DPP4-inhibitor improves neuronal insulin receptor function, brain mitochondrial function and cognitive function in rats with insulin resistance induced by high-fat diet consumption

To investigate the effects of three different conjugated linoleic acid (CLA) preparations containing different ratios of CLA isomers on insulin signalling, fatty acid oxidation and mitochondrial function, Sprague–Dawley rats were fed a high-fat diet either unsupplemented or supplemented with one of three CLA preparations at 1 % of the diet for 8 weeks. The first CLA preparation contained approximately 30 % cis-9, trans-11 (c9, t11)-CLA isomer and 40 % trans-10, cis-12 (t10, c12)-CLA isomer (CLA-mix). The other two preparations were an 80:20 mix (c9, t11-CLA-mix) or a 10:90 mix of two CLA isomers (t10, c12-CLA-mix). Insulin resistance was decreased in all three supplemented groups based on the results of homeostasis model assessment and the revised quantitative insulin-sensitivity check index. The phosphorylation of insulin receptor substrate-1 on serine decreased in the livers of all three supplemented groups, while subsequent Akt phosphorylation increased only in the t10, c12-CLA-mix group. Both the c9, t11-CLA-mix and the t10, c12-CLA-mix increased the expression of hepatic adiponectin receptors R1 and 2, which are thought to enhance insulin sensitivity and fat oxidation. The c9, t11-CLA-mix increased protein and mRNA levels of PPARα, acyl-CoA oxidase and uncoupling protein, which are involved in fatty acid oxidation and energy dissipation. The c9, t11-CLA-mix enhanced mitochondrial function and protection against oxidative stress by increasing the activities of cytochrome c oxidase, manganese-superoxide dismutase, glutathione peroxidase, and glutathione reductase and the level of GSH. In conclusion, all three CLA preparations reduced insulin resistance. Among them, the c9, t11-CLA-mix was the most effective based on the parameters reflecting insulin resistance and fat oxidation, and mitochondrial antioxidative enzyme activity in the liver.

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Necrostatin-1 Mitigates Cognitive Dysfunction in Prediabetic Rats With no Alteration in Insulin Sensitivity

10.2337/figshare.12145755.v1 ◽

2020 ◽

Author(s):

Ada Admin ◽

Kewarin Jinawong ◽

Nattayaporn Apaijai ◽

Supawit Wongsuchai ◽

Wasana Pratchayasakul ◽

...

Keyword(s):

Synaptic Plasticity ◽

Cognitive Function ◽

Insulin Sensitivity ◽

Cognitive Decline ◽

High Fat Diet ◽

Spine Density ◽

High Fat ◽

Dendritic Spine Density ◽

Microglial Morphology ◽

Brain Mitochondrial Function

Previous studies show that 12-week of high-fat diet (HFD) consumption caused not only prediabetes, but also cognitive decline and brain pathologies. Recently, necrostatin-1 (nec-1), a necroptosis inhibitor, showed beneficial effects in brain against stroke. However, the comparative effects of nec-1 and metformin on cognition and brain pathologies in prediabetes have not been investigated. We hypothesized that nec-1 and metformin equally attenuated cognitive decline and brain pathologies in prediabetic rats. Rats (n=32) were fed with either normal diet (ND) or high-fat diet (HFD) for 20 weeks. At week 13, ND-fed rats were given a vehicle (n=8) and HFD-fed rats were randomly assigned into 3 subgroups (n=8/subgroup) with vehicle, nec-1 or metformin for 8 weeks. Metabolic parameters, cognitive function, brain insulin receptor function, synaptic plasticity, dendritic spine density, microglial morphology, brain mitochondrial function, Alzheimer’s protein, and cell death were determined. HFD-fed rats exhibited prediabetes, cognitive decline, and brain pathologies. Nec-1 and metformin equally improved cognitive function, synaptic plasticity, dendritic spine density, microglial morphology, brain mitochondrial function, reduced hyperphosphorylated-tau and necroptosis in HFD-fed rats. Interestingly metformin, but not nec-1, improved brain insulin sensitivity in those rats. In conclusion, necroptosis inhibition directly improved cognition in prediabetic rats without alteration in insulin sensitivity.

