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

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.

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

Journal of Endocrinology ◽

10.1530/joe-18-0314 ◽

2018 ◽

Vol 239 (2) ◽

pp. 229-240 ◽

Cited By ~ 4

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.

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Betulinic acid inhibits high-fat diet-induced obesity and improves energy balance by activating AMPK

Nutrition Metabolism and Cardiovascular Diseases ◽

10.1016/j.numecd.2018.12.001 ◽

2019 ◽

Vol 29 (4) ◽

pp. 409-420 ◽

Cited By ~ 6

Author(s):

K.-D. Kim ◽

H.-Y. Jung ◽

H.G. Ryu ◽

B. Kim ◽

J. Jeon ◽

...

Keyword(s):

Energy Balance ◽

Betulinic Acid ◽

High Fat Diet ◽

High Fat ◽

Diet Induced Obesity

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Moderate Aerobic Exercise Training Prevents the Augmented Hepatic Glucocorticoid Response Induced by High-Fat Diet in Mice

International Journal of Molecular Sciences ◽

10.3390/ijms21207582 ◽

2020 ◽

Vol 21 (20) ◽

pp. 7582

Author(s):

Jonatan Dassonvalle ◽

Francisco Díaz-Castro ◽

Camila Donoso-Barraza ◽

Carlos Sepúlveda ◽

Francisco Pino-de la Fuente ◽

...

Keyword(s):

Metabolic Syndrome ◽

Energy Balance ◽

Aerobic Exercise ◽

High Fat Diet ◽

Aerobic Exercise Training ◽

Metabolic Effects ◽

Obese Mice ◽

High Fat ◽

Epididymal Fat ◽

Glucocorticoid Response

Glucocorticoids (GCs) are critical regulators of energy balance. Their deregulation is associated with the development of obesity and metabolic syndrome. However, it is not understood if obesity alters the tissue glucocorticoid receptor (GR) response, and moreover whether a moderate aerobic exercise prevents the alteration in GR response induced by obesity. Methods: To evaluate the GR response in obese mice, we fed C57BL6J mice with a high-fat diet (HFD) for 12 weeks. Before mice were sacrificed, we injected them with dexamethasone. To assess the exercise role in GR response, we fed mice an HFD and subjected them to moderate aerobic exercise three times a week. Results: We found that mice fed a high-fat diet for 12 weeks developed hepatic GC hypersensitivity without changes in the gastrocnemius or epididymal fat GR response. Therefore, moderate aerobic exercise improved glucose tolerance, increased the corticosterone plasma levels, and prevented hepatic GR hypersensitivity with an increase in epididymal fat GR response. Conclusion: Collectively, our results suggest that mice with HFD-induced obesity develop hepatic GR sensitivity, which could enhance the metabolic effects of HFD in the liver. Moreover, exercise was found to be a feasible non-pharmacological strategy to prevent the deregulation of GR response in obesity.

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

Current Topics in Nutraceutical Research ◽

10.37290/ctnr2641-452x.19:21-28 ◽

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.

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Herring Milt Protein Hydrolysate Improves Insulin Resistance in High-Fat-Diet-Induced Obese Male C57BL/6J Mice

Marine Drugs ◽

10.3390/md17080456 ◽

2019 ◽

Vol 17 (8) ◽

pp. 456 ◽

Cited By ~ 3

Author(s):

Yanwen Wang ◽

Jacques Gagnon ◽

Sandhya Nair ◽

Shelly Sha

Keyword(s):

Insulin Resistance ◽

Blood Glucose ◽

High Fat Diet ◽

Protein Hydrolysate ◽

Fasting Blood Glucose ◽

Model Assessment ◽

Homeostasis Model Assessment ◽

High Fat ◽

Diet Induced Obesity ◽

Dietary Casein

Protein consumption influences glucose homeostasis, but the effect depends on the type and origin of proteins ingested. The present study was designed to determine the effect of herring milt protein hydrolysate (HPH) on insulin function and glucose metabolism in a mouse model of diet-induced obesity. Male C57BL/6J mice were pretreated with a low-fat diet or a high-fat diet for 6 weeks. Mice on the high-fat diet were divided into four groups where one group continued on the high-fat diet and the other three groups were fed a modified high-fat diet where 15%, 35%, and 70%, respectively, of casein was replaced with an equal percentage of protein derived from HPH. After 10 weeks, mice that continued on the high-fat diet showed significant increases in body weight, blood glucose, insulin, and leptin levels and exhibited impaired oral glucose tolerance, insulin resistance, and pancreatic β-cell dysfunction. Compared to mice fed the high-fat diet, the 70% replacement of dietary casein with HPH protein reduced body weight, semi-fasting blood glucose, fasting blood glucose, insulin, leptin, and cholesterol levels and improved glucose tolerance, homeostasis model assessment of insulin resistance (HOMA-IR), and homeostasis model assessment of β-cell function (HOMA-β) indices. The 35% replacement of dietary casein with HPH protein showed moderate effects, while the 15% replacement of dietary casein with HPH protein had no effects. This is the first study demonstrating that replacing dietary casein with the same amount of protein derived from HPH can prevent high-fat-diet-induced obesity and insulin resistance.

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

Biological Chemistry ◽

10.1515/bc.2008.049 ◽

2008 ◽

Vol 389 (4) ◽

pp. 441-445 ◽

Cited By ~ 19

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.

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

Scientific Reports ◽

10.1038/s41598-021-96545-8 ◽

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.

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Autophagy-mediated metabolic effects of aspirin

Cell Death Discovery ◽

10.1038/s41420-020-00365-0 ◽

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.

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The Effects of Erythropoietin Dose Titration during High-Fat Diet-Induced Obesity

Journal of Biomedicine and Biotechnology ◽

10.1155/2011/373781 ◽

2011 ◽

Vol 2011 ◽

pp. 1-8 ◽

Cited By ~ 19

Author(s):

Amanda Foskett ◽

Mawadda Alnaeeli ◽

Li Wang ◽

Ruifeng Teng ◽

Constance T. Noguchi

Keyword(s):

Physical Activity ◽

Body Weight ◽

Food Intake ◽

Glucose Metabolism ◽

Glucose Tolerance ◽

Fat Mass ◽

High Fat Diet ◽

Metabolic Effects ◽

High Fat ◽

Diet Induced Obesity

Erythropoietin (Epo) is a pleotropic cytokine with several nonhematopoietic tissue effects. High-dose Epo treatment-mediated effects on body weight, fat mass and glucose tolerance have recently been reported, thus extending its pleotropic effects to fat and glucose metabolism. However, the exact dose range of Epo treatment required for such effects remains unidentified to date. We investigated Epo dosage effect (up to 1000 U/kg) on hematocrit, body weight, body composition, glucose metabolism, food intake, and physical activity, during high-fat diet-induced obesity. We report that Epo doses (1000, 600, 300, and 150 U/kg) significantly reduced body weight gain and fat mass, while, only Epo doses of 300 U/kg and higher significantly affected glucose tolerance. None of the tested Epo doses showed any detectable effects on food intake, and only 1000 U/kg dose significantly increased physical activity, suggesting that these parameters may only be partially responsible for the metabolic effects of Epo treatment.

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Acute and chronic metabolic effects of carvedilol in high-fructose, high fat diet-fed mice: Implication of β-arrestin2 pathway

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2021-0299 ◽

2021 ◽

Author(s):

Hoda M. S. Ahmed ◽

Samar G. Mohamed ◽

Wael S. Ibrahim ◽

Asmaa M. Rezk ◽

Amr A. A. Mahmoud ◽

...

Keyword(s):

Insulin Resistance ◽

Glucose Tolerance ◽

High Fat Diet ◽

Fasting Blood Glucose ◽

Metabolic Effects ◽

Activity Levels ◽

High Fat ◽

Insulin Resistant ◽

Chronic Effects ◽

High Fructose

We aimed to investigate the acute and chronic effects of carvedilol on insulin resistance in high-fructose, high-fat diet (HFrHFD)-fed mice and the implication of β-arrestin2 pathway. The acute effect of carvedilol (10 mg/kg, i.p.) on glucose tolerance and hepatic lipid signaling in normal and insulin resistant mice was investigated. Then, the chronic effect of carvedilol on insulin resistance and dyslipidemia in HFrHFD-fed mice was examined. Changes in β-arrestin2 and its down-stream signals in liver, skeletal muscle, and adipose tissue were measured. This involved measuring phosphatidylinositol 4,5-bisphosphate (PIP2) and diacylglycerol (DAG) levels and protein kinase B (Akt)-activity. Carvedilol acutely reduced fasting blood glucose levels in both normal and insulin resistant mice without significantly affecting the glucose tolerance. These acute effects were associated with increased hepatic PIP2 but decreased hepatic DAG levels. Chronic administration of carvedilol significantly ameliorated insulin resistance and dyslipidemia in HFrHFD-fed mice. These chronic effects were associated with increased β-arrestin2, PIP2 and Akt activity levels but decreased DAG levels in the classical insulin target tissues. In conclusion, carvedilol acutely maintains glucose homeostasis and chronically ameliorates insulin resistance and dyslipidemia in HFrHFD-fed mice. The insulin sensitizing effects of carvedilol are highly correlated with the upregulation of β-arrestin2 pathway.

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