Therapeutic Actions of an Insulin Receptor Activator and a Novel Peroxisome Proliferator-Activated Receptor γ Agonist in the Spontaneously Hypertensive Obese Rat Model of Metabolic Syndrome X

Akkermansia muciniphila is considered as one of the next-generation beneficial bacteria in the context of obesity and associated metabolic disorders. Although a first proof-of-concept of its beneficial effects has been established in the context of metabolic syndrome in humans, mechanisms are not yet fully understood. This study aimed at deciphering whether the bacterium exerts its beneficial properties through the modulation of the endocannabinoidome (eCBome). Circulating levels of 25 endogenous endocannabinoid-related lipids were quantified by liquid chromatography with tandem mass spectrometry (LC-MS/MS) in the plasma of overweight or obese individuals before and after a 3 months intervention consisting of the daily ingestion of either alive or pasteurized A. muciniphila. Results from multivariate analyses suggested that the beneficial effects of A. muciniphila were not linked to an overall modification of the eCBome. However, subsequent univariate analysis showed that the decrease in 1-Palmitoyl-glycerol (1-PG) and 2-Palmitoyl-glycerol (2-PG), two eCBome lipids, observed in the placebo group was significantly counteracted by the alive bacterium, and to a lower extent by the pasteurized form. We also discovered that 1- and 2-PG are endogenous activators of peroxisome proliferator-activated receptor alpha (PPARα). We hypothesize that PPARα activation by mono-palmitoyl-glycerols may underlie part of the beneficial metabolic effects induced by A. muciniphila in human metabolic syndrome.

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Protective Effects of PGC-1α Activators on Ischemic Stroke in a Rat Model of Photochemically Induced Thrombosis

Brain Sciences ◽

10.3390/brainsci11030325 ◽

2021 ◽

Vol 11 (3) ◽

pp. 325

Author(s):

Fatima M. Shakova ◽

Yuliya I. Kirova ◽

Denis N. Silachev ◽

Galina A. Romanova ◽

Sergey G. Morozov

Keyword(s):

Rat Model ◽

Nuclear Translocation ◽

Peroxisome Proliferator ◽

Protective Effects ◽

Protein Markers ◽

Peroxisome Proliferator Activated Receptor ◽

Pharmacological Agents ◽

Ischemic Brain ◽

Neuroprotective Therapy ◽

Dependent Protein

The pharmacological induction and activation of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), a key regulator of ischemic brain tolerance, is a promising direction in neuroprotective therapy. Pharmacological agents with known abilities to modulate cerebral PGC-1α are scarce. This study focused on the potential PGC-1α-modulating activity of Mexidol (2-ethyl-6-methyl-3-hydroxypyridine succinate) and Semax (ACTH(4–7) analog) in a rat model of photochemical-induced thrombosis (PT) in the prefrontal cortex. Mexidol (100 mg/kg) was administered intraperitoneally, and Semax (25 μg/kg) was administered intranasally, for 7 days each. The expression of PGC-1α and PGC-1α-dependent protein markers of mitochondriogenesis, angiogenesis, and synaptogenesis was measured in the penumbra via immunoblotting at Days 1, 3, 7, and 21 after PT. The nuclear content of PGC-1α was measured immunohistochemically. The suppression of PGC-1α expression was observed in the penumbra from 24 h to 21 days following PT and reflected decreases in both the number of neurons and PGC-1α expression in individual neurons. Administration of Mexidol or Semax was associated with preservation of the neuron number and neuronal expression of PGC-1α, stimulation of the nuclear translocation of PGC-1α, and increased contents of protein markers for PGC-1α activation. This study opens new prospects for the pharmacological modulation of PGC-1α in the ischemic brain.

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New Target Genes for the Peroxisome Proliferator-Activated Receptor-γ(PPARγ) Antitumour Activity: Perspectives from the Insulin Receptor

PPAR Research ◽

10.1155/2009/571365 ◽

2009 ◽

Vol 2009 ◽

pp. 1-8 ◽

Cited By ~ 2

Author(s):

Daniela P. Foti ◽

Francesco Paonessa ◽

Eusebio Chiefari ◽

Antonio Brunetti

Keyword(s):

Insulin Receptor ◽

Target Genes ◽

Tumour Progression ◽

Antitumour Activity ◽

Peptide Hormone ◽

Nuclear Hormone Receptor ◽

Peroxisome Proliferator ◽

Preclinical Research ◽

Peroxisome Proliferator Activated Receptor ◽

Wide Range

The insulin receptor (IR) plays a crucial role in mediating the metabolic and proliferative functions triggered by the peptide hormone insulin. There is considerable evidence that abnormalities in both IR expression and function may account for malignant transformation and tumour progression in some human neoplasias, including breast cancer. PPARγis a ligand-activated, nuclear hormone receptor implicated in many pleiotropic biological functions related to cell survival and proliferation. In the last decade, PPARγagonists—besides their known action and clinical use as insulin sensitizers—have proved to display a wide range of antineoplastic effects in cells and tissues expressing PPARγ, leading to intensive preclinical research in oncology. PPARγand activators affect tumours by different mechanisms, involving cell proliferation and differentiation, apoptosis, antiinflammatory, and antiangiogenic effects. We recently provided evidence that PPARγand agonists inhibit IR by non canonical, DNA-independent mechanisms affecting IR gene transcription. We conclude that IR may be considered a new PPARγ“target” gene, supporting a potential use of PPARγagonists as antiproliferative agents in selected neoplastic tissues that overexpress the IR.

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