Unspecific DNA recombination in AdipoqCre-ER<sup>T2</sup> – mediated knockout approaches in transgenic mice is sex-, age- and genotype-dependent

Lindhorst, Andreas; Bechmann, Ingo; Gericke, Martin

doi:10.1080/21623945.2019.1701394

Cited by 17 publications

(10 citation statements)

References 18 publications

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“…Lastly, we wanted to examine any possible differences in ketone bodies between placebo and low dose canagliflozin as the latter has been shown to cause euglycemic ketosis [ 47 ], however at this dose we did not note any difference in serum ketone body levels. There are reports of canagliflozin influencing mitochondrial function via AMPK-Sirt1-Pgc-1α signalling pathway [ 48 ] however we will note any differences in NAD: NADH ratio, however it will be worthwhile to investigate into these effects at higher doses.…”

Section: Discussionmentioning

confidence: 83%

Role of Canagliflozin on function of CD34+ve endothelial progenitor cells (EPC) in patients with type 2 diabetes

Nandula

Kundu

Awal

et al. 2021

Cardiovasc Diabetol

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Background Endothelial progenitor cells (EPCs) has been shown to be dysfunctional in both type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) leading to poor regeneration of endothelium and renal perfusion. EPCs have been shown to be a robust cardiovascular disease (CVD) risk indicator. Effect of sodium glucose channel inhibitors (SGLT2i) such as Canagliflozin (CG) on a cellular biomarker such as CD34+ve progenitor cells, which may help predict CVD risk, in patients with T2DM with established CKD has not been explored. Methods This is a pilot study where 29 subjects taking metformin and/or Insulin were enrolled in a 16 week, double blind, randomized placebo matched trial, with a low dose 100 mg CG as the intervention group compared to matched placebo. Type 2 diabetes subjects (30–70 years old), with hemoglobin A1c (HbA1c) of 7–10%, were enrolled. CD34+ve cell number, migratory function, gene expression along with vascular parameters such as arterial stiffness, serum biochemistry pertaining to cardio-metabolic health, resting energy expenditure and body composition were measured. Data were collected at week 0, 8 and 16. A mixed model regression analysis was done and p value less than 0.05 was considered statistically significant. Results A significant expression of CXCR4 receptor with a concomittant increase in migratory function of CD34+ve cells was observed in CG treated group as compared to placebo group. Gene expression analysis of CD34+ve cells showed an increase in expression of antioxidants (superoxide dismutase 2 or SOD2, Catalase and Glutathione Peroxidase or GPX) and notable endothelial markers (PECAM1, VEGF-A, and NOS3). A significant reduction in glucose and HbA1c levels were observed along with improved systolic and diastolic blood pressure in the CG group. A significant increase in adiponectin (p = 0.006) was also noted in treatment group. Urinary exosomal protein leak in urine, examining podocyte health (podocalyxin, Wilm’s tumor and nephrin) showed reduction with CG Conclusion Low dose Canagliflozin has a beneficial effect on CD34+ cell function, serum biochemistry and urinary podocyte specific exosomes in type 2 diabetes.

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Section: Discussionmentioning

confidence: 83%

Role of Canagliflozin on function of CD34+ve endothelial progenitor cells (EPC) in patients with type 2 diabetes

Nandula

Kundu

Awal

et al. 2021

Cardiovasc Diabetol

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“…For live-imaging of adipocytes–macrophage interactions, MacGreen mice were crossed with Adipoq CreER T2 :Rosa26-tdTomato flox/flox mice 20 . Of note, these mice exhibit previously reported sufficient tamoxifen-independent tdTomato (TDTO) expression, especially in homozygous mice 21 . Therefore, no tamoxifen induction was applied.…”

Section: Methodsmentioning

confidence: 82%

“…Formation quantification analyses were performed using Fiji software 2.0 (ref. 21 ).…”

