PPAR-γ agonist pioglitazone reduces microglial proliferation and NF-κB activation in the substantia nigra in the 6-hydroxydopamine model of Parkinson’s disease

Machado, Meira Maria Forcelini; Bassani, Taysa Bervian; Cóppola-Segovia, Valentín; Moura, Eric Luiz Rossa; Zanata, Sı́lvio M.; Andreatini, Roberto; Vital, Maria A.B.F.

doi:10.1016/j.pharep.2018.11.005

“…From the present and some previous studies [13][14][15][16][17][18][19][20][21][22], we can conclude that dietary PGZ can increase muscle fat deposition and improve the meat quality of food animals. It has potential as a new functional feed additive.…”

Section: Discussionsupporting

confidence: 62%

“…As adipogenic compounds, TZDs play a crucial role in adipocyte differentiation and have the potential to alter the formation of intramuscular or marbled fat [15,16]. As one of the TZDs, pioglitazone hydrochloride (PGZ) is a high-affinity ligand for peroxisome proliferator-activated receptor gamma (PPARγ) [17], and previous study has found that PGZ can promote adipocyte differentiation to modify intramuscular adipogenesis [15]. More adipocytes and larger cell sizes have been observed in mice supplemented with PGZ [13,14,18].…”

Section: Introductionmentioning

confidence: 99%

Dietary Supplementation with Pioglitazone Hydrochloride and Resveratrol Improves Meat Quality and Antioxidant Capacity of Broiler Chickens

Zhang

¹

,

Jin

²

,

Jiang

³

et al. 2020

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The study aimed to investigate the effects of pioglitazone hydrochloride (PGZ) and resveratrol (RES) on yellow-feathered broiler chickens. A total of 500 broiler chickens were randomly divided into four groups and fed a basic diet (control group) or a basic diet supplemented with 15 mg/kg PGZ, 400 mg/kg RES, or 15 mg/kg PGZ plus 400 mg/kg RES for 28 days. Compared with the control group, the PGZ and PGZ plus RES groups presented a significantly higher average daily gain and a decreased feed-to-gain ratio. Increases in the dressing percentage, semi-eviscerated yield, muscle intramuscular fat content, and C18:1n-9c, C18:3n-6, C20:3n-3, and monounsaturated fatty acid (MUFA) percentages were found in the PGZ plus RES group. Moreover, the diet supplemented with RES or PGZ plus RES increased the activities of catalase, glutathione peroxidase, and superoxide dismutase, and decreased the levels of reactive oxygen species of thigh muscle. Additionally, the mRNA abundance of peroxisome proliferator-activated receptor γ coactivator 1α, fatty acid-binding protein 3, nuclear factor erythroid-2-related factor 2, and superoxide dismutase 1 was increased in the PGZ plus RES group. In conclusion, this study suggested that dietary supplementation of PGZ combined with RES improved the growth performance, the muscle intramuscular fat content, and antioxidant ability of yellow-feathered broiler chickens.

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“…The prominent isoform expressed in inflammatory cells is PPARγ3. Pioglitazone, an agonist of PPARγ, has been shown to halt progression of Parkinsonism in a rodent model, ostensibly by inhibiting microglial inflammation and proliferation, although it is difficult to conclude if this is a direct effect on microglia given that the compound can affect a number of cells in these models. Targeting PPARγ for therapeutic benefit in AD has also recently been proposed .…”

Section: Discussionmentioning

confidence: 99%

A locked immunometabolic switch underlies TREM2 R47H loss of function in human iPSC‐derived microglia

Piers

¹

,

Cosker

²

,

Mallach

³

et al. 2019

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Loss‐of‐function genetic variants of triggering receptor expressed on myeloid cells 2 (TREM2) are linked with an enhanced risk of developing dementias. Microglia, the resident immune cell of the brain, express TREM2, and microglial responses are implicated in dementia pathways. In a normal surveillance state, microglia use oxidative phosphorylation for their energy supply, but rely on the ability to undergo a metabolic switch to glycolysis to allow them to perform rapid plastic responses. We investigated the role of TREM2 on the microglial metabolic function in human patient iPSC‐derived microglia expressing loss of function variants in TREM2. We show that these TREM2 variant iPSC‐microglia, including the Alzheimer's disease R47H risk variant, exhibit significant metabolic deficits including a reduced mitochondrial respiratory capacity and an inability to perform a glycolytic immunometabolic switch. We determined that dysregulated PPARγ/p38MAPK signaling underlies the observed phenotypic deficits in TREM2 variants and that activation of these pathways can ameliorate the metabolic deficit in these cells and consequently rescue critical microglial cellular function such as β‐Amyloid phagocytosis. These findings have ramifications for microglial focussed‐treatments in AD.

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“…The prominent isoform expressed in inflammatory cells is PPARγ3. Pioglitazone, an agonist of PPARγ, has been shown to halt progression of Parkinsonism in a rodent model, ostensibly by inhibiting microglial inflammation and proliferation (Machado et al, 2019), although it is difficult to conclude if this is a direct effect on microglia given that the compound can affect a number of cells in these models. Targeting PPARγ for therapeutic benefit in AD has also recently been proposed (Khan et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

A locked immunometabolic switch underlies TREM2 R47H loss of function in human iPSC--derived microglia

Piers

¹

,

Cosker

²

,

Mallach

³

et al. 2019

Preprint

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Loss‐of‐function genetic variants of triggering receptor expressed on myeloid cells 2 (TREM2) are linked with an enhanced risk of developing dementias. Microglia, the resident immune cell of the brain, express TREM2, and microglial responses are implicated in dementia pathways. In a normal surveillance state, microglia use oxidative phosphorylation for their energy supply, but rely on the ability to undergo a metabolic switch to glycolysis to allow them to perform rapid plastic responses. We investigated the role of TREM2 on the microglial metabolic function in human patient iPSC‐derived microglia expressing loss of function variants in TREM2. We show that these TREM2 variant iPSC‐microglia, including the Alzheimer's disease R47H risk variant, exhibit significant metabolic deficits including a reduced mitochondrial respiratory capacity and an inability to perform a glycolytic immunometabolic switch. We determined that dysregulated PPARγ/p38MAPK signaling underlies the observed phenotypic deficits in TREM2 variants and that activation of these pathways can ameliorate the metabolic deficit in these cells and consequently rescue critical microglial cellular function such as β‐Amyloid phagocytosis. These findings have ramifications for microglial focussed‐treatments in AD.

show abstract

PPAR-γ agonist pioglitazone reduces microglial proliferation and NF-κB activation in the substantia nigra in the 6-hydroxydopamine model of Parkinson’s disease

Cited by 72 publications

References 39 publications

Dietary Supplementation with Pioglitazone Hydrochloride and Resveratrol Improves Meat Quality and Antioxidant Capacity of Broiler Chickens

Dietary Supplementation with Pioglitazone Hydrochloride and Resveratrol Improves Meat Quality and Antioxidant Capacity of Broiler Chickens

A locked immunometabolic switch underlies TREM2 R47H loss of function in human iPSC‐derived microglia

A locked immunometabolic switch underlies TREM2 R47H loss of function in human iPSC--derived microglia

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