scholarly journals Autophagy-mediated metabolic effects of aspirin

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Francesca Castoldi ◽  
Juliette Humeau ◽  
Isabelle Martins ◽  
Sylvie Lachkar ◽  
Damarys Loew ◽  
...  
Keyword(s):  
High Fat Diet ◽  
Metabolic Effects ◽  
Tumor Control ◽  
Protein Acetylation ◽  
High Fat ◽  
Blood Leukocytes ◽  
Diet Induced Obesity ◽  
Autophagy Gene ◽  
General Protein ◽  
Deficient Mice

AbstractSalicylate, the active derivative of aspirin (acetylsalicylate), recapitulates the mode of action of caloric restriction inasmuch as it stimulates autophagy through the inhibition of the acetyltransferase activity of EP300. Here, we directly compared the metabolic effects of aspirin medication with those elicited by 48 h fasting in mice, revealing convergent alterations in the plasma and the heart metabolome. Aspirin caused a transient reduction of general protein acetylation in blood leukocytes, accompanied by the induction of autophagy. However, these effects on global protein acetylation could not be attributed to the mere inhibition of EP300, as determined by epistatic experiments and exploration of the acetyl-proteome from salicylate-treated EP300-deficient cells. Aspirin reduced high-fat diet-induced obesity, diabetes, and hepatosteatosis. These aspirin effects were observed in autophagy-competent mice but not in two different models of genetic (Atg4b−/− or Bcln1+/−) autophagy-deficiency. Aspirin also improved tumor control by immunogenic chemotherapeutics, and this effect was lost in T cell-deficient mice, as well as upon knockdown of an essential autophagy gene (Atg5) in cancer cells. Hence, the health-improving effects of aspirin depend on autophagy.

scholarly journals Minor role of mature adipocyte mineralocorticoid receptor in high-fat diet-induced obesity

2018 ◽  
Vol 239 (2) ◽  
pp. 229-240 ◽  
Author(s):  
A Feraco ◽  
A Armani ◽  
R Urbanet ◽  
A Nguyen Dinh Cat ◽  
V Marzolla ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Mouse Model ◽  
High Fat Diet ◽  
Mineralocorticoid Receptor ◽  
Metabolic Effects ◽  
Minor Role ◽  
High Fat ◽  
Mature Adipocyte ◽  
Diet Induced Obesity ◽  
Significant Difference

Obesity is a major risk factor that contributes to the development of cardiovascular disease and type 2 diabetes. Mineralocorticoid receptor (MR) expression is increased in the adipose tissue of obese patients and several studies provide evidence that MR pharmacological antagonism improves glucose metabolism in genetic and diet-induced mouse models of obesity. In order to investigate whether the lack of adipocyte MR is sufficient to explain these beneficial metabolic effects, we generated a mouse model with inducible adipocyte-specific deletion of Nr3c2 gene encoding MR (adipo-MRKO). We observed a significant, yet not complete, reduction of Nr3c2 transcript and MR protein expression in subcutaneous and visceral adipose depots of adipo-MRKO mice. Notably, only mature adipocyte fraction lacks MR, whereas the stromal vascular fraction maintains normal MR expression in our mouse model. Adipo-MRKO mice fed a 45% high-fat diet for 14 weeks did not show any significant difference in body weight and fat mass compared to control littermates. Glucose and insulin tolerance tests revealed that mature adipocyte MR deficiency did not improve insulin sensitivity in response to a metabolic homeostatic challenge. Accordingly, no significant changes were observed in gene expression profile of adipogenic and inflammatory markers in adipose tissue of adipo-MRKO mice. Moreover, pharmacological MR antagonism in mature primary murine adipocytes, which differentiated ex vivo from WT mice, did not display any effect on adipokine expression. Taken together, these data demonstrate that the depletion of MR in mature adipocytes displays a minor role in diet-induced obesity and metabolic dysfunctions.

scholarly journals DEPTOR in POMC neurons affects liver metabolism but is dispensable for the regulation of energy balance