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Metformin Averts High Fat Diet-Induced Insulin Resistance and Protects Mitochondrial Function

The Thoracic and Cardiovascular Surgeon ◽

10.1055/s-0037-1598870 ◽

2017 ◽

Vol 65 (S 01) ◽

pp. S1-S110

Author(s):

A. Schrepper ◽

M. Schwarzer ◽

T. Doenst

Keyword(s):

Insulin Resistance ◽

Mitochondrial Function ◽

High Fat Diet ◽

High Fat

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Exercise Alleviates Cognitive Functions by Enhancing Hippocampal Insulin Signaling and Neuroplasticity in High-Fat Diet-Induced Obesity

Nutrients ◽

10.3390/nu11071603 ◽

2019 ◽

Vol 11 (7) ◽

pp. 1603 ◽

Cited By ~ 10

Author(s):

Hye-Sang Park ◽

Sang-Seo Park ◽

Chang-Ju Kim ◽

Mal-Soon Shin ◽

Tae-Woon Kim

Keyword(s):

Insulin Resistance ◽

Cognitive Function ◽

Physical Exercise ◽

Dentate Gyrus ◽

Insulin Signaling ◽

High Fat Diet ◽

Treadmill Exercise ◽

High Fat ◽

Brain Functions ◽

Impaired Cognitive Function

Obesity, caused by a high-fat diet (HFD), leads to insulin resistance, which is a precursor of diabetes and a risk factor for impaired cognitive function, dementia, and brain diseases, such as Alzheimer’s disease. Physical exercise has positive effects on obesity and brain functions. We investigated whether the decline in cognitive function caused by a HFD could be improved through exercise by examining insulin signaling pathways and neuroplasticity in the hippocampus. Four-week-old C57BL/6 male mice were fed a HFD or a regular diet for 20 weeks, followed by 12 weeks of treadmill exercise. To ascertain the effects of treadmill exercise on impaired cognitive function caused by obesity, the present study implemented behavioral testing (Morris water maze, step-down). Moreover, insulin-signaling and neuroplasticity were measured in the hippocampus and dentate gyrus. Our results demonstrated that HFD-fed obesity-induced insulin resistance was improved by exercise. In addition, the HFD group showed a decrease in insulin signaling and neuroplasticity in the hippocampus and the dentate gyrus and increased cognitive function impairment, which were reversed by physical exercise. Overall, our findings indicate that physical exercise may act as a non-pharmacologic method that protects against cognitive dysfunction caused by obesity by improving hippocampal insulin signaling and neuroplasticity.

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Energy restriction combined with dipeptidyl peptidase-4 inhibitor exerts neuroprotection in obese male rats

British Journal Of Nutrition ◽

10.1017/s0007114516003871 ◽

2016 ◽

Vol 116 (10) ◽

pp. 1700-1708 ◽

Cited By ~ 5

Author(s):

Hiranya Pintana ◽

Pongpan Tanajak ◽

Wasana Pratchayasakul ◽

Piangkwan Sa-nguanmoo ◽

Titikorn Chunchai ◽

...

Keyword(s):

Insulin Resistance ◽

Synaptic Plasticity ◽

Cognitive Function ◽

Insulin Sensitivity ◽

Mitochondrial Function ◽

Male Rats ◽

Insulin Resistant ◽

Hippocampal Synaptic Plasticity ◽

Brain Insulin ◽

Brain Mitochondrial Function

AbstractDipeptidyl peptidase-4 (DDP-4) inhibitors and energy restriction (ER) are widely used to treat insulin resistance and type 2 diabetes mellitus. However, the effects of ER or the combination with vildagliptin on brain insulin sensitivity, brain mitochondrial function, hippocampal synaptic plasticity and cognitive function in obese insulin-resistant rats have never been investigated. We hypothesised that ER with DDP-4 inhibitor exerts better efficacy than ER alone in improving cognition in obese insulin-resistant male rats by restoring brain insulin sensitivity, brain mitochondrial function and hippocampal synaptic plasticity. A total of twenty-four male Wistar rats were divided into two groups and fed either a normal diet or a high-fat diet (HFD) for 12 weeks. At week 13, the HFD rats were divided into three subgroups (n 6/subgroup) to receive one of the following treatments: vehicle, ER (60 % of energy received during the previous 12 weeks) or ER plus vildagliptin (3 mg/kg per d, p.o.) for 4 weeks. At the end of the treatment, cognitive function, metabolic parameters, brain insulin sensitivity, hippocampal synaptic plasticity and brain mitochondrial function were determined. We found that HFD-fed rats demonstrated weight gain with peripheral insulin resistance, dyslipidaemia, oxidative stress, brain insulin resistance, impaired brain mitochondrial function and cognitive dysfunction. Although HFD-fed rats treated with ER and ER plus vildagliptin showed restored peripheral insulin sensitivity and improved lipid profiles, only ER plus vildagliptin rats had restored brain insulin sensitivity, brain mitochondrial function, hippocampal synaptic plasticity and cognitive function. These findings suggest that only a combination of ER with DPP-4 inhibitor provides neuroprotective effects in obese insulin-resistant male rats.

