Gravin Scaffolding Protein Mediates Signaling in High Fat Diet Model

Recruited adipose tissue macrophages contribute to chronic and low-grade inflammation causing insulin resistance in obesity. Similarly, we hypothesized here that Kupffer cells, the hepatic resident macrophages, play a pathogenic role in hepatic insulin resistance induced by a high-fat diet. Mice were fed a normal diet or high-fat diet for 3 days. Kupffer cell activation was evaluated by immunohistochemistry and quantitative RT-PCR. Insulin sensitivity was assessed in vivo by hyperinsulinemic-euglycemic clamp and insulin-activated signaling was investigated by Western blot. Liposome-encapsulated clodronate was injected intravenously to deplete macrophages prior to a short-term exposure to high-fat diet. Here, we characterized a short-term high-fat diet model in mice and demonstrated early hepatic insulin resistance and steatosis concurrent with Kupffer cell activation. We demonstrated that selective Kupffer cell depletion obtained by intravenous clodronate, without affecting adipose tissue macrophages, was sufficient to enhance insulin-dependent insulin signaling and significantly improve hepatic insulin sensitivity in vivo in this short-term high-fat diet model. Our study clearly shows that hepatic macrophage response participates to the onset of high-fat diet-induced hepatic insulin resistance and may therefore represent an attractive target for prevention and treatment of diet- and obesity-induced insulin resistance.

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A pilot of the feasibility and usefulness of an aged obese model for use in stroke research

Wellcome Open Research ◽

10.12688/wellcomeopenres.16592.1 ◽

2021 ◽

Vol 6 ◽

pp. 104

Author(s):

Annastazia E. Learoyd ◽

Ryan Calmus ◽

Chelsea N. Cunningham ◽

Tim J. England ◽

Tracy D. Farr ◽

...

Keyword(s):

High Fat Diet ◽

Artery Occlusion ◽

Standard Diet ◽

High Fat ◽

Stroke Research ◽

Obese Rats ◽

Develop Type ◽

Cerebral Artery Occlusion ◽

Diet Model

Background: Animal models of stroke have been criticised as having poor predictive validity, lacking risk factors prevalent in an aging population. This pilot study examined the development of comorbidities in a combined aged and high-fat diet model, and then examined the feasibility of modelling stroke in such rats. Methods: Twelve-month old male Wistar-Han rats (n=15) were fed a 60% fat diet for 8 months during which monthly serial blood samples were taken to assess the development of metabolic syndrome and pro-inflammatory markers. Following this, to pilot the suitability of these rats for undergoing surgical models of stroke, they underwent 30min of middle cerebral artery occlusion (MCAO) alongside younger controls fed a standard diet (n=10). Survival, weight and functional outcome were monitored, and blood vessels and tissues collected for analysis. Results: A high fat diet in aged rats led to substantial obesity. These rats did not develop type 2 diabetes or hypertension. There was thickening of the thoracic arterial wall and vacuole formation in the liver; but of the cytokines examined changes were not seen. MCAO surgery and behavioural assessment was possible in this model (with some caveats discussed in manuscript). Conclusions: This study shows MCAO is possible in aged, obese rats. However, this model is not ideal for recapitulating the complex comorbidities commonly seen in stroke patients.

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Interleukin-23 promotes intestinal T helper type17 immunity and ameliorates obesity-associated metabolic syndrome in a murine high-fat diet model

Immunology ◽

10.1111/imm.12946 ◽

2018 ◽

Vol 154 (4) ◽

pp. 624-636 ◽

Cited By ~ 8

Author(s):

Larissa M. S. Martins ◽

Malena M. Perez ◽

Camila A. Pereira ◽

Frederico R. C. Costa ◽

Murilo S. Dias ◽

...

Keyword(s):

Metabolic Syndrome ◽

High Fat Diet ◽

T Helper ◽

High Fat ◽

Interleukin 23 ◽

Diet Model

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Chronic stress: a crucial promoter of cell apoptosis in atherosclerosis

Journal of International Medical Research ◽

10.1177/0300060518814606 ◽

2019 ◽

Vol 48 (1) ◽

pp. 030006051881460 ◽

Cited By ~ 1

Author(s):

Ling-bing Meng ◽

Meng-jie Shan ◽

Ze-mou Yu ◽

Jian Lv ◽

Ruo-mei Qi ◽

...