2016 ◽  
Vol 310 (11) ◽  
pp. R1322-R1331 ◽  
Author(s):  
Alexandre Caron ◽  
Sébastien M. Labbé ◽  
Mathilde Mouchiroud ◽  
Renaud Huard ◽  
Denis Richard ◽  
...  
Keyword(s):  
Energy Balance ◽  
High Fat Diet ◽  
Fasting Blood Glucose ◽  
Metabolic Effects ◽  
High Fat ◽  
Interacting Protein ◽  
Neuronal Populations ◽  
Diet Induced Obesity ◽  
Glucose And Lipid Homeostasis ◽  
Locomotion Activity

We have recently demonstrated that specific overexpression of DEP-domain containing mTOR-interacting protein (DEPTOR) in the mediobasal hypothalamus (MBH) protects mice against high-fat diet-induced obesity, revealing DEPTOR as a significant contributor to energy balance regulation. On the basis of evidence that DEPTOR is expressed in the proopiomelanocortin (POMC) neurons of the MBH, the present study aimed to investigate whether these neurons mediate the metabolic effects of DEPTOR. Here, we report that specific DEPTOR overexpression in POMC neurons does not recapitulate any of the phenotypes observed when the protein was overexpressed in the MBH. Unlike the previous model, mice overexpressing DEPTOR only in POMC neurons 1) did not show differences in feeding behavior, 2) did not exhibit changes in locomotion activity and oxygen consumption, 3) did not show an improvement in systemic glucose metabolism, and 4) were not resistant to high-fat diet-induced obesity. These results support the idea that other neuronal populations are responsible for these phenotypes. Nonetheless, we observed a mild elevation in fasting blood glucose, insulin resistance, and alterations in liver glucose and lipid homeostasis in mice overexpressing DEPTOR in POMC neurons. Taken together, these results show that DEPTOR overexpression in POMC neurons does not affect energy balance regulation but could modulate metabolism through a brain-liver connection.

High-fat diet-induced hyperinsulinemia and tissue-specific insulin resistance in Cry-deficient mice

2013 ◽  
Vol 304 (10) ◽  
pp. E1053-E1063 ◽  
Author(s):  
Johanna L. Barclay ◽  
Anton Shostak ◽  
Alexei Leliavski ◽  
Anthony H. Tsang ◽  
Olaf Jöhren ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Insulin Secretion ◽  
High Fat Diet ◽  
Energy Homeostasis ◽  
Genetic Manipulation ◽  
Metabolic Effects ◽  
Lipid Uptake ◽  
High Fat ◽  
Obesity And Diabetes ◽  
Deficient Mice

Perturbation of circadian rhythmicity in mammals, either by environmental influences such as shiftwork or by genetic manipulation, has been associated with metabolic disturbance and the development of obesity and diabetes. Circadian clocks are based on transcriptional/translational feedback loops, comprising positive and negative components. Whereas the metabolic effects of deletion of the positive arm of the clock gene machinery, as in Clock- or Bmal1-deficient mice, have been well characterized, inactivation of Period genes ( Per1–3) as components of the negative arm have more complex, sometimes contradictory effects on energy homeostasis. The CRYPTOCHROMEs are critical interaction partners of PERs, and simultaneous deletion of Cry1 and - 2 results in behavioral and molecular circadian arrhythmicity. We show that, when challenged with a high-fat diet, Cry1/2−/− mice rapidly gain weight and surpass that of wild-type mice, despite displaying hypophagia. Transcript analysis of white adipose tissue reveals upregulated expression of lipogenic genes, many of which are insulin targets. High-fat diet-induced hyperinsulinemia, as a result of potentiated insulin secretion, coupled with selective insulin sensitivity in adipose tissue of Cry1/2−/− mice, correlates with increased lipid uptake. Collectively, these data indicate that Cry deficiency results in an increased vulnerability to high-fat diet-induced obesity that might be mediated by increased insulin secretion and lipid storage in adipose tissues.