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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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Metabolic consequences of ENPP1 overexpression in adipose tissue

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00087.2011 ◽

2011 ◽

Vol 301 (5) ◽

pp. E901-E911 ◽

Cited By ~ 26

Author(s):

Wentong Pan ◽

Ester Ciociola ◽

Manish Saraf ◽

Batbayar Tumurbaatar ◽

Demidmaa Tuvdendorj ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Fatty Liver ◽

Insulin Receptor ◽

High Fat Diet ◽

Tolerance Test ◽

Chow Diet ◽

High Fat ◽

The Metabolic Syndrome ◽

Feeding Protocol

Ectonucleotide pyrophosphate phosphodiesterase (ENPP1) has been shown to negatively modulate insulin receptor and to induce cellular insulin resistance when overexpressed in various cell types. Systemic insulin resistance has also been observed when ENPP1 is overexpressed in multiple tissues of transgenic models and attributed largely to tissue insulin resistance induced in skeletal muscle and liver. Another key tissue in regulating glucose and lipid metabolism is adipose tissue (AT). Interestingly, obese patients with insulin resistance have been reported to have increased AT ENPP1 expression. However, the specific effects of ENPP1 in AT have not been studied. To better understand the specific role of AT ENPP1 on systemic metabolism, we have created a transgenic mouse model (C57/Bl6 background) with targeted overexpression of human ENPP1 in adipocytes, using aP2 promoter in the transgene construct ( AdiposeENPP1-TG). Using either regular chow or pair-feeding protocol with 60% fat diet, we compared body fat content and distribution and insulin signaling in adipose, muscle, and liver tissues of AdiposeENPP1-TG and wild-type (WT) siblings. We also compared response to intraperitoneal glucose tolerance test (IPGTT) and insulin tolerance test (ITT). Our results show no changes in Adipose ENPP1-TG mice fed a regular chow diet. After high-fat diet with pair-feeding protocol, AdiposeENPP1-TG and WT mice had similar weights. However, AdiposeENPP1-TG mice developed fatty liver in association with changes in AT characterized by smaller adipocyte size and decreased phosphorylation of insulin receptor Tyr1361 and Akt Ser473. These changes in AT function and fat distribution were associated with systemic abnormalities of lipid and glucose metabolism, including increased plasma concentrations of fatty acid, triglyceride, plasma glucose, and insulin during IPGTT and decreased glucose suppression during ITT. Thus, our results show that, in the presence of a high-fat diet, ENPP1 overexpression in adipocytes induces fatty liver, hyperlipidemia, and dysglycemia, thus recapitulating key manifestations of the metabolic syndrome.

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Abstract 213: Phospholipid Transfer Protein Deficiency Attenuates High-Fat Diet--Induced Obesity and Insulin Resistance

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.34.suppl_1.213 ◽

2014 ◽

Vol 34 (suppl_1) ◽

Author(s):

Guohua Song ◽

Chuanlong Zong ◽

Mingzhu Shao ◽

Yang Yu ◽

Shoudong Guo ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Insulin Receptor ◽

High Fat Diet ◽

Phospholipid Transfer Protein ◽

Insulin Stimulation ◽

High Fat ◽

Transfer Protein ◽

Diet Induced Obesity ◽

Phospholipid Transfer

Increased phospholipid transfer protein (PLTP) activity has been found to be associated with diabetes, obesity, and metabolic syndrome in humans. However, whether or not PLTP has a direct effect on insulin sensitivity and obesity is largely unknown. Here we analyzed the effect by using PLTP knockout (PLTP-/-) mouse model. Although, PLTP-/- mice have normal body-weight-gain under chow diet, these mice were protected from high-fat-diet-induced obesity and insulin resistance, compared with wild type mice. In order to understand the mechanism, we evaluated insulin receptor and Akt activation and found that PLTP deficiency significantly enhanced phosphorylated insulin receptor and Akt levels in high-fat-diet fed mouse livers, adipose tissues, and muscles after insulin stimulation, while total Akt and insulin receptor levels were unchanged. Moreover we found that the deficiency induced significantly more GLUT4 immunostaining in the plasma membranes of adipocytes and muscle cells after insulin stimulation. Finally, we found that PLTP deficient hepatocytes had less sphingomyelin and free cholesterol in the plasma membrane and lipid raft than that of controls and this may provide a molecular basis for PLTP deficiency-mediated increasing in insulin sensitivity. We have concluded that PLTP deficiency leads to an improvement in tissue and whole-body insulin sensitivity in high-fat-diet induced insulin resistance mice model. Foundation:National Natural Science Foundation of China (# 81070247, 81170785) and Taishan Scholar Foundation of Shandong Province.

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