Keyword(s):

Chronic Stress ◽

Cell Apoptosis ◽

High Fat Diet ◽

Control Group ◽

Model Group ◽

Balloon Injury ◽

High Fat ◽

Caspase 9 ◽

Stress Group ◽

Diet Model

Objective Chronic stress may lead to augmented incidence rates of coronary and cerebrovascular diseases associated with atherosclerosis. However, few studies have focused on the effect of chronic stress on atherosclerosis plaque formation. Therefore, this study was designed to directly evaluate how chronic stress affects atherosclerosis. Methods Thirty rabbits were divided into three groups: the control group, balloon-injury operation + high-fat diet model group, and chronic stress + balloon-injury operation + high-fat diet model group. Physical and social stress were induced, and proteomic methods were applied to identify specific markers. Results After protein determination, the chronic stress + balloon-injury operation + high-fat diet model group exhibited significant upregulation of the following apoptosis-related proteins: UBE2K, caspase 3, caspase 9, BAX, P53, and FAS. In particular, real-time polymerase chain reaction showed that the protein expression of caspase 9 was significantly downregulated in the stress group compared with the non-stress groups. However, the other proteins showed significantly increased expression in the stress group. Conclusion Chronic stress may promote cell apoptosis in the physiopathologic process of atherosclerosis.

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Unlike a high‐fat diet model, mitochondrial ROS production does not appear to contribute to bed rest‐induced insulin resistance

The Journal of Physiology ◽

10.1113/jp279575 ◽

2020 ◽

Vol 598 (12) ◽

pp. 2289-2290

Author(s):

Erik D. Marchant ◽

Wyatt M. Corbin ◽

Chandler L. Eyre ◽

Nathan D. Marchant

Keyword(s):

Insulin Resistance ◽

High Fat Diet ◽

Bed Rest ◽

Ros Production ◽

High Fat ◽

Mitochondrial Ros ◽

Diet Model

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AKAP150 Contributes to Enhanced Vascular Tone by Facilitating Large-Conductance Ca 2+ -Activated K + Channel Remodeling in Hyperglycemia and Diabetes Mellitus

Circulation Research ◽

10.1161/circresaha.114.302168 ◽

2014 ◽

Vol 114 (4) ◽

pp. 607-615 ◽

Cited By ~ 66

Author(s):

Matthew A. Nystoriak ◽

Madeline Nieves-Cintrón ◽

Patrick J. Nygren ◽

Simon A. Hinke ◽

C. Blake Nichols ◽

...

Keyword(s):

Diabetes Mellitus ◽

High Fat Diet ◽

Vascular Tone ◽

Scaffolding Protein ◽

K Channel ◽

High Fat ◽

Activated T Cells ◽

Genetic Ablation ◽

Channel Function ◽

Arterial Blood

Rationale : Increased contractility of arterial myocytes and enhanced vascular tone during hyperglycemia and diabetes mellitus may arise from impaired large-conductance Ca 2+ -activated K + (BK Ca ) channel function. The scaffolding protein A-kinase anchoring protein 150 (AKAP150) is a key regulator of calcineurin (CaN), a phosphatase known to modulate the expression of the regulatory BK Ca β1 subunit. Whether AKAP150 mediates BK Ca channel suppression during hyperglycemia and diabetes mellitus is unknown. Objective : To test the hypothesis that AKAP150-dependent CaN signaling mediates BK Ca β1 downregulation and impaired vascular BK Ca channel function during hyperglycemia and diabetes mellitus. Methods and Results : We found that AKAP150 is an important determinant of BK Ca channel remodeling, CaN/nuclear factor of activated T-cells c3 (NFATc3) activation, and resistance artery constriction in hyperglycemic animals on high-fat diet. Genetic ablation of AKAP150 protected against these alterations, including augmented vasoconstriction. d -glucose–dependent suppression of BK Ca channel β1 subunits required Ca 2+ influx via voltage-gated L-type Ca 2+ channels and mobilization of a CaN/NFATc3 signaling pathway. Remarkably, high-fat diet mice expressing a mutant AKAP150 unable to anchor CaN resisted activation of NFATc3 and downregulation of BK Ca β1 subunits and attenuated high-fat diet–induced elevation in arterial blood pressure. Conclusions : Our results support a model whereby subcellular anchoring of CaN by AKAP150 is a key molecular determinant of vascular BK Ca channel remodeling, which contributes to vasoconstriction during diabetes mellitus.

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