Klotho-Deficient Mice Are Resistant to High-Fat Diet-Induced Obesity

2011 ◽  
pp. P3-368-P3-368
Author(s):  
Junko Akiyoshi ◽  
Mutsuko Ohnishi ◽  
Shigeko Kato ◽  
Khadijah Turkistani ◽  
Azeddine Atfi ◽  
...  
Keyword(s):  
High Fat Diet ◽  
High Fat ◽  
Diet Induced Obesity ◽  
Deficient Mice

Differential Modulation of the Metabolic Effects of Diet-Induced Obesity by Probiotic Lactobacillus Paracasei K56 and Prebiotic α-Galactooligosaccharides

2020 ◽  
Vol 19 (1) ◽  
pp. 21-28
Author(s):  
Qing-Qing Min ◽  
Ting Sun ◽  
Jia-Ying Xu ◽  
Yu-Zhong Chen ◽  
Wei-Hsien Liu ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
High Fat Diet ◽  
Lactobacillus Paracasei ◽  
Metabolic Effects ◽  
High Fat ◽  
Glucose And Lipid Metabolism ◽  
Diet Induced Obesity ◽  
High Level ◽  
Strain Dependent

While both probiotics and prebiotics have an important role in controlling obesity, the effectiveness of probiotic bacteria is strain dependent. Herein, we have examined the role of Lactobacillus paracasei strain K56 and prebiotic α-galactooligosaccharides in modulating metabolic consequences of obesity. To this end, we have employed high fat diet induced obesity in a mouse model. The results show that mice fed a high fat diet exhibited increased body weight, adiposity, and abnormal glucose and lipid metabolism. Treatment with L. paracasei K56 and/or α-galactooligosaccharides significantly decreased body and fat weights, particularly when α-galactooligosaccharide was combined with a high level of L. paracasei K56. In conclusion, the treatments with L. paracasei K56 and/or α-galactooligosaccharides significantly modulated against obesity and improved lipid metabolism.

Sub-chronic administration of the 11β-HSD1 inhibitor, carbenoxolone, improves glucose tolerance and insulin sensitivity in mice with diet-induced obesity

2008 ◽  
Vol 389 (4) ◽  
pp. 441-445 ◽  
Author(s):  
Ashley Taylor ◽  
Nigel Irwin ◽  
Aine M. McKillop ◽  
Peter R. Flatt ◽  
Victor A. Gault
Keyword(s):  
Gene Expression ◽  
Body Weight ◽  
Plasma Glucose ◽  
High Fat Diet ◽  
Receptor Gene ◽  
Daily Administration ◽  
Metabolic Effects ◽  
High Fat ◽  
Diet Induced Obesity ◽  
Glucocorticoid Receptor Gene

Abstract We have examined the metabolic effects of daily administration of carbenoxolone (CBX), a naturally occurring 11β-hydroxysteroid dehydrogenase (11β-HSD1) inhibitor, in mice with high fat diet-induced insulin resistance and obesity. Eight-week-old male Swiss TO mice placed on a synthetic high fat diet received daily intraperitoneal injections of either saline vehicle or CBX over a 16-day period. Daily administration of CBX had no effect on food intake, but significantly lowered body weight (1.1- to 1.2-fold) compared to saline-treated controls. Non-fasting plasma glucose levels were significantly decreased (1.6-fold) by CBX treatment on day 4 and remained lower throughout the treatment period. Circulating plasma corticosterone levels were not significantly altered by CBX treatment. Plasma glucose concentrations of CBX-treated mice were significantly reduced (1.4-fold) following an intraperitoneal glucose load compared with saline controls. Similarly, after 16-day treatment with CBX, exogenous insulin evoked a significantly greater reduction in glucose concentrations (1.4- to 1.8-fold). 11β-HSD1 gene expression was significantly down-regulated in liver, whereas glucocorticoid receptor gene expression was increased in both liver and adipose tissue following CBX treatment. The reduced body weight and improved metabolic control in mice with high fat diet-induced obesity upon daily CBX administration highlights the potential value of selective 11β-HSD1 inhibition as a new route for the treatment of type 2 diabetes and obesity.

scholarly journals Systemic versus local adipokine expression differs in a combined obesity and osteoarthritis mouse model

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Marie-Lisa Hülser ◽  
Yubin Luo ◽  
Klaus Frommer ◽  
Rebecca Hasseli ◽  
Kernt Köhler ◽  
...  
Keyword(s):  
High Fat Diet ◽  
Medial Meniscus ◽  
Degenerative Joint Disease ◽  
Mechanisms Of Action ◽  
Normal Diet ◽  
Joint Disease ◽  
Metabolic Effects ◽  
High Fat ◽  
Joint Function ◽  
Diet Induced Obesity

