scholarly journals Loss of APJ mediated β-arrestin signalling improves high-fat diet induced metabolic dysfunction but does not alter cardiac function in mice

2020 ◽  
Vol 477 (17) ◽  
pp. 3313-3327
Author(s):  
Na Li ◽  
Xiaochuan Ma ◽  
Ting Ban ◽  
Shaohua Xu ◽  
Yingli Ma ◽  
...  
Keyword(s):  
Cardiac Function ◽  
G Protein ◽  
High Fat Diet ◽  
Pressure Overload ◽  
Receptor Activation ◽  
Chow Diet ◽  
Metabolic Dysfunction ◽  
High Fat ◽  
Protein Activity ◽  
Fat Composition

Apelin receptor (APJ) is a G protein-coupled receptor that contributes to many physiological processes and is emerging as a therapeutic target to treat a variety of diseases. For most disease indications the role of G protein vs β-arrestin signalling in mitigating disease pathophysiology remains poorly understood. This hinders the development of G protein biased APJ agonists, which have been proposed to have several advantages over balanced APJ signalling agonists. To elucidate the contribution of APJ β-arrestin signalling, we generated a transgenic mouse harbouring a point mutation (APJ I107A) that maintains full G protein activity but fails to recruit β-arrestin following receptor activation. APJ I107A mutant mice did not alter cardiac function at rest, following exercise challenge or in response to pressure overload induced cardiac hypertrophy. Additionally, APJ I107A mice have comparable body weights, plasma glucose and lipid levels relative to WT mice when fed a chow diet. However, APJ I107A mice showed significantly lower body weight, blood insulin levels, improved glucose tolerance and greater insulin sensitivity when fed a high-fat diet. Furthermore, loss of APJ β-arrestin signalling also affected fat composition and the expression of lipid metabolism related genes in adipose tissue from high-fat fed mice. Taken together, our results suggest that G protein biased APJ activation may be more effective for certain disease indications given that loss of APJ mediated β-arrestin signalling appears to mitigate several aspects of diet induced metabolic dysfunction.

scholarly journals Atypical cannabinoid ligands O-1602 and O-1918 administered chronically in diet-induced obesity

2019 ◽  
Vol 8 (3) ◽  
pp. 203-216 ◽  
Author(s):  
Anna C Simcocks ◽  
Kayte A Jenkin ◽  
Lannie O’Keefe ◽  
Chrishan S Samuel ◽  
Michael L Mathai ◽  
...  
Keyword(s):  
Body Weight ◽  
G Protein ◽  
High Fat Diet ◽  
Chow Diet ◽  
Sprague Dawley ◽  
High Fat ◽  
G Protein Coupled Receptor ◽  
Diet Induced Obesity ◽  
Sprague Dawley Rats ◽  
G Protein Coupled

Atypical cannabinoid compounds O-1602 and O-1918 are ligands for the putative cannabinoid receptors G protein-coupled receptor 55 and G protein-coupled receptor 18. The role of O-1602 and O-1918 in attenuating obesity and obesity-related pathologies is unknown. Therefore, we aimed to determine the role that either compound had on body weight and body composition, renal and hepatic function in diet-induced obesity. Male Sprague–Dawley rats were fed a high-fat diet (40% digestible energy from lipids) or a standard chow diet for 10 weeks. In a separate cohort, male Sprague–Dawley rats were fed a high-fat diet for 9 weeks and then injected daily with 5 mg/kg O-1602, 1 mg/kg O-1918 or vehicle (0.9% saline/0.75% Tween 80) for a further 6 weeks. Our data demonstrated that high-fat feeding upregulates whole kidney G protein receptor 55 expression. In diet-induced obesity, we also demonstrated O-1602 reduces body weight, body fat and improves albuminuria. Despite this, treatment with O-1602 resulted in gross morphological changes in the liver and kidney. Treatment with O-1918 improved albuminuria, but did not alter body weight or fat composition. In addition, treatment with O-1918 also upregulated circulation of pro-inflammatory cytokines including IL-1α, IL-2, IL-17α, IL-18 and RANTES as well as plasma AST. Thus O-1602 and O-1918 appear not to be suitable treatments for obesity and related comorbidities, due to their effects on organ morphology and pro-inflammatory signaling in obesity.

