Impaired glucose and lipid metabolism in ageing aryl hydrocarbon receptor deficient mice

Biljes, Daniel; Hammerschmidt-Kamper, Christiane; Kadow, Stephanie; Diel, Patrick; Weigt, Carmen; Burkart, Volker; Esser, Charlotte

doi:10.17179/excli2015-638

Cited by 17 publications

(5 citation statements)

References 43 publications

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“…Despite no difference in fasting blood glucose, glucose‐, pyruvate‐, and lipid tolerance between young and old mice, we demonstrate that the administration of D&Q improved metabolic function in old mice. The lack of difference in metabolic function between young and old mice is well‐evident in the literature (Biljes et al, 2015 ; Marmentini et al, 2021 ; Oh et al, 2016 ; Petr et al, 2021 ; Reynolds et al, 2019 ). However, a preclinical model that recapitulates every aspect of metabolic dysfunction that is observed in older human is currently unavailable.…”

Section: Discussionmentioning

confidence: 82%

Senolytic drugs, dasatinib and quercetin, attenuate adipose tissue inflammation, and ameliorate metabolic function in old age

et al. 2023

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Aging results in an elevated burden of senescent cells, senescence‐associated secretory phenotype (SASP), and tissue infiltration of immune cells contributing to chronic low‐grade inflammation and a host of age‐related diseases. Recent evidence suggests that the clearance of senescent cells alleviates chronic inflammation and its associated dysfunction and diseases. However, the effect of this intervention on metabolic function in old age remains poorly understood. Here, we demonstrate that dasatinib and quercetin (D&Q) have senolytic effects, reducing age‐related increase in senescence‐associated β‐galactosidase, expression of p16 and p21 gene and P16 protein in perigonadal white adipose tissue (pgWAT; all p ≤ 0.04). This treatment also suppressed age‐related increase in the expression of a subset of pro‐inflammatory SASP genes ( mcp1, tnf‐α, il‐1α, il‐1β, il‐6, cxcl2, and cxcl10 ), crown‐like structures, abundance of T cells and macrophages in pgWAT (all p ≤ 0.04). In the liver and skeletal muscle, we did not find a robust effect of D&Q on senescence and inflammatory SASP markers. Although we did not observe an age‐related difference in glucose tolerance, D&Q treatment improved fasting blood glucose ( p = 0.001) and glucose tolerance ( p = 0.007) in old mice that was concomitant with lower hepatic gluconeogenesis. Additionally, D&Q improved insulin‐stimulated suppression of plasma NEFAs ( p = 0.01), reduced fed and fasted plasma triglycerides (both p ≤ 0.04), and improved systemic lipid tolerance ( p = 0.006). Collectively, results from this study suggest that D&Q attenuates adipose tissue inflammation and improves systemic metabolic function in old age. These findings have implications for the development of therapeutic agents to combat metabolic dysfunction and diseases in old age.

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Section: Discussionmentioning

confidence: 82%

Senolytic drugs, dasatinib and quercetin, attenuate adipose tissue inflammation, and ameliorate metabolic function in old age

et al. 2023

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“…However, it is important to note that βAhr KO females displayed normal fasted and glucosestimulated plasma insulin levels in vivo, potentially pointing to increased insulin clearance in βAhr KO females; more detailed analyses are required to understand this phenotype. Interestingly, previous studies report normal fasting blood glucose, fasting c-peptide levels, and glucose tolerance in young global Ahr KO female mice (3 -4 months of age), but glucose intolerance, hypoinsulinemia, and insulin resistance in aged Ahr null female mice (7 -15 months of age) [41,42]. Given that the subset of female mice that were maintained until 6 week post-injection in our study were ~3-5 months of age, longer-term studies in βAhr KO mice are warranted to better understand the role of AhR in β-cells.…”

Section: Discussionmentioning

confidence: 96%

The aryl hydrocarbon receptor in β-cells mediates the effects of TCDD on glucose homeostasis in mice

Hoyeck,

Ching,

Basu

et al. 2023

Preprint

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Chronic exposure to persistent organic pollutants (POPs) is associated with increased incidence of type 2 diabetes, hyperglycemia, and poor insulin secretion in humans. Dioxins and dioxin-like compounds are a broad class of POPs that exert cellular toxicity through activation of the aryl hydrocarbon receptor (AhR). We previously showed that a single high-dose injection of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, aka dioxin; 20 ug/kg) in vivo reduced fasting and glucose-stimulated plasma insulin levels for up to 6 weeks in male and female mice. TCDD-exposed male mice were also modestly hypoglycemic and had increased insulin sensitivity, whereas TCDD-exposed females were transiently glucose intolerant; whether these effects are driven by AhR activation in beta-cells requires investigation. Here we exposed female and male beta-cell specific AhR knockout (beta-AhrKO) mice and littermate Ins1-Cre genotype controls (beta-AhrWT) to a single high dose of 20 ug/kg TCDD and tracked the mice for 6 weeks. We found that deleting AhR from beta-cells increased insulin secretion ex vivo in female mouse islets and promoted modest weight gain in male mice under baseline conditions. Importantly, high-dose TCDD exposure impaired glucose homeostasis and beta-cell function in beta-AhrWT mice, but these phenotypes were largely abolished in TCDD-exposed beta-AhrKO mice. Our study demonstrates that AhR signaling in beta-cell is important for regulating baseline beta-cell function in female mice and energy homeostasis in male mice. We also show that beta-cell AhR signaling largely mediates the effects of TCDD on glucose homeostasis in both female and male mice, suggesting that the effects of TCDD on beta-cell function/health are driving metabolic phenotypes in peripheral tissues.

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“…However, it is important to note that βAhr KO females displayed normal fasted and glucose-stimulated plasma insulin levels compared to βAhr WT females, potentially pointing to increased insulin clearance in βAhr KO females; more detailed analyses are required to understand this phenotype, including assessing the interaction between βAhR and sex hormones [ [41] , [42] , [43] , [44] ]. Interestingly, previous studies report normal fasting blood glucose, fasting c-peptide levels, and glucose tolerance in young global Ahr KO female mice (3–4 months of age), but glucose intolerance, hypoinsulinemia, and insulin resistance in aged Ahr KO female mice (7–15 months of age) [ 45 , 46 ]. Given that the subset of female mice that were maintained until 6 weeks post-injection in our study were ∼3–5 months of age, longer-term studies in older βAhr KO mice are warranted.…”

Section: Discussionmentioning

confidence: 99%

The aryl hydrocarbon receptor in β-cells mediates the effects of TCDD on glucose homeostasis in mice

Hoyeck,

Angela Ching,

Basu

et al. 2024

Molecular Metabolism

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Impaired glucose and lipid metabolism in ageing aryl hydrocarbon receptor deficient mice

Cited by 17 publications

References 43 publications

Senolytic drugs, dasatinib and quercetin, attenuate adipose tissue inflammation, and ameliorate metabolic function in old age

Senolytic drugs, dasatinib and quercetin, attenuate adipose tissue inflammation, and ameliorate metabolic function in old age

The aryl hydrocarbon receptor in β-cells mediates the effects of TCDD on glucose homeostasis in mice

The aryl hydrocarbon receptor in β-cells mediates the effects of TCDD on glucose homeostasis in mice

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