AbstractOsteoarthritis (OA) is a degenerative joint disease characterized by cartilage loss and reduced joint function. OA risk factors are age and obesity. Many adipokines are altered by obesity but also OA although systemic adipokine regulation in OA is not always clear. Therefore, metabolic effects of diet-induced obesity on OA development as well as the influence of obesity and OA progression on systemic vs. local adipokine expression in joints were compared. C57Bl/6-mice fed with HFD (high fat diet) or normal diet prior to destabilization of the medial meniscus (DMM) were sacrificed 4/6/8 weeks after surgery. Sera were evaluated for adiponectin, leptin, visfatin, cytokines. Liver grading and staging for non-alcoholic steatohepatitis (NASH) was performed and crown-like structures (CLS) in adipose tissue measured. OA progression was scored histologically. Adipokine-expressing cells and types were evaluated by immunohistochemistry. Time-dependent changes in DMM-progression were reflected by increased systemic adiponectin levels in DMM especially combined with HFD. While HFD increased serum leptin, DMM reduced systemic leptin significantly. OA scores correlated with bodyweight, leptin and hepatic scoring. Locally, increased numbers of adiponectin- and leptin-producing fibroblasts were observed in damaged menisci but visfatin was not changed. Local adipokine expression was independent from systemic levels, suggesting different mechanisms of action.

scholarly journals Casitas b-Lineage Lymphoma-Deficient Mice Are Protected Against High-Fat Diet-Induced Obesity and Insulin Resistance

Diabetes ◽  
2006 ◽  
Vol 55 (3) ◽  
pp. 708-715 ◽  
Author(s):  
J. C. Molero ◽  
S. G. Waring ◽  
A. Cooper ◽  
N. Turner ◽  
R. Laybutt ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
High Fat Diet ◽  
High Fat ◽  
Diet Induced Obesity ◽  
B Lineage ◽  
Deficient Mice

scholarly journals Loss of Monoacylglycerol O-Acyltransferase 2 can be Compensated for by Diacylglycerol O-Acyltransferases 1 and 2 in High-Fat Diet-Induced Obesity and Mammary Cancer Development

2021 ◽  
Author(s):  
Yan Mei ◽  
Jing Wang ◽  
Jia-Bin Lu ◽  
Guan-Ming Lu ◽  
Li-Xia Peng ◽  
...  
Keyword(s):  
Overall Survival ◽  
Mammary Tumor ◽  
High Fat Diet ◽  
Triple Negative ◽  
Tumor Development ◽  
Breast Adenocarcinoma ◽  
High Fat ◽  
Diet Induced Obesity ◽  
Increased Risk ◽  
Deficient Mice

Abstract Background: Dietary fat absorption involves the re-esterification of digested triacylglycerol in the enterocytes, it is a biological process catalyzed by monoacylglycerol O-acyltransferase 2 (MOGAT2, aka MGAT2), which is highly expressed in the small intestine. A previous study showed that the loss of the Mogat2 gene can prevent high-fat diet-induced obesity in mice. Obesity is associated with an increased risk of several types of cancer including postmenopausal breast cancer.Methods: We collected 147 patients with triple negative breast adenocarcinoma to explore the relationship between the expression of MOGAT2 and patient overall survival. And we generated a Mogat2-deficient mouse mammary tumor model by crossing Mogat2-deficient mice with MMTV-PyMT mice to examine the effect of losing MOGAT2 in vivo.Results: Our founding suggest that obesity was induced by a relatively high-fat diet (37% of calories from fat) in the mice with or without Mogat2 knockout. Mammary tumor development was deteriorated by a relatively high-fat diet regardless of Mogat2 deficiency. As a compensation mechanism, upregulation of diacylglycerol O-acyltransferases 1 and 2 (Dgat1 and Dgat2) in the Mogat2 deficient mice was found. Conclusions: Elevated expression of MOGAT2 in triple negative breast adenocarcinoma predicts poorer patient overall survival. With the compensation of Dgat1 and Dgat2, Mogat2 deficiency alone cannot prevent fat diet-induced obesity, nor prevent mammary tumor development in a mouse model.

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