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DICER is downregulated in mouse adipose tissue during high-fat diet feeding

ABSTRACT: The adipose tissue plays an important role in controlling whole-body energy balance, and proper regulation of adipose tissue function is essential for metabolic health. In response to energy surplus, the adipose tissue needs to expand, which may lead to local areas of hypoxia within the tissue. This is thought to promote whole-body insulin resistance. Here we report that DICER, a key enzyme in the maturation of miRNAs and a potential marker of adipocyte health, is profoundly downregulated in mouse adipose tissue within the first week of high-fat diet (HFD) feeding, and this effect is sustained in response to long-term HFD feeding. The downregulation of DICER protein occurs in both mature adipocytes and in the stromal vascular cells. Mechanistically, we provide evidence that hypoxia and hypoxia-inducible factor 1-α (HIF1α) facilitate ubiquitination of DICER to target it for autophagy-mediated degradation, and we show that DICER and HIF1α interact in adipose tissue after HFD feeding, which may signal for DICER degradation. Finally, despite reductions in DICER protein, we were not able to detect any differences in global miRNA levels in subcutaneous adipose tissue of mice after one or three weeks of HFD-feeding. In conclusion, the nutritional challenge of HFD feeding in mice leads to a large reduction in adipose tissue DICER protein, which is induced by hypoxia during tissue expansion and mediated through an interaction with HIF1α.

ORGANISM(S): Mus musculus

PROVIDER: GSE254511 | GEO | 2024/11/12

REPOSITORIES: GEO

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Project description:Using standardized, semipurified diets is a crucial factor for reproducibility of experimental nutritional studies. For the purpose of comparability and integration of research, two European consortia, Mitofood and BIOCLAIMS, proposed an AIN-93-based standard reference diet, the standardized BIOCLAIMS low-fat diet (LFD) as well as a high-fat diet (HFD). In order to evaluate the BIOCLAIMS LFD and HFD, we performed short-term (5 days) and long-term (12 weeks) feeding experiments using male C57BL/6 mice. The HFD has the same composition as the LFD except the fat content is increased to 40% energy in exchange for carbohydrates. Both diets were accepted by the animals and proof of principle was given that the BIOCLAIMS HFD increases body weight and body fat and affects glucose homeostasis. Short-term feeding trials (5 days) were performed in order to identify metabolic and molecular parameters which can serve as acute predictors for metabolic disorders due to high-fat diet-induced obesity. We analyzed gene expression in gonadal white adipose tissue of short- and long-term fed animals with whole genome microarrays. The BIOCLAIMS HFD strongly influenced gene expression in white adipose tissue after short- and long-term intervention. A total number of 973 and 4678 transcripts were significantly different between both diets after 5 days feeding and 12 weeks feeding, respectively. A total number of 764 transcripts encoding 549 genes were significantly differentially regulated between LF and HF animals after 12 weeks feeding as well as after 5 days feeding. Of these 549 overlapping genes, a substantial number (434 genes) were expressed at a lower level and 115 genes were expressed at a higher level in the HF mice compared to the LF mice. Without exception, all genes were regulated equally. Pathway analysis revealed a prominent role for genes involved in lipid metabolism, carbohydrate metabolism and oxidative phosphorylation. This was confirmed by quantitative real-time reverse transcription PCR. The high predictive value of gene expression changes in our short-term study compared to long-term high fat feeding is a promising step to get well-defined, early biomarkers that could shorten animal trials considerably and allow a more rapid and efficient screening of different compounds. C57BL/6J wildtype male mice, aged 12 weeks, received a low-fat diet or a high-fat diet for 5 days or 12 weeks. After sacrification, white adipose tissue depots were dissected, and immediately snap frozen in liquid nitrogen. Total RNA was isolated, quantified and qualified, and subsequently used for global gene expression profiling using Agilent 4x44K microarrays.

Project description:High fat diet (HFD) during early development may increase the susceptibility to metabolic diseases later in life. Adipose tissue is an important regulator of energy metabolism through secretion of endocrine and paracrine/autocrine factors. In the present study we first screened the expression profiles of about 500 miRNAs in visceral white adipose tissue (VAT) from mice fed a control diet (CD) and mice fed a matched HFD during three different life stages i) in utero (UT), ii) in utero and lactation (UL), iii) in utero until termination at age 23 weeks (WL). Fourteen differentially expressed miRNAs were identified and these miRNAs were used for prediction of targeted signalling pathways. In addition, analysis of high abundance miRNAs showed a marked downregulation of the miR-200 family members in the UT group. Subsequently, the transcript levels of 89 selected genes represented in the predicted signalling pathways were determined. Six genes (Deptor, Il6, Irs1, lep, Lpin1 and prkaa1) showed a significant differential expression due to HFD feeding compared to controls, and HFD treatment had significant effects on the WL-groups. The expression pattern of Deptor, Il6, Irs1, Lep genes showed a similar direction of change across all HFD treatment groups. The differential expression of Irs1 and Deptor genes points to a persistent modification of the insulin receptor – mTOR signalling network. This finding is supported by increased serum insulin and IGF-1 levels and impaired glucose regulation in the HFD groups. This study shows that developmental HFD can lead to persistent changes in VAT miRNA expression levels that is associated with a modification of key signalling pathways regulating energy metabolism also in animals with normal BMI.dy we have screened over 500 miRNAs for differential expression in visceral white adipose tissue (vWAT) between mice fed a control diet (CD; 10% kcal from fat) and mice fed a matched high fat diet (HFD; 45% kcal from fat) during three different life stages i) in utero (UT), ii) in utero and lactation (UL), iii) in utero until termination (WL). All animals were sacrifices at an age of 23 weeks.

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DICER is downregulated in mouse adipose tissue during high-fat diet feeding

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