Abstract 117: Ponatinib Mediated Cardiotoxicity Is Driven By Pro-inflammatory S100A8/A9-NLRP3-IL-1β Signaling Circuit

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Anand P Singh ◽  
Sultan Tousif ◽  
Prachi Umbarkar ◽  
Cristi L Galindo ◽  
Nicholas Wheeler ◽  
...  
Keyword(s):  
Cardiac Function ◽  
High Fat Diet ◽  
Kinase Inhibitor ◽  
Clinical Investigation ◽  
Pressure Overload ◽  
Immunosuppressive Agent ◽  
Myelogenous Leukemia ◽  
High Fat

Background: Ponatinib is a third-generation tyrosine kinase inhibitor (TKI) for chronic myelogenous leukemia (CML) treatment. Of note, ponatinib is the only treatment option for CML patients with T315I (gatekeeper) mutation. Unexpected clinical cardiotoxicity, including fatal myocardial infarction and congestive heart failure, has hampered its clinical use. Herein, we aimed to investigate the cardiotoxic mechanism of ponatinib and strategies to prevent the cardiotoxic manifestations. Methods: We employed wild-type C57BL/6, cardiovascular (CV) comorbidity models e.g., transverse aortic constriction (TAC)-pressure overload (cardiac comorbidity) and high-fat diet fed ApoE -/- (vascular comorbidity), to investigate the cardiotoxic mechanism of ponatinib. Echocardiography was performed to assess cardiac function. Comprehensive immune profiling was performed to identify ponatinib-induced immune dynamics using flow cytometry analysis. Results: Echocardiographic assessment of ponatinib treated high-fat diet fed ApoE -/- and pressure overload (PO) murine model showed significant decline in cardiac function, suggesting the key role of CV-comorbidities in ponatinib-induced cardiomyopathy. An unbiased RNA-Seq analysis identified the enrichment of dysregulated inflammatory genes, including a multi-fold upregulation of alarmins S100A8/A9 as a top hit in ponatinib-treated hearts. A combination of in vitro and in vivo mechanistic analysis, identified that ponatinib activates the S100A8/9-TLR4-NLRP3-IL-1β signaling pathway in cardiac and systemic myeloid cells (monocytes and neutrophils), thereby leading to excessive myocardial and systemic inflammation. Finally, we demonstrate that ponatinib-induced excessive inflammation is central to the cardiac pathology because a broad immunosuppressive agent dexamethasone abolished the adverse cardiac remodeling and dysfunction of ponatinib treated hearts. Conclusions: These findings uncover a novel mechanism of ponatinib-induced cardiac inflammation leading to cardiac dysfunction. Our results provide critical preclinical data and rationale for clinical investigation into immunosuppressive interventions to mitigate ponatinib-induced cardiotoxicity.

scholarly journals Adipocyte Utx Deficiency Promotes High-Fat Diet-Induced Metabolic Dysfunction in Mice

Cells ◽  
2022 ◽  
Vol 11 (2) ◽  
pp. 181
Author(s):  
Fenfen Li ◽  
Shirong Wang ◽  
Xin Cui ◽  
Jia Jing ◽  
Liqing Yu ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
High Fat Diet ◽  
Whole Body ◽  
Brown Adipocyte ◽  
Chow Diet ◽  
Main Function ◽  
Metabolic Dysfunction ◽  
High Fat ◽  
Brown Adipose

While the main function of white adipose tissue (WAT) is to store surplus of energy as triacylglycerol, that of brown adipose tissue (BAT) is to burn energy as heat. Epigenetic mechanisms participate prominently in both WAT and BAT energy metabolism. We previously reported that the histone demethylase ubiquitously transcribed tetratricopeptide (Utx) is a positive regulator of brown adipocyte thermogenesis. Here, we aimed to investigate whether Utx also regulates WAT metabolism in vivo. We generated a mouse model with Utx deficiency in adipocytes (AUTXKO). AUTXKO animals fed a chow diet had higher body weight, more fat mass and impaired glucose tolerance. AUTXKO mice also exhibited cold intolerance with an impaired brown fat thermogenic program. When challenged with high-fat diet (HFD), AUTXKO mice displayed adipose dysfunction featured by suppressed lipogenic pathways, exacerbated inflammation and fibrosis with less fat storage in adipose tissues and more lipid storage in the liver; as a result, AUTXKO mice showed a disturbance in whole body glucose homeostasis and hepatic steatosis. Our data demonstrate that Utx deficiency in adipocytes limits adipose tissue expansion under HFD challenge and induces metabolic dysfunction via adipose tissue remodeling. We conclude that adipocyte Utx is a key regulator of systemic metabolic homeostasis.

