High dietary fat and sucrose result in an extensive and time-dependent deterioration in health of multiple physiological systems in mice

Burchfield, James G.; Kebede, Melkam A.; Meoli, Christopher C.; Stöckli, Jacqueline; Whitworth, P. Tess; Wright, Anthony R.; Hoffman, Nolan J.; Minard, Annabel Y.; Ma, Xiuquan; Krycer, James R.; Nelson, Marin E.; Tan, Shi‐Xiong; Yau, Belinda; Thomas, Kristen C.; Wee, Natalie K.Y.; Khor, Ee-Cheng; Enriquez, Ronaldo F.; Vissel, Bryce; Biden, Trevor J.; Baldock, Paul A.; Hoehn, Kyle L.; Cantley, James; Cooney, Gregory J.; James, David E.; Fazakerley, Daniel J.

doi:10.1074/jbc.ra117.000808

Cited by 78 publications

(59 citation statements)

References 65 publications

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“…1 , A and B ). Similarly, 14-day high-fat high-sucrose diet (HFHSD) feeding, which is sufficient to induce maximal adipose tissue insulin resistance ( 24 , 25 ), impaired insulin-stimulated 2DOG uptake into adipose tissue explants ( Fig. 1 C ).…”

Section: Resultsmentioning

confidence: 99%

Mitochondrial oxidative stress causes insulin resistance without disrupting oxidative phosphorylation

Fazakerley

Minard

Krycer

et al. 2018

Journal of Biological Chemistry

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126

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Mitochondrial oxidative stress, mitochondrial dysfunction, or both have been implicated in insulin resistance. However, disentangling the individual roles of these processes in insulin resistance has been difficult because they often occur in tandem, and tools that selectively increase oxidant production without impairing mitochondrial respiration have been lacking. Using the dimer/monomer status of peroxiredoxin isoforms as an indicator of compartmental hydrogen peroxide burden, we provide evidence that oxidative stress is localized to mitochondria in insulin-resistant 3T3-L1 adipocytes and adipose tissue from mice. To dissociate oxidative stress from impaired oxidative phosphorylation and study whether mitochondrial oxidative stress per se can cause insulin resistance, we used mitochondria-targeted paraquat (MitoPQ) to generate superoxide within mitochondria without directly disrupting the respiratory chain. At ≤10 μm, MitoPQ specifically increased mitochondrial superoxide and hydrogen peroxide without altering mitochondrial respiration in intact cells. Under these conditions, MitoPQ impaired insulin-stimulated glucose uptake and glucose transporter 4 (GLUT4) translocation to the plasma membrane in both adipocytes and myotubes. MitoPQ recapitulated many features of insulin resistance found in other experimental models, including increased oxidants in mitochondria but not cytosol; a more profound effect on glucose transport than on other insulin-regulated processes, such as protein synthesis and lipolysis; an absence of overt defects in insulin signaling; and defective insulin- but not AMP-activated protein kinase (AMPK)-regulated GLUT4 translocation. We conclude that elevated mitochondrial oxidants rapidly impair insulin-regulated GLUT4 translocation and significantly contribute to insulin resistance and that MitoPQ is an ideal tool for studying the link between mitochondrial oxidative stress and regulated GLUT4 trafficking.

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Section: Resultsmentioning

confidence: 99%

Mitochondrial oxidative stress causes insulin resistance without disrupting oxidative phosphorylation

Fazakerley

Minard

Krycer

et al. 2018

Journal of Biological Chemistry

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126

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“…Tissue embedding and Haematoxylin-Eosin (H&E) and Sirius Red staining [22,25] were performed by the Histopathology Department, University of Sydney. Immunohistochemistry procedures on mouse tissues have been described previously [23,25,26].…”

Section: Histology and Immunohistochemistrymentioning

confidence: 99%

Fibroblast activation protein enzyme deficiency prevents liver steatosis, insulin resistance and glucose intolerance and increases fibroblast growth factor-21 in diet induced obese mice

