Diverse coactivator recruitment through differential PPARγ nuclear receptor agonism

Abstract

The PPARγ nuclear receptor regulates the expression of genes involved in lipid and carbohydrate metabolism, and it has protective effects in some patients with type 2 diabetes. Nevertheless, the therapeutic value of the PPARγ nuclear receptor protein is limited due to the secondary effects of some PPARγ ligands. Because the downstream effects of PPARγ are determined by the binding of specific cofactors that are mediated by ligand-induced conformational changes, we evaluated the differential effects of various ligands on the binding of certain cofactors associated with PPARγ. The ligands used were rosiglitazone for treating type 2 diabetes and telmisartan for treating arterial hypertension. Functional, phenotypic, and molecular studies were conducted on pre-adipocyte 3T3-L1 and functional studies in U2OS cells. The moderating influence of various cofactor families was evaluated using transient transfection assays. Our findings confirm that telmisartan has a partial modulating effect on PPARγ activity compared to rosiglitazone. The cofactors SRC1 and GRIP1 mediate the activity of telmisartan and rosiglitazone and partially determine the difference in their effects. Studying the modulating activity of these cofactors can provide interesting insights for developing new therapeutic approaches for certain metabolic diseases.

Delta-9-tetrahydrocannabinol protects against MPP+ toxicity in SH-SY5Y cells by restoring proteins involved in mitochondrial biogenesis

“…The PPARγ receptor is able to regulate the expression of a vast variety of target genes. It is now increasingly recognised that the extent of expression of these genes can vary depending on the agonist used as they may alter intracellular factors such as the availability of specific co-activators [42], interaction with other nuclear receptors [43] as well as receptor phosphorylation, ubiquitination and sumoylation [44, 45]. This might explain why, despite being PPARγ target genes, neither Δ 9 -THC nor pioglitazone had any effect on catalase or SOD1 expression.…”

Excessive gestational calorie intake in sows regulates early postnatal adipose tissue development in the offspring

“…Thus, as established through surgically-induced placental insufficiency [23,24] and diet-induced maternal obesity [25], consumption of excess energy during gestation in pigs can also result in the modification of the histone code. Additionally, SRC1 increases the transcriptional activity of PPARγ [26]. