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Long-Term Fructose Intake Increases Adipogenic Potential: Evidence of Direct Effects of Fructose on Adipocyte Precursor Cells.

ABSTRACT: We have previously addressed that fructose rich diet (FRD) intake for three weeks increases the adipogenic potential of stromal vascular fraction cells from the retroperitoneal adipose tissue (RPAT). We have now evaluated the effect of prolonged FRD intake (eight weeks) on metabolic parameters, number of adipocyte precursor cells (APCs) and in vitro adipogenic potential from control (CTR) and FRD adult male rats. Additionally, we have examined the direct fructose effects on the adipogenic capacity of normal APCs. FRD fed rats had increased plasma levels of insulin, triglyceride and leptin, and RPAT mass and adipocyte size. FACS studies showed higher APCs number and adipogenic potential in FRD RPAT pads; data is supported by high mRNA levels of competency markers: PPAR?2 and Zfp423. Complementary in vitro experiments indicate that fructose-exposed normal APCs displayed an overall increased adipogenic capacity. We conclude that the RPAT mass expansion observed in eight week-FRD fed rats depends on combined accelerated adipogenesis and adipocyte hypertrophy, partially due to a direct effect of fructose on APCs.

SUBMITTER: Zubiria MG

PROVIDER: S-EPMC4848667 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Long-Term Fructose Intake Increases Adipogenic Potential: Evidence of Direct Effects of Fructose on Adipocyte Precursor Cells.

Zubiría María Guillermina MG Alzamendi Ana A Moreno Griselda G Rey María Amanda MA Spinedi Eduardo E Giovambattista Andrés A

Nutrients 20160402 4

We have previously addressed that fructose rich diet (FRD) intake for three weeks increases the adipogenic potential of stromal vascular fraction cells from the retroperitoneal adipose tissue (RPAT). We have now evaluated the effect of prolonged FRD intake (eight weeks) on metabolic parameters, number of adipocyte precursor cells (APCs) and in vitro adipogenic potential from control (CTR) and FRD adult male rats. Additionally, we have examined the direct fructose effects on the adipogenic capaci ...[more]

PMID: 27049396

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Project description:Introduction: The molecular regulation mechanism of fat deposition in bovine and its improvement on beef quality are important research directions in the livestock industry. The research of molecular mechanisms that govern the regulation and differentiation of adipocytes may conduct to understand the mechanism of obesity, lipid disorders, and fat deposition. In the recent decade, small-molecule compounds have been widely used in reprogramming and transdifferentiation fields, which can promote the induction efficiency, replace exogenous genes, or even induce cell fate conversion alone. Furthermore, small-molecule compound induction is expected to be a novel approach to generate new cell types from somatic cells in vitro and in vivo. Methods: In this study, we established rapid chemically induced platform for transdifferentiation of bovine ear fibroblasts into adipocyte-like cells using a small-molecule cocktail (Repsox, VPA, TTNPB). The chemically induced adipocytes (CiADCs) were characterized by lipid staining, qRT-PCR and WB. Bovine natural adipocytes were used as positive control, and the expression of adipocyte-related marker genes in CiADCs were analyzed. Moreover, RNA-Seq explore the mechanism of RVB in the regulation of Bovine adipocyte transdifferentiation. Results: In this study, the chemically induced adipocytes (CiADCs) could be identified as early as day 6. The CiADCs appeared to be circular and rich of lipid droplets. The adipocyte-specific genes of LPL, PPARγ, IGF1, GPD1, C/EBPδ, ADIPOQ, PCK2, FAS, C/EBPβ, PPARGC1A, C/EBPα, and CFD were detected to be significantly upregulated in both CiADCs and natural adipocytes. Western blot analysis also confirmed the increase C/EBPα and PPARγ protein level in induced adipocytes (CiADCs-6d) treated with RVB. In addition, we also found that the signaling pathways (PPAR signaling pathway, PI3K-Akt signaling pathway, p53 signaling pathway, MAPK signaling pathway, and ECM-receptor interaction) regulated by the DEGs played a vital role in adipogenesis. Discussion: In the present study, a combination of small-molecule compounds RVB was used to transdifferentiate bovine ear fibroblasts into the chemically-induced adipocyte cells (CiADCs) that have a large number of lipid droplets. Importantly, the small-molecule cocktail significantly shortened the reprogramming turnaround time. The morphology of CiADCs is close to the "ring type" of natural differentiated adipocytes on sixth day. And, the CiADCs showed similar adipocyte-specific gene expression patterns to natural adipocytes. Furthermore, RVB increased protein expression of PPARγ and C/EBPα in the chemically-induced adipocytes (CiADCs-6d). Our findings reveal that the signaling pathways of C/EBPα and PPARγ play pivotal roles in this transdifferentiation process. In addition, we also found that the signaling pathways (PPAR signaling pathway, PI3K-Akt signaling pathway, p53 signaling pathway, MAPK signaling pathway, and ECM-receptor interaction) regulated by the DEGs played a vital role in adipogenesis. In general, this study provides valuable evidence to deepen our understanding of the molecular mechanism of small molecule cocktails in regulating adipogenesis.

