Role of anti‐inflammatory interventions in high‐fat‐diet‐induced obesity

Cellular hypertrophy is regulated by coordinated pro- and antigrowth machineries. Foxo transcription factors initiate an atrophy-related gene program to counter hypertrophic growth. This study was designed to evaluate the role of Akt, the forkhead transcription factor Foxo3a, and atrophy genes muscle-specific RING finger (MuRF)-1 and atrogin-1 in cardiac hypertrophy and contractile dysfunction associated with high-fat diet-induced obesity. Mice were fed a low- or high-fat diet for 6 mo along with a food-restricted high-fat weight control group. Echocardiography revealed decreased fractional shortening and increased end-systolic diameter and cardiac hypertrophy in high-fat obese but not in weight control mice. Cardiomyocytes from high-fat obese but not from weight control mice displayed contractile and intracellular Ca2+ defects including depressed maximal velocity of shortening/relengthening, prolonged duration of shortening/relengthening, and reduced intracellular Ca2+ rise and clearance. Caspase activities were greater in high-fat obese but not in weight control mouse hearts. Western blot analysis revealed enhanced basal Akt and Foxo3a phosphorylation and reduced insulin-stimulated phosphorylation of Akt and Foxo3a without changes in total protein expression of Akt and Foxo3a in high-fat obese hearts. RT-PCR and immunoblotting results displayed reduced levels of the atrogens atrogin-1 and MuRF-1, the upregulated hypertrophic markers GATA4 and ciliary neurotrophic factor receptor-α, as well as the unchanged calcineurin and proteasome ubiquitin in high-fat obese mouse hearts. Transfection of H9C2 myoblast cells with dominant-negative Foxo3a adenovirus mimicked palmitic acid (0.8 mM for 24 h)-induced GATA4 upregulation without an additive effect. Dominant-negative Foxo3a-induced upregulation of pAkt and repression of phosphatase and tensin homologue were abrogated by palmitic acid. These results suggest a cardiac hypertrophic response in high-fat diet-associated obesity at least in part through inactivation of Foxo3a by the Akt pathway.

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Role of human pregnane X receptor in high fat diet-induced obesity in pre-menopausal female mice

Biochemical Pharmacology ◽

10.1016/j.bcp.2014.03.019 ◽

2014 ◽

Vol 89 (3) ◽

pp. 399-412 ◽

Cited By ~ 25

Author(s):

Krisstonia Spruiell ◽

Dominique Z. Jones ◽

John M. Cullen ◽

Emmanuel M. Awumey ◽

Frank J. Gonzalez ◽

...

Keyword(s):

High Fat Diet ◽

Pregnane X Receptor ◽

High Fat ◽

Female Mice ◽

Diet Induced Obesity

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Potential Role of Central Microglia Activation in High Fat Diet‐Induced Obesity

The FASEB Journal ◽

10.1096/fasebj.2018.32.1_supplement.682.7 ◽

2018 ◽

Vol 32 (S1) ◽

Author(s):

Aneesh Singal ◽

Caitlin R. Coker ◽

Sarah S. Bingaman ◽

Amy C. Arnold ◽

Yuval Silberman

Keyword(s):

High Fat Diet ◽

Potential Role ◽

Microglia Activation ◽

High Fat ◽

Diet Induced Obesity

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Comparative Study of the Antioxidant and Anti-Inflammatory Effects of Leaf Extracts from Four Different Morus alba Genotypes in High Fat Diet-Induced Obesity in Mice

Antioxidants ◽

10.3390/antiox9080733 ◽

2020 ◽

Vol 9 (8) ◽

pp. 733

Author(s):

Francisco Javier Leyva-Jiménez ◽

Antonio Jesús Ruiz-Malagón ◽

José Alberto Molina-Tijeras ◽

Patricia Diez-Echave ◽

Teresa Vezza ◽

...