Maternal and postweaning diet interaction alters hypothalamic gene expression and modulates response to a high-fat diet in male offspring

2009 ◽  
Vol 297 (4) ◽  
pp. R1049-R1057 ◽  
Author(s):  
Kathleen C. Page ◽  
Raleigh E. Malik ◽  
Joshua A. Ripple ◽  
Endla K. Anday
Keyword(s):  
Body Weight ◽  
High Fat Diet ◽  
Saturated Fat ◽  
Male Offspring ◽  
Regulatory Subunit ◽  
Cytokine Signaling ◽  
Chow Diet ◽  
Metabolic Dysfunction ◽  
High Fat ◽  
Pregnancy And Lactation

Epidemiological data and results from animal studies indicate that imbalances in maternal nutrition impact the expression of metabolic disorders in the offspring. We tested the hypothesis that consumption of excess saturated fats during pregnancy and lactation contributes to adult metabolic dysfunction and that these disturbances can be further influenced by the postweaning diet. Adult male offspring from chow-fed dams were compared with males from dams fed a diet high in saturated fat (45 kcal/100 kcal) before mating, pregnancy, and lactation. Offspring were weaned to a standard chow diet or high fat diet. Animals were killed at 120 days after a 24-h fast. Body weight, energy intake, fat deposition, serum leptin, and insulin were significantly higher in offspring from control or high-fat dams if fed a high-fat diet from weaning to adulthood. Only fat-fed offspring from fat-fed dams were hyperglycemic. Leptin receptor, proopiomelanocortin, and neuropeptide Y (NPY) were also significantly increased in offspring exposed to excess saturated fat during gestation and into adulthood, whereas NPY1 receptor was downregulated. Signal transducer and activator of transcription 3 mRNA level was significantly higher in offspring from high-fat-fed dams compared with controls; however, no change was detected in cocaine and amphetamine-regulated transcript or suppressor of cytokine signaling 3. An increase in agouti-related protein expression did not reach significance. A significant reduction in phosphatidylinositol 3-kinase regulatory subunit (p85α) coupled to an upregulation of protein kinase B was observed in offspring from high-fat-fed dams transitioned to chow food, whereas p85α expression was significantly increased in high-fat offspring weaned to the high-fat diet. These data support the hypothesis that early life exposure to excess fat is associated with changes in hypothalamic regulation of body weight and energy homeostasis and that postweaning diet influences development of metabolic dysfunction and obesity.

scholarly journals Short-term high fat diet alters genes associated with metabolic and vascular dysfunction during adolescence in rats: a pilot study

PeerJ ◽  
2021 ◽  
Vol 9 ◽  
pp. e11714
Author(s):  
Alex E. Mohr ◽  
Rebecca A. Reiss ◽  
Monique Beaudet ◽  
Johnny Sena ◽  
Jay S. Naik ◽  
...  
Keyword(s):  
Gene Expression ◽  
High Fat Diet ◽  
Vascular Dysfunction ◽  
Critical Role ◽  
Chow Diet ◽  
Hormone Regulation ◽  
Metabolic Dysfunction ◽  
High Fat ◽  
Network Analyses ◽  
Vascular Regulation

Background Diet-induced metabolic dysfunction precedes multiple disease states including diabetes, heart disease, and vascular dysfunction. The critical role of the vasculature in disease progression is established, yet the details of how gene expression changes in early cardiovascular disease remain an enigma. The objective of the current pilot project was to evaluate whether a quantitative assessment of gene expression within the aorta of six-week old healthy male Sprague-Dawley rats compared to those exhibiting symptoms of metabolic dysfunction could reveal potential mediators of vascular dysfunction. Methods RNA was extracted from the aorta of eight rats from a larger experiment; four animals fed a high-fat diet (HFD) known to induce symptoms of metabolic dysfunction (hypertension, increased adiposity, fasting hyperglycemia) and four age-matched healthy animals fed a standard chow diet (CHOW). The bioinformatic workflow included Gene Ontology (GO) biological process enrichment and network analyses. Results The resulting network contained genes relevant to physiological processes including fat and protein metabolism, oxygen transport, hormone regulation, vascular regulation, thermoregulation, and circadian rhythm. The majority of differentially regulated genes were downregulated, including several associated with circadian clock function. In contrast, leptin and 3-hydroxy-3-methylglutaryl-CoA synthase 2 (Hmgcs2) were notably upregulated. Leptin is involved in several major energy balance signaling pathways and Hmgcs2 is a mitochondrial enzyme that catalyzes the first reaction of ketogenesis. Conclusion Together, these data describe changes in gene expression within the aortic wall of HFD rats with early metabolic dysfunction and highlight potential pathways and signaling intermediates that may impact the development of early vascular dysfunction.

Irisin induces white adipose tissue browning in mice as assessed by magnetic resonance imaging

2021 ◽  
pp. 153537022110060
Author(s):  
Yue Chen ◽  
Jie Ding ◽  
Yufei Zhao ◽  
Shenghong Ju ◽  
Hui Mao ◽  
...  
Keyword(s):  
Magnetic Resonance Imaging ◽  
Adipose Tissue ◽  
Magnetic Resonance ◽  
White Adipose Tissue ◽  
High Fat Diet ◽  
Chow Diet ◽  
Resonance Imaging ◽  
High Fat ◽  
White Adipocytes ◽  
Fat Fraction

