Two Isomeric C16 Oxo-Fatty Acids from the Diatom Chaetoceros karianus Show Dual Agonist Activity towards Human Peroxisome Proliferator-Activated Receptors (PPARs) α/γ

Peroxisome-proliferator-activated receptors (PPARs) α and γ are ligand-dependent transcription factors that are key regulators of lipid and carbohydrate homoeostasis. Fatty acids bind to the ligand-binding domains (LBDs) of PPARα and PPARγ and activate these receptors. To clarify whether fatty-acyl-CoAs interact directly with the LBDs of PPARα and PPARγ, we performed a competition binding assay with radiolabelled KRP-297, a known dual agonist for these receptors. We show here that fatty-acyl-CoAs bind directly to PPARα and PPARγ. Interestingly, fatty-acyl-CoAs, unlike fatty acids, failed to recruit steroid receptor co-activator 1 (SRC-1), on the basis of conformational changes in the LBDs of PPARα and PPARγ. Moreover, fatty-acyl-CoAs also markedly inhibited agonist-induced recruitment of SRC-1. These findings demonstrate that fatty-acyl-CoAs have a novel function in the signalling pathways of PPARα and PPARγ.

Download Full-text

Two antibacterial and PPARα/γ-agonistic unsaturated keto fatty acids from a coral-associated actinomycete of the genus Micrococcus

Beilstein Journal of Organic Chemistry ◽

10.3762/bjoc.16.29 ◽

2020 ◽

Vol 16 ◽

pp. 297-304 ◽

Cited By ~ 1

Author(s):

Amit Raj Sharma ◽

Enjuro Harunari ◽

Naoya Oku ◽

Nobuyasu Matsuura ◽

Agus Trianto ◽

...

Keyword(s):

Fatty Acids ◽

Spectroscopic Analysis ◽

Culture Broth ◽

Peroxisome Proliferator ◽

Simulation Studies ◽

Fish Pathogen ◽

Chemical Structures ◽

Agonistic Activity ◽

Isoform Specificity ◽

Peroxisome Proliferator Activated Receptors

A pair of geometrically isomeric unsaturated keto fatty acids, (6E,8Z)- and (6E,8E)-5-oxo-6,8-tetradecadienoic acids (1 and 2), were isolated from the culture broth of an actinomycete of the genus Micrococcus, which was associated with a stony coral, Catalaphyllia sp. Their chemical structures were elucidated by spectroscopic analysis including NMR and MS, with special assistance of spin system simulation studies for the assignment of an E geometry at C8 in 2. As metabolites of microbes, compounds 1 and 2 are unprecedented in terms of bearing a 2,4-dienone system. Both 1 and 2 showed antibacterial activity against the plant pathogen Rhizobium radiobacter and the fish pathogen Tenacibaculum maritimum, with a contrasting preference that 1 is more effective to the former strain while 2 is so to the latter. In addition, compounds 1 and 2 displayed agonistic activity against peroxisome proliferator-activated receptors (PPARs) with an isoform specificity towards PPARα and PPARγ.

Download Full-text

Molecular Recognition of Fatty Acids by Peroxisome Proliferator–Activated Receptors

Molecular Cell ◽

10.1016/s1097-2765(00)80467-0 ◽

1999 ◽

Vol 3 (3) ◽

pp. 397-403 ◽

Cited By ~ 785

Author(s):

H.Eric Xu ◽

Millard H Lambert ◽

Valerie G Montana ◽

Derek J Parks ◽

Steven G Blanchard ◽

...

Keyword(s):

Fatty Acids ◽

Molecular Recognition ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptors

Download Full-text

GLP-1-mediated delivery of the PPAR𝛼/𝛾 dual-agonist Tesaglitazar improves obesity and glucose metabolism in mice

10.21203/rs.3.rs-1081959/v1 ◽

2021 ◽

Author(s):

Carmelo Quarta ◽

Kerstin Stemmer ◽

Aaron Novikoff ◽

Bin Yang ◽

Felix Klingelhuber ◽

...