Keyword(s):

Mass Spectrometry ◽

Electrospray Ionization ◽

High Fat Diet ◽

High Fat ◽

Ionization Time ◽

Flight Mass Spectrometry ◽

Diet Induced Obesity ◽

Obesity In Mice ◽

Anti Inflammatory ◽

Tof Ms

Increased levels of reactive oxygen species (ROS) and a low-grade chronic inflammation in multiple organs have been demonstrated in obesity. Morus alba leaves extracts (MAEs) have been used in traditional medicine as anti-inflammatory agents. In this work, the bioactive compounds of different genotypes of M. alba L. (Filipina, Valenciana Temprana, Kokuso, and Italia) were analyzed not only by reverse phase high performance liquid chromatography–electrospray ionization-time of flight-mass spectrometry (RP-HPLC-ESI-TOF-MS) and hydrophilic interaction chromatography–electrospray ionization-time of flight-mass spectrometry (HILIC-ESI-TOF-MS), but also screened for in vitro and in vivo antioxidant activity by means of DPPH• radical scavenging assay and Caenorhabditis elegans model. These MAEs were administered daily in a model of diet-induced obesity in mice. Filipina and Italia genotypes significantly reduced weight gain, the glycemic levels in high fat diet, as well as, levels of LDL-cholesterol and triglycerides. Filipina and Italia MAEs also reduced the expression of proinflammatory mediators such as Tnf-α, Il-1β, Il-6 and increased the levels of adiponectin and AMPK, which exert anti-inflammatory effects. Moreover, Italia genotype ameliorated the intestinal barrier function. In conclusion, Filipina and Italia methanolic extracts show the highest antioxidant and anti-inflammatory effect, due to the presence of compounds such as protocatechuic acid or quercetin-3-glucoside, and they could be developed as a complementary treatment for obesity and metabolic disorders.

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Colonic dysmotility and inflammation associated with high fat diet-induced obesity: role of the enteric glia

Proceedings of The Nutrition Society ◽

10.1017/s0029665120004425 ◽

2020 ◽

Vol 79 (OCE2) ◽

Author(s):

Matteo Fornai ◽

Carolina Pellegrini ◽

Vanessa D'Antongiovanni ◽

Laura Benvenuti ◽

Nunzia Bernardini ◽

...

Keyword(s):

High Fat Diet ◽

Mucosal Barrier ◽

Tlr4 Expression ◽

High Fat ◽

Glucose Levels ◽

Diet Induced Obesity ◽

Epididymal Fat ◽

Junction Protein ◽

Colonic Dysmotility

AbstractIntroductionEnteric glial cells (EGCs) contribute to the regulation of bowel motility, and have been implicated in the onset and development of several digestive disorders. However, the involvement of EGCs in obesity-related intestinal dysmotility is unknown. Accordingly, this study examined the role of EGCs in colonic neuromuscular dysfunctions in a mouse model of diet-induced obesity.Materials and MethodsC57BL/6 male mice (n = 6 per group) were fed with standard diet (SD) or high fat diet (HFD) for 8 weeks. Body and epididymal fat weight, and blood fasting glucose levels were evaluated the day before sacrifice. Colonic longitudinal muscle strips were set up in organ baths with Krebs solution and connected to isometric transducers. The effects of fluorocitrate (FC, gliotoxin) were tested on contractile responses mediated by NK1 tachykininergic receptors upon application of electrical stimuli (0.5 ms, 28 V, 10 Hz) [incubation with atropine, guanethidine, L-NAME, GR159897 and SB218795 (NK2 and NK3 antagonists, respectively)] or exogenous substance P (SP). Colonic levels of interleukin (IL)-1β, IL-6, malondialdehyde (MDA) and occludin (a tight junction protein involved the maintenance of mucosal barrier) were measured. Cultured rat EGCs were exposed to palmitate and lipopolysaccharide (LPS), either alone or in combination, to mimic the exposure to HFD. IL-1β and SP levels were then assessed in cell supernatants, while toll-like receptor 4 (TLR4) expression was evaluated in cell lysates.ResultsHFD-mice displayed increments of body weight, epididymal fat weight and blood glucose levels. In in vitro experiments, electrically induced colonic tachykininergic contractions were enhanced in HFD mice, as compared with SD animals. No differences were observed when comparing contractions to exogenous SP. The increase in electrically evoked tachykininergic contractions was blunted upon incubation with the gliotoxin FC. Exogenous SP-induced contractions were not affected by FC. HFD mice displayed an increase in colonic IL-1β, IL-6 and MDA levels and a reduced occludin expression, as compared with SD mice. Exposure of EGCs to palmitate, alone or in combination with LPS, resulted in a significant increase in TLR4 expression, while LPS alone was without effects. The combination of palmitate and LPS increased significantly IL-1β and SP levels in cell supernatants, while single treatments were without effects.DiscussionHFD is characterized by colonic dysmotility along with bowel inflammation, oxidative stress, and an impairment of mucosal barrier integrity. In this setting, the hyperactivation of EGCs, likely via TLR4, appears to contribute to inflammation and colonic tachykininergic motor dysfunctions.

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