Moderate SirT1 Overexpression Protects against High Fat Diet Induced Insulin Resistance and Mitochondrial Dysfunction

High-fat diet (HFD) not only induces insulin resistance in liver, but also causes autophagic imbalance and metabolic disorders, increases chronic inflammatory response and induces mitochondrial dysfunction. Calcium/calmodulin-dependent protein kinase IV (CaMKIV) has recently emerged as an important regulator of glucose metabolism and skeletal muscle insulin action. Its activation has been involved in the improvement of hepatic and adipose insulin action. But the underlying mechanism is not fully understood. In the present study, we aimed to address the direct effects of CaMKIV in vivo and to evaluate the potential interaction of impaired insulin sensitivity and autophagic disorders in hepatic insulin resistance. Our results indicated obese mice receiving CaMKIV showed decreased blood glucose and serum insulin and improved insulin sensitivity as well as increased glucose tolerance compared with vehicle injection. Meanwhile, defective hepatic autophagy activity, impaired insulin signaling, increased inflammatory response and mitochondrial dysfunction in liver tissues which are induced by high-fat diet were also effectively alleviated by injection of CaMKIV. Consistent with these results, the addition of CaMKIV to the culture medium of BNL cl.2 hepatocytes markedly restored palmitate-induced hepatic insulin resistance and autophagic imbalance. These effects were nullified by blockade of cyclic AMP response element-binding protein (CREB), indicating the causative role of CREB in action of CaMKIV. Our findings suggested that CaMKIV restores hepatic autophagic imbalance and improves impaired insulin sensitivity via phosphorylated CREB signaling pathway, which may offer novel opportunities for treatment of obesity and diabetes.

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132 Mitochondrial dysfunction preceeds insulin resistance in skeletal muscle of mice fed high fat diet

Mitochondrion ◽

10.1016/j.mito.2009.12.123 ◽

2010 ◽

Vol 10 (2) ◽

pp. 237 ◽

Cited By ~ 1

Author(s):

Sihem Boudina ◽

Sandra Sena ◽

Robert C. Cooksey ◽

Deborah Jones ◽

Donald A. McClain ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Mitochondrial Dysfunction ◽

High Fat Diet ◽

High Fat

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Comparative effects of sex hormone deprivation on the brain of insulin-resistant rats

Journal of Endocrinology ◽

10.1530/joe-18-0552 ◽

2019 ◽

Vol 241 (1) ◽

pp. 1-15 ◽

Cited By ~ 1

Author(s):

Jirapas Sripetchwandee ◽

Hiranya Pintana ◽

Piangkwan Sa-nguanmoo ◽

Chiraphat Boonnag ◽

Wasana Pratchayasakul ◽

...

Keyword(s):

Oxidative Stress ◽

Insulin Resistance ◽

Cognitive Decline ◽

Mitochondrial Dysfunction ◽

Dendritic Spine ◽

High Fat Diet ◽

High Fat ◽

Long Term Depression ◽

Impaired Insulin

Obese-insulin resistance following chronic high-fat diet consumption led to cognitive decline through several mechanisms. Moreover, sex hormone deprivation, including estrogen and testosterone, could be a causative factor in inducing cognitive decline. However, comparative studies on the effects of hormone deprivation on the brain are still lacking. Adult Wistar rats from both genders were operated upon (sham operations or orchiectomies/ovariectomies) and given a normal diet or high-fat diet for 4, 8 and 12 weeks. Blood was collected to determine the metabolic parameters. At the end of the experiments, rats were decapitated and their brains were collected to determine brain mitochondrial function, brain oxidative stress, hippocampal plasticity, insulin-induced long-term depression, dendritic spine density and cognition. We found that male and female rats fed a high-fat diet developed obese-insulin resistance by week 8 and brain defects via elevated brain oxidative stress, brain mitochondrial dysfunction, impaired insulin-induced long-term depression, hippocampal dysplasticity, reduced dendritic spine density and cognitive decline by week 12. In normal diet-fed rats, estrogen deprivation, not testosterone deprivation, induced obese-insulin resistance, oxidative stress, brain mitochondrial dysfunction, impaired insulin-induced long-term depression, hippocampal dysplasticity and reduced dendritic spine density. In high-fat–diet-fed rats, estrogen deprivation, not testosterone deprivation, accelerated and aggravated obese-insulin resistance and brain defects at week 8. In conclusion, estrogen deprivation aggravates brain dysfunction more than testosterone deprivation through increased oxidative stress, brain mitochondrial dysfunction, impaired insulin-induced long-term depression and dendritic spine reduction. These findings may explain clinical reports which show more severe cognitive decline in aging females than males with obese-insulin resistance.

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Glutaredoxin 2 (GRX2) deficiency exacerbates high fat diet (HFD)-induced insulin resistance, inflammation and mitochondrial dysfunction in brain injury: A mechanism involving GSK-3β

Biomedicine & Pharmacotherapy ◽

10.1016/j.biopha.2019.108940 ◽

2019 ◽

Vol 118 ◽

pp. 108940 ◽

Cited By ~ 4

Author(s):

Zhao Wohua ◽

Xu Weiming

Keyword(s):

Insulin Resistance ◽

Brain Injury ◽

Mitochondrial Dysfunction ◽

High Fat Diet ◽

High Fat ◽

Gsk 3Β

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High-fat diet in mice leads to amplified ozone-induced airway hyperresponsiveness (AHR), mitochondrial dysfunction and insulin resistance

10.1183/13993003.congress-2016.pa4664 ◽

2016 ◽

Author(s):

Fabiën Hogema ◽

Ranran Dai ◽

Xiang Li ◽

Christos Rossios ◽

Fan Chung ◽

...

Keyword(s):

Insulin Resistance ◽

Mitochondrial Dysfunction ◽

High Fat Diet ◽

Airway Hyperresponsiveness ◽

High Fat

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Carnitine supplementation in high-fat diet-fed rats does not ameliorate lipid-induced skeletal muscle mitochondrial dysfunction in vivo

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00144.2015 ◽

2015 ◽

Vol 309 (7) ◽

pp. E670-E678 ◽

Cited By ~ 7

Author(s):

Bart Wessels ◽

Nicole M. A. van den Broek ◽

Jolita Ciapaite ◽

Sander M. Houten ◽

Ronald J. A. Wanders ◽

...

Keyword(s):

Insulin Resistance ◽

Mitochondrial Dysfunction ◽

Mitochondrial Function ◽

High Fat Diet ◽

Ex Vivo ◽

Carnitine Supplementation ◽

High Fat ◽

Muscle Lipid ◽

Lipid Status

Muscle lipid overload and the associated accumulation of lipid intermediates play an important role in the development of insulin resistance. Carnitine insufficiency is a common feature of insulin-resistant states and might lead to incomplete fatty acid oxidation and impaired export of lipid intermediates out of the mitochondria. The aim of the present study was to test the hypothesis that carnitine supplementation reduces high-fat diet-induced lipotoxicity, improves muscle mitochondrial function, and ameliorates insulin resistance. Wistar rats were fed either normal chow or a high-fat diet for 15 wk. One group of high-fat diet-fed rats was supplemented with 300 mg·kg−1·day−1 l-carnitine during the last 8 wk. Muscle mitochondrial function was measured in vivo by 31P magnetic resonance spectroscopy (MRS) and ex vivo by high-resolution respirometry. Muscle lipid status was determined by 1H MRS (intramyocellular lipids) and tandem mass spectrometry (acylcarnitines). High-fat diet feeding induced insulin resistance and was associated with decreases in muscle and blood free carnitine, elevated levels of muscle lipids and acylcarnitines, and an increased number of muscle mitochondria that showed an improved capacity to oxidize fat-derived substrates when tested ex vivo. This was, however, not accompanied by an increase in muscle oxidative capacity in vivo, indicating that in vivo mitochondrial function was compromised. Despite partial normalization of muscle and blood free carnitine content, carnitine supplementation did not induce improvements in muscle lipid status, in vivo mitochondrial function, or insulin sensitivity. Carnitine insufficiency, therefore, does not play a major role in high-fat diet-induced muscle mitochondrial dysfunction in vivo.

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Polyphenol-rich virgin olive oil reduces insulin resistance and liver inflammation and improves mitochondrial dysfunction in high-fat diet fed rats

Molecular Nutrition & Food Research ◽

10.1002/mnfr.201600418 ◽

2016 ◽

Vol 61 (3) ◽

pp. 1600418 ◽

Cited By ~ 29

Author(s):

Adriano Lama ◽

Claudio Pirozzi ◽

Maria Pia Mollica ◽

Giovanna Trinchese ◽

Francesca Di Guida ◽

...

