Intestinal PPARδ protects against diet-induced obesity, insulin resistance and dyslipidemia

Doktorova, Marcela; Zwarts, Irene; Zutphen, Tim van; Dijk, Theo H. van; Bloks, Vincent W.; Harkema, Liesbeth; Bruin, Alain de; Downes, Michael; Evans, Ronald M.; Verkade, Henkjan J.; Jonker, Johan W.

doi:10.1038/s41598-017-00889-z

Cited by 35 publications

(27 citation statements)

References 49 publications

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“…Mice were single housed in a Comprehensive Laboratory Animal Monitoring System (Phenomaster; TSE Systems GmbH) at PN154 for 4 d as previously described (14) .…”

Section: Calorimetrymentioning

confidence: 99%

Programming effects of an early life diet containing large phospholipid-coated lipid globules are transient under continuous exposure to a high-fat diet

et al. 2019

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Breast-feeding is associated with a lower risk of developing obesity during childhood and adulthood compared with feeding infant milk formula (IMF). Previous studies have shown that an experimental IMF (eIMF; comprising Nuturis®) programmed mouse pups for a lower body weight and fat mass gain in adulthood when challenged with a high-fat diet (HFD) compared with a control IMF (cIMF). Nuturis has a lipid composition and structure more similar to breast milk. Here, the long-term effects were tested of a similar eIMF, but with an adapted lipid composition and a cIMF, on body weight, glucose homoeostasis, liver and adipose tissue. Nutrient composition was similar for the eIMF and cIMF; the lipid fractions comprised approximately 50 % milk fat. C57BL/6JOlaHsd mice were fed cIMF or eIMF from postnatal day (PN) 16–42 followed by an HFD until PN168. Feeding eIMF v. cIMF in early life resulted in a lower body weight (–9 %) and body fat deposition (–14 %) in adulthood (PN105). The effect appeared transient, as from PN126 onwards, after 12 weeks’ HFD, eIMF-fed mice caught up on controls and body and fat weights became comparable between groups. Glucose and energy metabolism were similar between groups. At dissection (PN168), eIMF-fed mice showed larger (+27 %) epididymal fat depots and a lower (–26 %) liver weight without clear morphological aberrations. Our data suggest the size and coating but not the lipid composition of IMF fat globules underlie the programming effect observed. Prolonged exposure to an HFD challenge partly overrules the programming effect of early diet.

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“…Mice were single housed in a Comprehensive Laboratory Animal Monitoring System (Phenomaster; TSE Systems GmbH) at PN154 for 4 d as previously described (14) .…”

Section: Calorimetrymentioning

confidence: 99%

Programming effects of an early life diet containing large phospholipid-coated lipid globules are transient under continuous exposure to a high-fat diet

et al. 2019

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“…PPARδ is located in the chromosomal region 6p21.2-p21.1 and consists of nine exons. It is an important regulator of skeletal muscle metabolism, particularly lipid and lipoprotein metabolism, as well as lipid oxidation (18,19). Lipid metabolism dysfunction has been demonstrated to be important in the pathogenesis of obesity-associated IR (20).…”

Section: Microrna-29a Is Involved Lipid Metabolism Dysfunction and Inmentioning

confidence: 99%

MicroRNA‑29a is involved lipid metabolism dysfunction and insulin resistance in C2C12 myotubes by targeting PPARδ