Project description:BackgroundFructose consumption is a potential risk factor for hyperuricemia because uric acid (UA) is a byproduct of fructose metabolism caused by the rapid consumption of adenosine triphosphate and accumulation of adenosine monophosphate (AMP) and other purine nucleotides. Additionally, a clinical experiment with four gout patients demonstrated that intravenous infusion of fructose increased the purine de novo synthesis rate, which implied fructose-induced hyperuricemia might be related to purine nucleotide synthesis. Moreover, the mechanistic (mammalian) target of rapamycin (mTOR) is a key protein both involved in fructose metabolism and purine de novo synthesis. The present study was conducted to elucidate how fructose influences mTOR and purine de novo synthesis in a hepatic cell line and livers of mice.Materials and methodsRNA-sequencing in NCTC 1469 cells treated with 0- and 25-mM fructose for 24 h and metabolomics analysis on the livers of mice fed with 0- and 30-g/kg fructose for 2 weeks were assessed. Gene and protein expression of phosphoribosyl pyrophosphate synthase (PRPSAP1), Glutamine PRPP aminotransferase (PPAT), adenyl succinate lyase (ADSL), adenyl succinate synthetase isozyme-1 (Adss1), inosine-5'-monophosphate dehydrogenase (IMPDH), and guanine monophosphate synthetase (GMPS) was measured. The location of PRPSAP1 and PPAT in the liver was assessed by an immunofluorescence assay.ResultsMetabolite profiling showed that the level of AMP, adenine, adenosine, hypoxanthine, and guanine was increased significantly. RNA-sequencing showed that gene expression of phosphoribosyl pyrophosphate synthase (PRPS2), phosphoribosyl glycinamide formyl transferase (GART), AICAR transformylase (ATIC), ADSL, Adss1, and IMPDH were raised, and gene expression of adenosine monophosphate deaminase 3 (AMPD3), adenosine deaminase (ADA), 5',3'-nucleotidase, cytosolic (NT5C), and xanthine oxidoreductase (XOR) was also increased significantly. Fructose increased the gene expression, protein expression, and fluorescence intensity of PRPSAP1 and PPAT in mice livers by increasing mTOR expression. Fructose increased the expression and activity of XOR, decreased the expression of uricase, and increased the serum level of UA.ConclusionThis study demonstrated that the increased purine de novo synthesis may be a crucial mechanism for fructose-induced hyperuricemia.

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Long-Term Fructose Intake Increases Adipogenic Potential: Evidence of Direct Effects of Fructose on Adipocyte Precursor Cells.

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Long-Term Fructose Intake Increases Adipogenic Potential: Evidence of Direct Effects of Fructose on Adipocyte Precursor Cells.

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