Keyword(s):

Insulin Resistance ◽

Mitochondrial Dysfunction ◽

Olive Oil ◽

High Fat Diet ◽

Virgin Olive Oil ◽

Liver Inflammation ◽

High Fat

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Leucine supplementation increases SIRT1 expression and prevents mitochondrial dysfunction and metabolic disorders in high-fat diet-induced obese mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00198.2012 ◽

2012 ◽

Vol 303 (10) ◽

pp. E1234-E1244 ◽

Cited By ~ 78

Author(s):

Hongliang Li ◽

Mingjiang Xu ◽

Jiyeon Lee ◽

Chaoyong He ◽

Zhonglin Xie

Keyword(s):

Insulin Resistance ◽

Mitochondrial Dysfunction ◽

High Fat Diet ◽

Dominant Negative ◽

Sirtuin 1 ◽

Acid Oxidation ◽

High Fat ◽

Leucine Supplementation ◽

Nicotinamide Phosphoribosyltransferase ◽

Sirt1 Expression

Leucine supplementation has been shown to prevent high-fat diet (HFD)-induced obesity, hyperglycemia, and dyslipidemia in animal models, but the underlying mechanisms are not fully understood. Recent studies suggest that activation of Sirtuin 1 (SIRT1) is an important mechanism to maintain energy and metabolic homeostasis. We therefore examined the involvement of SIRT1 in leucine supplementation-prevented obesity and insulin resistance. To accomplish this goal, male C57BL/6J mice were fed normal diet or HFD, supplemented with or without leucine. After 2 mo of treatment, alterations in SIRT1 expression, insulin signaling, and energy metabolism were analyzed. Eight weeks of HFD induced obesity, fatty liver, mitochondrial dysfunction, hyperglycemia, and insulin resistance in mice. Addition of leucine to HFD correlated with increased expression of SIRT1 and NAMPT (nicotinamide phosphoribosyltransferase) as well as higher intracellular NAD+ levels, which decreased acetylation of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α) and forkhead box O1 (FoxO1). The deacetylation of PGC1α may contribute to upregulation of genes controlling mitochondrial biogenesis and fatty acid oxidation, thereby improving mitochondrial function and preventing HFD-induced obesity in mice. Moreover, decreased acetylation of FoxO1 was accompanied by decreased expression of pseudokinase tribble 3 (TRB3) and reduced the association between TRB3 and Akt, which enhanced insulin sensitivity and improved glucose metabolism. Finally, transfection of dominant negative AMPK prevented activation of SIRT1 signaling in HFD-Leu mice. These data suggest that increased expression of SIRT1 after leucine supplementation may lead to reduced acetylation of PGC1α and FoxO1, which is associated with attenuation of HFD-induced mitochondrial dysfunction, insulin resistance, and obesity.

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Cardioprotective Effects of Metformin and Vildagliptin in Adult Rats with Insulin Resistance Induced by a High-Fat Diet

Endocrinology ◽

10.1210/en.2012-1262 ◽

2012 ◽

Vol 153 (8) ◽

pp. 3878-3885 ◽

Cited By ~ 56

Author(s):

Nattayaporn Apaijai ◽

Hiranya Pintana ◽

Siriporn C. Chattipakorn ◽

Nipon Chattipakorn

Keyword(s):

Oxidative Stress ◽

Insulin Resistance ◽

Body Weight ◽

Mitochondrial Dysfunction ◽

Cardiac Dysfunction ◽

High Fat Diet ◽

Plasma Insulin ◽

High Fat ◽

Antidiabetic Drug ◽

Sympathovagal Imbalance

Insulin resistance has been shown to be associated with cardiac sympathovagal imbalance, myocardial dysfunction, and cardiac mitochondrial dysfunction. Whereas metformin is a widely used antidiabetic drug to improve insulin resistance, vildagliptin is a novel oral antidiabetic drug in a group of dipeptidyl peptidase-4 inhibitors in which its cardiac effect is unclear. This study aimed to determine the cardiovascular effects of metformin and vildagliptin in rats with insulin resistance induced by high-fat diet. Male Wistar rats were fed with either a normal diet or high-fat diet (n =24 each) for 12 wk. Rats in each group were divided into three subgroups to receive the vehicle, metformin (30 mg/kg, twice daily), or vildagliptin (3 mg/kg, once daily) for another 21 d. Heart rate variability (HRV), cardiac function, and cardiac mitochondrial function were determined and compared among these treatment groups. Rats exposed to a high-fat diet developed increased body weight, visceral fat, plasma insulin, cholesterol, oxidative stress, depressed HRV, and cardiac mitochondrial dysfunction. Metformin and vildagliptin did not alter body weight and plasma glucose levels but decreased the plasma insulin, total cholesterol, and oxidative stress levels. Although both metformin and vildagliptin attenuated the depressed HRV, cardiac dysfunction, and cardiac mitochondrial dysfunction, vildagliptin was more effective in this prevention. Furthermore, only vildagliptin prevented cardiac mitochondrial membrane depolarization caused by consumption of a high-fat diet. We concluded that vildagliptin is more effective in preventing cardiac sympathovagal imbalance and cardiac dysfunction, as well as cardiac mitochondrial dysfunction, than metformin in rats with insulin resistance induced by high-fat diet.

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