Wang

Jiang

et al. 2018

Mol Med Report

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MicroRNA‑29a (miR‑29a) expression has been reported to be closely associated with skeletal muscle insulin resistance and type 2 diabetes. The present study investigated the effect of miR‑29a on palmitic acid (PA)‑induced lipid metabolism dysfunction and insulin resistance in C2C12 myotubes via overexpressing or silencing of miR‑29a expression. Mouse C2C12 myoblasts were cultured, differentiated and transfected with miR‑29a or miR‑29a inhibitor lentiviral with or without subsequent palmitic acid (PA) treatment. Reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) and western blot analysis were performed to assess the mRNA and protein levels of related genes, respectively. PA treatment increased the expression of miR‑29a in a time‑ and dose‑ dependent manner. miR‑29a silencing improved insulin‑induced glucose uptake and increased glucose transporter‑4 (GLUT4) transportation to the plasma membrane by upregulating its target peroxisome proliferator‑activated receptor δ (PPARδ). Furthermore, it was observed that miR‑29a regulated the expression of genes associated with lipid metabolism, including pyruvate dehydrogenase kinase isoform, mitochondrial uncoupling protein (UCP)2, UCP3, long chain specific acyl‑CoA dehydrogenase, mitochondrial and fatty acid transport protein 2. The results confirmed that silencing miR‑29a induced a decrease in glucose transport and affected lipid metabolism in PA‑treated C2C12 cells, and therefore may be involved in insulin resistance by targeting PPARδ in skeletal muscle. Therefore, the inhibition of miR‑29a may be a potential novel strategy for treating insulin resistance and type 2 diabetes.

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“…PPARβ/δ is strongly related to metabolic alterations under obese conditions and has a major role in glucose and lipid homeostasis by promoting fatty acid oxidation, overall energy expenditure, reverse cholesterol transport and insulin sensibilization . Indeed, mice overexpressing a constitutively activate form of PPARβ/δ have been shown to be resistant to obesity induced by high‐fat diet or genetic modifications .…”

Section: Discussionmentioning

confidence: 99%

GQ‐130, a novel analogue of thiazolidinedione, improves obesity‐induced metabolic alterations in rats: Evidence for the involvement of PPARβ/δ pathway

Silva

Ribeiro-Filho

Avelino

et al. 2020

Clin Exp Pharma Physio

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The present investigation aimed to characterize the effect of a short‐time treatment with a new thiazolidinedione (TZD) derivative, GQ‐130, on metabolic alterations in rats fed a high‐fat diet (HFD). We investigated whether metabolic alterations induced by GQ‐130 were mediated though a mechanism that involves PPARβ/δ transactivation. Potential binding and transactivation of PPARα, PPARβ/δ or PPARγ by GQ‐130 were examined through cell transactivation, 8‐anilino‐1‐naphthalenesulfonic acid (ANS) fluorescence quenching assays and thermal shift assay. For in vivo experiments, male 8‐week‐old Wistar rats were divided into three groups fed for 6 weeks with: (a) a standard rat chow (14% fat) (control group), (b) a HFD (57.8% fat) alone (HFD group), or (c) a HFD associated with an oral treatment with GQ‐130 (10 mg/kg/d) during the last week (HFD‐GQ group). In 293T cells, unlike rosiglitazone, GQ‐130 did not cause significant transactivation of PPARγ but was able to activate PPARβ/δ by 153.9 folds in comparison with control values (DMSO). Surprisingly, ANS fluorescence quenching assay reveals that GQ‐130 does not bind directly to PPARβ/δ binding site, a finding that was further corroborated by thermal shift assay which evaluates the thermal stability of PPARβ/δ in the presence of GQ‐130. Compared to the control group, rats of the HFD group showed obesity, increased systolic blood pressure (SBP), insulin resistance, impaired glucose intolerance, hyperglycaemia, and dyslipidaemia. GQ‐130 treatment abolished the increased SBP and improved all metabolic dysfunctions observed in the HFD group. Oral treatment with GQ‐130 was effective in improving HFD‐induced metabolic alterations probably through a mechanism that involves PPARβ/δ activation.

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Intestinal PPARδ protects against diet-induced obesity, insulin resistance and dyslipidemia

Cited by 35 publications

References 49 publications

Programming effects of an early life diet containing large phospholipid-coated lipid globules are transient under continuous exposure to a high-fat diet

Programming effects of an early life diet containing large phospholipid-coated lipid globules are transient under continuous exposure to a high-fat diet

MicroRNA‑29a is involved lipid metabolism dysfunction and insulin resistance in C2C12 myotubes by targeting PPARδ

GQ‐130, a novel analogue of thiazolidinedione, improves obesity‐induced metabolic alterations in rats: Evidence for the involvement of PPARβ/δ pathway

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