Maternal Transmission of Human OGG1 Protects Mice Against Genetically- and Diet-Induced Obesity Through Increased Tissue Mitochondrial Content

Burchat, Natalie; Sharma, Pulkit; Ye, Hong; Komakula, Sai Santosh Babu; Dobrzyń, Agnieszka; Vartanian, Vladimir; Lloyd, R. Stephen; Sampath, Harini

doi:10.3389/fcell.2021.718962

Cited by 7 publications

(6 citation statements)

References 48 publications

(72 reference statements)

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“…Energy expenditure was measured by indirect calorimetry (Oxymax, Columbus Instruments, Columbus, OH) after 8 weeks of feeding, as previously described ( 41 ). Briefly, oxygen consumption (VO 2 ) and carbon dioxide production (VCO 2 ) were determined in individually housed animals with ad libitum access to HFD and water; both DHF and Abx were maintained in drinking water of respective groups during the calorimetry studies.…”

Section: Methodsmentioning

confidence: 99%

Metabolic protection by the dietary flavonoid 7,8-dihydroxyflavone requires an intact gut microbiome

Sharma

Silva²,

Pfreundschuh³

et al. 2022

Front. Nutr.

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Background7,8-dihydroxyflavone (DHF) is a naturally occurring flavonoid found in Godmania, Tridax, and Primula species that confers protection against high-fat diet (HFD) induced metabolic pathologies selectively in female mice. We have previously reported that this metabolic protection is associated with early and stable remodeling of the intestinal microbiome, evident in female but not male DHF-supplemented mice. Early changes in the gut microbiome in female DHF-fed mice were highly predictive of subsequent metabolic protection, suggesting a causative association between the gut microbiome and the metabolic effects of DHF.ObjectiveTo investigate a causal association between the gut microbiome and the metabolic effects of DHF using a model of antibiotic-induced gut microbiome ablation.Materials and methodsAge-matched male and female C57Bl6/J mice were given ad libitum access to HFD and drinking water containing vehicle or DHF for 12 weeks. For antibiotic (Abx) treatment, female mice were given drinking water containing a cocktail of antibiotics for 2 weeks prior to HFD feeding and throughout the feeding period. Metabolic phenotyping consisted of longitudinal assessments of body weights, body composition, food, and water intake, as well as measurement of energy expenditure, glucose tolerance, and plasma and hepatic lipids. Protein markers mediating the cellular effects of DHF were assessed in brown adipose tissue (BAT) and skeletal muscle.ResultsMetabolic protection conferred by DHF in female HFD-fed mice was only apparent in the presence of an intact gut microbiome. Abx-treated mice were not protected from HFD-induced obesity by DHF administration. Further, tissue activation of the tropomyosin-related kinase receptor B (TrkB) receptor, which has been attributed to the biological activity of DHF, was lost upon gut microbiome ablation, indicating a requirement for microbial “activation” of DHF for its systemic effects. In addition, we report for the first time that DHF supplementation significantly activates TrkB in BAT of female, but not male, mice uncovering a novel target tissue of DHF. DHF supplementation also increased uncoupling protein 1 (UCP1) and AMP-activated protein kinase (AMPK) protein in BAT, consistent with protection from diet-induced obesity.ConclusionThese results establish for the first time a requirement for the gut microbiome in mediating the metabolic effects of DHF in female mice and uncover a novel target tissue that may mediate these sexually-dimorphic protective effects.

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Section: Methodsmentioning

confidence: 99%

Metabolic protection by the dietary flavonoid 7,8-dihydroxyflavone requires an intact gut microbiome

Sharma

Silva²,

Pfreundschuh³

et al. 2022

Front. Nutr.

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“…Since data from both the Ogg1 −/− and Neil1 −/− mouse models indicated that BERmediated repair in mitochondria likely plays an integral role in regulating energy balance, we hypothesized that in contrast to decreased repair levels, increased expression of a mitochondrial-targeted human OGG1 might render mice more resistant to obesity and metabolic syndrome [121][122][123]. These studies utilized a transgenic OGG1 model (OGG1 Tg ) developed in the lab of Dr. Lars Eide, in which OGG1 Tg mice constitutively expressed the human OGG1a gene coupled with the mitochondrial targeting sequence of the manganese superoxide dismutase gene.…”

Section: Metabolic Syndromementioning

confidence: 99%

“…While all of the above studies utilized a high-fat diet to accelerate the manifestations of metabolic syndrome, yellow Agouti mice (A y /α) represent a genetic model of obesity driven by hyperphagia. To test whether global expression of the human OGG1 transgene could also confer resistance to weight gain in these mice, the A y /α were crossed with OGG1 Tg mice and selected A y /α Tg [122]. Even though there were trends for increased food intake in the A y /α Tg versus the A y /α, both weight and fat mass were significantly decreased in A y /α Tg males and females.…”