Chowdhury

Song

Zhang

et al. 2018

Preprint

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Background & AimsFibroblast activation protein-a (FAP) is a post-proline peptidase closely related to dipeptidyl peptidase-4. FAP degrades bioactive peptides including fibroblast growth factor-21 (FGF-21) and neuropeptide Y. We examined metabolic outcomes of specific genetic ablation of FAP and its enzyme activity in a mouse model of diet-induced obesity (DIO) causing fatty liver.MethodsWildtype (WT) and genetically modified FAP deficient mice that specifically lacked either the FAP protein or FAP enzyme activity received chow, or an atherogenic diet for 8 to 20 weeks of DIO.ResultsFAP deficient male and female mice in the DIO model were more metabolically healthy than controls. The FAP deficient mice had less glucose intolerance, liver lipid, adiposity, insulin resistance, pancreatic and plasma insulin, pancreatic β-cell hyperplasia, serum alanine transaminase and circulating cholesterol compared to wild type controls. Furthermore, FAP deficiency lowered respiratory exchange ratio and greatly increased intrahepatic non-esterified free fatty acids, indicative of increased lipolysis and β-oxidation. Concordantly, lipogenic genes (Pparg, Gck, Acc, Fasn) and hepatic triglyceride and fatty acid uptake genes (Cd36, Apoc3, Ldlr) and plasma low-density lipoprotein cholesterol were downregulated. Glucagon like peptide-1 levels were unaltered. FAP was localized to human pancreatic β-cells and pancreas from diabetes mellitus patients contained elevated FAP activity. Comparable data from a FAP gene knockout mouse and a novel mouse lacking FAP enzyme activity indicated that these metabolic changes depended upon the enzymatic activity of FAP. These changes may be driven by FGF-21, which was upregulated in livers of FAP deficient DIO mice.ConclusionThis is the first study to show that specific genetic ablation of FAP activity or protein protects against DIO-driven glucose intolerance, hyperinsulinaemia, insulin resistance, hypercholesterolaemia and liver steatosis in mice and provide mechanistic insights.

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“…Lac et al [6] demonstrated that high fat diet (HFD) intake during the growing period has deleterious effects on bone parameters in rats. Burchfield et al [7] found that prolonged exposure to HFD results in morbid obesity and led to extensive bone loss in mice. Other studies also showed that HFD-induced obesity (DIO) increases bone resorption and/or decrease bone formation, resulting in reduced bone mass and bone strength in various rodent models [8].…”

Section: Introductionmentioning

confidence: 99%

Vaspin antagonizes high fat-induced bone loss in rats and promotes osteoblastic differentiation in primary rat osteoblasts through Smad-Runx2 signaling pathway

Wang

Chen

et al. 2020

Nutr Metab (Lond)

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Background: Visceral adipose tissue-derived serine protease inhibitor (vaspin), an adipose-derived hormone, exhibits various biological functions. Recently, studies showed that vaspin is closely related to bone metabolism. However, how vaspin influences bone formation and its underlying mechanisms in high fat-induced obese rats and rat primary osteoblasts (OBs) are not fully understood. In this study, the effects of vaspin on bone mechanical parameters and microarchitecture were evaluated.Methods: A total of 40 male Sprague-Dawley (SD) rats at 5-week old were fed with high fat diet (HFD) and normal diet (ND) for 12 weeks followed by treatment of vaspin for 10 weeks. Micro CT and three-point bending tests were conducted to evaluate bone microstructure and biomechanics. The alkaline phosphatase (ALP) activity, expression of Runt-related transcription factor 2 (Runx2), Osterix (Osx), Collegen alpha1 (Colla1) procollagen I N-terminal peptide (PINP), C-telopeptide of type I collagen (CTX), Smad2/3 and p-Smad2/3 was detected by different methods. Results: Our data indicated that, compared with ND rats, HFD rats exhibited high body weight, decreased bone strength and deteriorative bone quality. In contrast, vaspin reduced the body weight, improved the whole body metabolic status, enhanced bone strength, trabecular bone mass, and expression of Runx2, Osx, PINP, and decreased the expression level of plasma CTX. In vitro studies showed that vaspin promoted osteogenic differentiation and ALP activity in rat primary OBs in a dose dependent manner. Vaspin also upregulated mRNA expression of osteogenesis-related genes Runx2, Osx and Colla1 and protein expression of Runx2, Smad2/3 and p-Smad2/3. Conclusions:Our results indicated that vaspin protects against HFD-induced bone loss, and promotes osteogenic differentiation by activating the Smad2/3-Runx2 signaling pathway.

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High dietary fat and sucrose result in an extensive and time-dependent deterioration in health of multiple physiological systems in mice

Cited by 78 publications

References 65 publications

Mitochondrial oxidative stress causes insulin resistance without disrupting oxidative phosphorylation

Mitochondrial oxidative stress causes insulin resistance without disrupting oxidative phosphorylation

Fibroblast activation protein enzyme deficiency prevents liver steatosis, insulin resistance and glucose intolerance and increases fibroblast growth factor-21 in diet induced obese mice

Vaspin antagonizes high fat-induced bone loss in rats and promotes osteoblastic differentiation in primary rat osteoblasts through Smad-Runx2 signaling pathway

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