Dataset Information

Intracellular peptides mediate phenotypic differences between wild type and thimet oligopeptidase null mice possibly through their binding to microRNAs

ABSTRACT: The constant increase in the obese and overweight population creates opportunities for novel therapeutic innovations to allow people to eat without getting fat and getting sick. Here, fed a hyperlipidic diet (HD)C57BL6 thimet oligopeptidase null (THOP1-/-) male mice were shown to gain only 25% (females gained 60%) of the weight gained by control wild type (WT) mice. Distinct from WT mice,THOP1-/- fed HD exhibited normal blood glucose levels and no insulin resistance. THOP1-/-fed HD phenotype benefits also include regular blood cholesterol levels, reduced fat in adipose and liver tissues, increased adipose tissue adrenergic-stimulated lipolysis, and greater resistance and endurance on treadmill running tests at high intensity. THOP1-/-compared to WT have alterations on the expression levels of specific genes and microRNAs related to obesity. Intracellular peptides that had their relative levels altered in THOP1-/-were shown to modulate the expression levels of genes and mature microRNAs associated to obesity, in 3T3L1 adipocyte. The ubiquitous existence of intracellular peptides in different cells of different species suggests a broader biological significance of the present results, connecting proteasomal protein degradation to protein synthesis. These exciting results suggest THOP1 and intracellular peptides as novel therapeutic targets to control obesity and obesity-associated diseases.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Mus Musculus (mouse)

SUBMITTER: Amanda Miquilini Cordibello

LAB HEAD: Emer Suavinho Ferro

PROVIDER: PXD016265 | Pride | 2020-02-24

REPOSITORIES: Pride

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Publications

The Relevance of Thimet Oligopeptidase in the Regulation of Energy Metabolism and Diet-Induced Obesity.

Gewehr Mayara C F MCF Teixeira Alexandre A S AAS Santos Bruna A C BAC Biondo Luana A LA Gozzo Fábio C FC Cordibello Amanda M AM Eichler Rosangela A S RAS Reckziegel Patrícia P Da Silva Renée N.O. RNO Dos Santos Nilton B NB Camara Niels O S NOS Castoldi Angela A Barreto-Chaves Maria L M MLM Dale Camila S CS Senger Nathalia N Lima Joanna D C C JDCC Seelaender Marilia C L MCL Inada Aline C AC Akamine Eliana H EH Castro Leandro M LM Rodrigues Alice C AC Neto José C Rosa JCR Ferro Emer S ES

Biomolecules 20200217 2

Thimet oligopeptidase (EC 3.4.24.15; EP24.15; THOP1) is a potential therapeutic target, as it plays key biological functions in processing biologically functional peptides. The structural conformation of THOP1 provides a unique restriction regarding substrate size, in that it only hydrolyzes peptides (optimally, those ranging from eight to 12 amino acids) and not proteins. The proteasome activity of hydrolyzing proteins releases a large number of intracellular peptides, providing THOP1 substrate ...[more]

PMID: 32079362

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Project description:To profile the expression of circulating miRNAs in a mouse model of diet-induced obesity (DIO) with subsequent weight-reduction with low-fat diet (LFD), eighteen C57BL/6 male mice were grouped into three subgroups as: (1) Control: the mice fed with the standard AIN-76A (fat: 11.5 kcal%) diet for 12 wks; (2) DIO: the mice fed with 58 kcal% high-fat diet for 12 wks; (3) DIO+LFD: the mice fed with high-fat diet for 8 wks to induce obesity, then changed to 10.5 kcal% low-fat diet for subsequent 4 wks. C57BL/6 mice were purchased from BioLasco (Taipei, Taiwan). All housing conditions were maintained, and surgical procedures, including analgesia, were performed in an Association for Assessment and Accreditation of Laboratory Animal Care International (AAALAC)-accredited SPF facility according to national and institutional guidelines. In this experiment, eighteen C57BL/6 wild type male mice were randomly grouped into three subgroups (n=6 in each group): (1) Control: the control mice were fed ad libitum a standard AIN-76A (fat: 11.5 kcal%) diet for 12 wks; (2) DIO: the mice were fed ad libitum a 58 kcal% HFD (D12331; Research Diets Inc., New Brunswick, NJ) for 12 wks to induce obesity; (3) DIO+LFD: the mice fed ad libitum a 58 kcal% HFD (D12331) for 8 wks to induce obesity, then continued the feeding of 10.5 kcal% LFD (D 12329; Research Diets Inc.) for additional 4 wks. Weight measurements were performed on a weekly basis to for these three groups of mice. Evaluation of blood glucose levels was performed at the beginning and in the end of the experiment to confirm that the HFD-fed mice developed an obese and insulin resistant phenotype. After the end of experiment at 12w, all mice were killed. The abdominal WAT of each mice was removed and weighted. Paraffin-embedded abdominal WAT was sectioned at 5 M-NM-<m and stained with hematoxylin and eosin to measure mean adipocyte area. A volume of 1 mL of whole blood was collected into a plain tube and allowed to clot for 1 hour. The sera samples were aliquoted after centrifugation at 3,000 M-CM-^W g for 10 minutes and stored at M-bM-^HM-^R80M-BM-0C until further analysis.

Dataset Information

Intracellular peptides mediate phenotypic differences between wild type and thimet oligopeptidase null mice possibly through their binding to microRNAs

Publications

The Relevance of Thimet Oligopeptidase in the Regulation of Energy Metabolism and Diet-Induced Obesity.

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