Section: Metabolic Syndromementioning

confidence: 99%

Complex Roles of NEIL1 and OGG1: Insights Gained from Murine Knockouts and Human Polymorphic Variants

Lloyd

2022

DNA

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DNA glycosylases promote genomic stability by initiating base excision repair (BER) in both the nuclear and mitochondrial genomes. Several of these enzymes have overlapping substrate recognition, through which a degree of redundancy in lesion recognition is achieved. For example, OGG1 and NEIL1 both recognize and release the imidazole-ring-fragmented guanine, FapyGua as part of a common overall pathway to cleanse the genome of damaged bases. However, these glycosylases have many differences, including their differential breadth of substrate specificity, the contrasting chemistries through which base release occurs, the subsequent steps required to complete the BER pathway, and the identity of specific protein-binding partners. Beyond these differences, the complexities and differences of their in vivo biological roles have been primarily elucidated in studies of murine models harboring a knockout of Neil1 or Ogg1, with the diversity of phenotypic manifestations exceeding what might have been anticipated for a DNA glycosylase deficiency. Pathologies associated with deficiencies in nuclear DNA repair include differential cancer susceptibilities, where Ogg1-deficient mice are generally refractory to carcinogenesis, while deficiencies in Neil1-deficient mice confer cancer susceptibility. In contrast to NEIL1, OGG1 functions as a key transcription factor in regulating inflammation and other complex gene cascades. With regard to phenotypes attributed to mitochondrial repair, knockout of either of these genes results in age- and diet-induced metabolic syndrome. The adverse health consequences associated with metabolic syndrome can be largely overcome by expression of a mitochondrial-targeted human OGG1 in both wild-type and Ogg1-deficient mice. The goal of this review is to compare the roles that NEIL1 and OGG1 play in maintaining genomic integrity, with emphasis on insights gained from not only the diverse phenotypes that are manifested in knockout and transgenic mice, but also human disease susceptibility associated with polymorphic variants.

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“…Subsequent challenging with pollen extract intranasally resulted in a significantly lower allergic inflammatory response in the OGG1 siRNA treated mice compared to the mice receiving control siRNA. Moreover, Ogg1 -/- mice exhibited metabolic disorders (Komakula et al , 2018; Sampath & Lloyd, 2019; Sampath et al , 2012a; Burchat et al , 2021), which has been shown to be an important comorbidity with asthma (Peters et al , 2018; Miethe et al , 2020; Mohan et al , 2019).…”

Section: Introductionmentioning

confidence: 99%

OGG1 inhibitor TH5487 alleviates allergic airway inflammation in mice

Tanner

Bergwik

Bhongir

et al. 2022

Preprint

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Allergic asthma is a complex disease characterized by dyspnea, coughing, chest tightness and airway remodeling, for which there is no cure and is symptomatically treated with inhaled β2-agonist and/or corticosteroids. Molecular mechanisms underlying its complex pathogenesis are not fully understood. However, the 8-oxoguanine DNA glycosylase-1 (OGG1), a DNA repair protein may play a central role, as OGG1 deficiency decreases both innate and allergic inflammatory responses. In this study, administration of TH5487 to mice with OVA-induced allergic airway inflammation significantly decreased goblet cell hyperplasia and mucus production. TH5487 treatment also decreased levels of activated NF-κB and expression of proinflammatory cytokines resulting in significantly lower recruitment of eosinophils and other immune cells to the lungs. Gene expression profiling of asthma and allergy-related proteins after TH5487 treatment revealed down regulation of Arg1, Mcp1 and Ccl11, and upregulation of the negative regulator of TH2, Bcl6. In addition, the OVA-induced airway hyperresponsiveness was significantly reduced by TH5487 treatment. Taken together, the data presented in this study suggest a clinically relevant utilization of TH5487 for the treatment of allergic inflammation.

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Maternal Transmission of Human OGG1 Protects Mice Against Genetically- and Diet-Induced Obesity Through Increased Tissue Mitochondrial Content

Cited by 7 publications

References 48 publications

Metabolic protection by the dietary flavonoid 7,8-dihydroxyflavone requires an intact gut microbiome

Metabolic protection by the dietary flavonoid 7,8-dihydroxyflavone requires an intact gut microbiome

Complex Roles of NEIL1 and OGG1: Insights Gained from Murine Knockouts and Human Polymorphic Variants

OGG1 inhibitor TH5487 alleviates allergic airway inflammation in mice

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