Keyword(s):

Body Weight ◽

Glucose Metabolism ◽

Peroxisome Proliferator ◽

Protein Targets ◽

Beneficial Effects ◽

Glucose And Lipid Metabolism ◽

Therapeutic Value ◽

Affect Body Weight ◽

Peroxisome Proliferator Activated Receptors ◽

Dual Agonist

Abstract Dual-agonists activating the peroxisome proliferator-activated receptors alpha and gamma (PPAR𝛼/𝛾) have shown beneficial effects on glucose and lipid metabolism in patients with type 2 diabetes, but their development was discontinued due to unfavorable cardiovascular and/or renal effects. Here we report the design and preclinical evaluation of a molecule that covalently links the PPAR𝛼/𝛾 dual-agonist Tesaglitazar to GLP-1 to allow for the GLP-1 receptor-dependent delivery of Tesaglitazar. GLP-1/Tesaglitazar does not differ from matched GLP-1 in GLP-1R signaling, but shows GLP-1R-dependent PPAR𝛾-RXR heterodimerization with enhanced efficacy to improve body weight, food intake, and glucose metabolism relative to GLP-1 or Tesaglitazar in mice with diet- and genetically-induced obesity. The conjugate fails to affect body weight and glucose metabolism in GLP-1R knockout (ko) mice and shows preserved effects in DIO mice at doses subthreshold for GLP-1 and Tesaglitazar to improve metabolism. Consistent with the GLP-1R expression pattern, LC/MS-based proteomics identified a series of novel PPAR protein targets in the hypothalamus that are acutely upregulated by Tesaglitazar and by GLP-1/Tesaglitazar, but not by treatment with GLP-1. Collectively, our data show that GLP-1/Tesaglitazar improves energy and glucose metabolism with superior efficacy to GLP-1 or Tesaglitazar alone and suggest that this conjugate holds therapeutic value to treat hyperglycemia and insulin resistance.

Download Full-text

Peroxisome proliferator-activated receptors (PPARs) as a mediator of dietary fatty acids affects reproductive performance in broiler breeder roosters

Theriogenology ◽

10.1016/j.theriogenology.2020.09.020 ◽

2020 ◽

Vol 158 ◽

pp. 331-338

Author(s):

Laya Pourazadi ◽

Mohsen Sharafi ◽

Mohammad Amir Karimi Torshizi ◽

Abdolhossein Shahverdi ◽

AliReza Alizadeh

Keyword(s):

Fatty Acids ◽

Reproductive Performance ◽

Dietary Fatty Acids ◽

Peroxisome Proliferator ◽

Broiler Breeder ◽

Peroxisome Proliferator Activated Receptors

Download Full-text

Peroxisome Proliferator-Activated Receptor Delta: A Conserved Director of Lipid Homeostasis through Regulation of the Oxidative Capacity of Muscle

PPAR Research ◽

10.1155/2008/172676 ◽

2008 ◽

Vol 2008 ◽

pp. 1-7 ◽

Cited By ~ 23

Author(s):

Pieter de Lange ◽

Assunta Lombardi ◽

Elena Silvestri ◽

Fernando Goglia ◽

Antonia Lanni ◽

...

Keyword(s):

Skeletal Muscle ◽

Fatty Acids ◽

Oxidative Capacity ◽

Whole Body ◽

Lipid Homeostasis ◽

Peroxisome Proliferator ◽

Transcriptional Program ◽

Peroxisome Proliferator Activated Receptor ◽

Peroxisome Proliferator Activated Receptors ◽

Metabolic Action

The peroxisome proliferator-activated receptors (PPARs), which are ligand-inducible transcription factors expressed in a variety of tissues, have been shown to perform key roles in lipid homeostasis. In physiological situations such as fasting and physical exercise, one PPAR subtype, PPARδ, triggers a transcriptional program in skeletal muscle leading to a switch in fuel usage from glucose/fatty acids to solely fatty acids, thereby drastically increasing its oxidative capacity. The metabolic action of PPARδ has also been verified in humans. In addition, it has become clear that the action of PPARδ is not restricted to skeletal muscle. Indeed, PPARδ has been shown to play a crucial role in whole-body lipid homeostasis as well as in insulin sensitivity, and it is active not only in skeletal muscle (as an activator of fat burning) but also in the liver (where it can activate glycolysis/lipogenesis, with the produced fat being oxidized in muscle) and in the adipose tissue (by incrementing lipolysis). The main aim of this review is to highlight the central role for activated PPARδ in the reversal of any tendency toward the development of insulin resistance.

