, has been reported to improve lipid metabolism in high fat diet- (HFD-)fed mice. However, the effect of allantoin on obesity remains unclear. In the present study, we investigated the effects of allantoin on HFD-induced obesity. The chronic administration of allantoin to HFD-fed mice for 8 weeks significantly decreased their body weight, and this effect was reversed by efaroxan at a dose sufficient to block I1R. The epididymal white adipose tissue (eWAT) cell size and weight in HFD-fed mice were also decreased by allantoin via the activation of I1R. In addition, allantoin significantly decreased the energy intake of HFD-fed mice, and this reduction was associated with a decrease in the NPY levels in the brain. However, no inhibitory effect of allantoin on energy intake was observed in db/db mice. Moreover, allantoin lowered HFD-induced hyperleptinemia, and this activity was abolished by I1R blockade with efaroxan. Taken together, these data suggest that allantoin can ameliorate energy intake and eWAT accumulation by activating I1R to improve HFD-induced obesity.

scholarly journals Paradoxical Increase of Insulin Sensitivity Despite Blunted Adipose Tissue Browning in Genetic Ablation of IRP1 (OR09-08-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Mikyoung You ◽  
Jin-Seon Yook ◽  
Soonkyu Chung
Keyword(s):  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Iron Metabolism ◽  
Core Body Temperature ◽  
Serum Levels ◽  
Genetic Ablation ◽  
Ucp1 Expression ◽  
Core Body ◽  
Tissue Browning

Abstract Objectives Iron regulatory protein 1 (IRP1) plays a key regulator of cellular iron metabolism, systemic oxygen sensing, and erythropoiesis. Deletion of IRP1 leads to profound HIF2a-dependent abnormalities in erythropoiesis and iron metabolism. Previously, we demonstrated that modulation of adipose tissue iron metabolism is necessary for adipose tissue browning. However, the role of IRP1 in adipose tissue browning and its metabolic consequences are uncertain. This study aimed to investigate the role of IRP1 in regulating adipose tissue browning in a mouse model of genetic ablation of IPR1 (IRP1−/−). Methods The IRP1−/− mice and wildtype (WT) controls were kept either at room (25°C) or cold (6°C) temperature for 7 days. Adipose tissue browning was evaluated by UCP1 expression and prevalence of beige-like structure in inguinal fat. Thermogenic heat release captured by infrared camera and core body temperature was measured by a rectal thermometer. The modulation of iron metabolism was assessed by serum levels of ferritin, hematocrit, and erythropoietin levels by ELISA. To investigate the role of IRP1 on energy metabolism, IRP1−/− and WT controls were fed a high-fat diet (45%) for 14 weeks. Insulin sensitivity was determined by glucose and insulin tolerance test and HOMA-IR score. [3H]-2-deoxyglucose (DOG) was injected to determine the distribution of 3H-radioactivity was quantified. Results IRP1−/− mice dramatically increased serum levels of erythropoietin but decreased hepcidin. IRP1−/− developed polycythemia and reticulocytosis, which was not affected by cold exposure. IRP1−/− were completely blunted in cold-induced browning in the inguinal fat showing no changes in UCP1 and adipocyte morphology. Unexpectedly, IRP1−/− showed higher core body temperature and heat release than control independent of UCP1 expression. Chronic intake of HF diet paradoxically increased the insulin sensitivity regardless of obesity. 2-DOG distribution was significantly increased in red blood cells, suggesting that red blood cell-dependent energy expenditure significantly contributed to rapid glucose disposal. Conclusions Disruption of IRP1 blunted adipose tissue browning. The paradoxical rise in insulin sensitivity in IRP1−/− is likely due to red blood cells-mediated energy expenditure. Funding Sources None.

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