Section: Methodsmentioning

confidence: 99%

Adipocyte death triggers a pro-inflammatory response and induces metabolic activation of resident macrophages

et al. 2021

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A chronic low-grade inflammation within adipose tissue (AT) seems to be the link between obesity and some of its associated diseases. One hallmark of this AT inflammation is the accumulation of AT macrophages (ATMs) around dead or dying adipocytes, forming so-called crown-like structures (CLS). To investigate the dynamics of CLS and their direct impact on the activation state of ATMs, we established a laser injury model to deplete individual adipocytes in living AT from double reporter mice (GFP-labeled ATMs and tdTomato-labeled adipocytes). Hence, we were able to detect early ATM-adipocyte interactions by live imaging and to determine a precise timeline for CLS formation after adipocyte death. Further, our data indicate metabolic activation and increased lipid metabolism in ATMs upon forming CLS. Most importantly, adipocyte death, even in lean animals under homeostatic conditions, leads to a locally confined inflammation, which is in sharp contrast to other tissues. We identified cell size as cause for the described pro-inflammatory response, as the size of adipocytes is above a critical threshold size for efferocytosis, a process for anti-inflammatory removal of dead cells during tissue homeostasis. Finally, experiments on parabiotic mice verified that adipocyte death leads to a pro-inflammatory response of resident ATMs in vivo, without significant recruitment of blood monocytes. Our data indicate that adipocyte death triggers a unique degradation process and locally induces a metabolically activated ATM phenotype that is globally observed with obesity.

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“…Furthermore, the Cre recombinase is most often inserted randomly into the genome and its correct position and number of copies are unknown. Additionally, Cre leakage was observed in some cases leading to unwanted recombination events (Lindhorst et al, 2020; Song and Palmiter, 2018). Due to these potential problems and to exclude developmental effects in our deletion approach above, we delivered a construct expressing the codon-improved Cre -recombinase ( iCre ) using engineered adeno-associated viruses (AAVs).…”

Section: Resultsmentioning

confidence: 99%

Deletion of the Clock GenePeriod2 (Per2)in Glial Cells Alters Mood-Related Behavior in Mice

Martini

Ripperger

Stalin

et al. 2020

Preprint

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The circadian clock regulates many biochemical and physiological pathways, and lack of clock genes, such as Period (Per) 2, do not only affect circadian activity rhythms, but can also modulate food-anticipatory and mood-related behaviors. However, it is not known how cell-type specific expression of Per2 contributes to these behaviors. In this study, we find that Per2 in glial cells is important for balancing mood-related behaviors. Genetic and adeno-associated virus-mediated deletion of Per2 in glial cells of mice leads to a depression-resistant phenotype, as manifested in reduced despair and anxiety. This is paralleled by an increase of the GABA transporter 3 (Gat3) mRNA and a reduction of glutamate levels in the nucleus accumbens (NAc). Exclusive deletion of Per2 in glia of the NAc reduced despair, but had no influence on anxiety. Our data provide strong evidence for an important role of glial Per2 in regulating mood-related behavior.

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Unspecific DNA recombination in AdipoqCre-ER^T2 – mediated knockout approaches in transgenic mice is sex-, age- and genotype-dependent

Abstract: Gericke (2020) Unspecific DNA recombination in AdipoqCre-ER T2-mediated knockout approaches in transgenic mice is sex-, age

Cited by 17 publications

References 18 publications

Role of Canagliflozin on function of CD34+ve endothelial progenitor cells (EPC) in patients with type 2 diabetes

Role of Canagliflozin on function of CD34+ve endothelial progenitor cells (EPC) in patients with type 2 diabetes

Adipocyte death triggers a pro-inflammatory response and induces metabolic activation of resident macrophages

Deletion of the Clock GenePeriod2 (Per2)in Glial Cells Alters Mood-Related Behavior in Mice

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Unspecific DNA recombination in AdipoqCre-ERT2 – mediated knockout approaches in transgenic mice is sex-, age- and genotype-dependent

Abstract: Gericke (2020) Unspecific DNA recombination in AdipoqCre-ER T2-mediated knockout approaches in transgenic mice is sex-, age

Cited by 17 publications

References 18 publications

Role of Canagliflozin on function of CD34+ve endothelial progenitor cells (EPC) in patients with type 2 diabetes

Role of Canagliflozin on function of CD34+ve endothelial progenitor cells (EPC) in patients with type 2 diabetes

Adipocyte death triggers a pro-inflammatory response and induces metabolic activation of resident macrophages

Deletion of the Clock GenePeriod2 (Per2)in Glial Cells Alters Mood-Related Behavior in Mice

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Unspecific DNA recombination in AdipoqCre-ER^T2 – mediated knockout approaches in transgenic mice is sex-, age- and genotype-dependent