Download Full-text

Erratum to “Short communication: Characterization of Madin-Darby bovine kidney cell line for peroxisome proliferator-activated receptors: Temporal response and sensitivity to fatty acids” (J. Dairy Sci. 91:2808–2813)

Journal of Dairy Science ◽

10.3168/jds.2009-92-9-4715 ◽

2009 ◽

Vol 92 (9) ◽

pp. 4715 ◽

Cited By ~ 1

Author(s):

M. Bionaz ◽

C.R. Baumrucker ◽

E. Shirk ◽

J.P. Vanden Heuvel ◽

E. Block ◽

...

Keyword(s):

Fatty Acids ◽

Cell Line ◽

Kidney Cell ◽

Short Communication ◽

Peroxisome Proliferator ◽

Kidney Cell Line ◽

Temporal Response ◽

Bovine Kidney ◽

Peroxisome Proliferator Activated Receptors

Download Full-text

Triterpenoids from Hibiscus sabdariffa L. with PPARδ/γ Dual Agonist Action: In Vivo, In Vitro and In Silico Studies

Planta Medica ◽

10.1055/a-0824-1316 ◽

2019 ◽

Vol 85 (05) ◽

pp. 412-423 ◽

Cited By ~ 5

Author(s):

Abraham Giacoman-Martínez ◽

Francisco Alarcón-Aguilar ◽

Alejandro Zamilpa ◽

Sergio Hidalgo-Figueroa ◽

Gabriel Navarrete-Vázquez ◽

...

Keyword(s):

Glucose Transporter ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Messenger Ribonucleic Acid ◽

Transporter Protein ◽

Agonist Action ◽

Fatty Acid Transporter ◽

Peroxisome Proliferator Activated Receptors ◽

Glucose Transporter Type 4 ◽

Dual Agonist

Abstract Hibiscus sabdariffa is a medicinal plant consumed as a diuretic and anti-obesity remedy. Several pharmacological studies have shown its beneficial effects in metabolism. Peroxisome proliferator-activated receptors δ and γ may play a role in the actions of H. sabdariffa. These nuclear receptors regulate lipid and glucose metabolism and are therapeutic targets for type 2 diabetes. This research aimed to perform a phytochemical study guided by a bioassay from H. sabdariffa to identify compounds with peroxisome proliferator-activated receptor δ and peroxisome proliferator-activated receptor γ agonist activity, supported by messenger ribonucleic acid expression, molecular docking, lipid accumulation, and an antihyperglycemic effect. An oral glucose tolerance test in mice with the aqueous extract of H. sabdariffa and the dichloromethane extract of H. sabdariffa was performed. The dichloromethane extract of H. sabdariffa exhibited an antihyperglycemic effect. The dichloromethane extract of H. sabdariffa was fractioned, and four fractions were evaluated in 3T3-L1 adipocytes on peroxisome proliferator-activated receptor δ, peroxisome proliferator-activated receptor γ, fatty acid transporter protein, and glucose transporter type 4 messenger ribonucleic acid expression. Fraction F3 exhibited peroxisome proliferator-activated receptor δ/γ dual agonist activity, and a further fractionation yielded two subfractions, F3-1 and F3-2, which also increased peroxisome proliferator-activated receptor δ and peroxisome proliferator-activated receptor γ expression. Subfractions were analyzed by GC/MS. The main compounds identified in F3-1 were linoleic acid, oleic acid, and palmitic acid, while in F3-2, the main compounds identified were α-amyrin and lupeol. These molecules were subjected to molecular docking analysis. α-Amyrin and lupeol showed the highest affinity. Moreover, both produced an increase in peroxisome proliferator-activated receptor δ, peroxisome proliferator-activated receptor γ, fatty acid transporter protein, and glucose transporter type 4 expression. Additionally, α-amyrin and lupeol decreased lipid accumulation in 3T3-L1 adipocytes and blood glucose in mice. Until now, α-amyrin and lupeol have not been reported with activity on peroxisome proliferator-activated receptors. This study provides evidence that α-amyrin and lupeol possess antidiabetic effects through a peroxisome proliferator-activated receptor δ/γ dual agonist action.

Download Full-text