This study aimed to track and evaluate the effect of low-dose irisin on the browning of white adipose tissue (WAT) in mice using magnetic resonance imaging (MRI) noninvasively in vivo. Mature white adipocytes extracted from mice were cultured, induced and characterized before being treated by irisin. The volume and fat fraction of WAT were quantified using MRI in normal chow diet and high fat mice after injection of irisin. The browning of cultured white adipocytes and WAT in mice were validated by immunohistochemistry and western blotting for uncoupling protein 1 (UCP1) and deiodinase type II (DIO2). The serum indexes were examined with high fat diet after irisin intervention. UCP1 and DIO2 in adipocytes showed increases responding to the irisin treatment. The size of white adipocytes in mice receiving irisin intervention was reduced. MRI measured volumes and fat fraction of WAT were significantly lower after Irisin treatment. Blood glucose and cholesterol levels were reduced in high fat diet mice after irisin treatment. Irisin intervention exerted browning of WAT, resulting reduction of volume and fat fraction of WAT as measured by MRI. Furthermore, it improved the condition of mice with diet-induced obesity and related metabolic disorders.

scholarly journals Partial Deficiency of Zfp217 Resists High-Fat Diet-Induced Obesity by Increasing Energy Metabolism in Mice

2021 ◽  
Vol 22 (10) ◽  
pp. 5390
Author(s):  
Qianhui Zeng ◽  
Nannan Wang ◽  
Yaru Zhang ◽  
Yuxuan Yang ◽  
Shuangshuang Li ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Weight Gain ◽  
Insulin Sensitivity ◽  
Energy Metabolism ◽  
Glucose Tolerance ◽  
High Fat Diet ◽  
Chow Diet ◽  
High Fat ◽  
Glycolipid Metabolism ◽  
Partial Deficiency

Obesity-induced adipose tissue dysfunction and disorders of glycolipid metabolism have become a worldwide research priority. Zfp217 plays a crucial role in adipogenesis of 3T3-L1 preadipocytes, but about its functions in animal models are not yet clear. To explore the role of Zfp217 in high-fat diet (HFD)-induced obese mice, global Zfp217 heterozygous knockout (Zfp217+/−) mice were constructed. Zfp217+/− mice and Zfp217+/+ mice fed a normal chow diet (NC) did not differ significantly in weight gain, percent body fat mass, glucose tolerance, or insulin sensitivity. When challenged with HFD, Zfp217+/− mice had less weight gain than Zfp217+/+ mice. Histological observations revealed that Zfp217+/− mice fed a high-fat diet had much smaller white adipocytes in inguinal white adipose tissue (iWAT). Zfp217+/− mice had improved metabolic profiles, including improved glucose tolerance, enhanced insulin sensitivity, and increased energy expenditure compared to the Zfp217+/+ mice under HFD. We found that adipogenesis-related genes were increased and metabolic thermogenesis-related genes were decreased in the iWAT of HFD-fed Zfp217+/+ mice compared to Zfp217+/− mice. In addition, adipogenesis was markedly reduced in mouse embryonic fibroblasts (MEFs) from Zfp217-deleted mice. Together, these data indicate that Zfp217 is a regulator of energy metabolism and it is likely to provide novel insight into treatment for obesity.

scholarly journals Olive Leaf Extract Attenuates Obesity in High-Fat Diet-Fed Mice by Modulating the Expression of Molecules Involved in Adipogenesis and Thermogenesis

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Ying Shen ◽  
Su Jin Song ◽  
Narae Keum ◽  
Taesun Park
Keyword(s):  
Adipose Tissue ◽  
High Fat Diet ◽  
Leaf Extract ◽  
Body Weight Gain ◽  
Plasma Lipid ◽  
Epididymal Adipose Tissue ◽  
Chow Diet ◽  
Olive Leaf ◽  
High Fat ◽  
Olive Leaf Extract

The present study aimed to investigate whether olive leaf extract (OLE) prevents high-fat diet (HFD)-induced obesity in mice and to explore the underlying mechanisms. Mice were randomly divided into groups that received a chow diet (CD), HFD, or 0.15% OLE-supplemented diet (OLD) for 8 weeks. OLD-fed mice showed significantly reduced body weight gain, visceral fat-pad weights, and plasma lipid levels as compared with HFD-fed mice. OLE significantly reversed the HFD-induced upregulation of WNT10b- and galanin-mediated signaling molecules and key adipogenic genes (PPARγ, C/EBPα, CD36, FAS, and leptin) in the epididymal adipose tissue of HFD-fed mice. Furthermore, the HFD-induced downregulation of thermogenic genes involved in uncoupled respiration (SIRT1, PGC1α, and UCP1) and mitochondrial biogenesis (TFAM, NRF-1, and COX2) was also significantly reversed by OLE. These results suggest that OLE exerts beneficial effects against obesity by regulating the expression of genes involved in adipogenesis and thermogenesis in the visceral adipose tissue of HFD-fed mice.

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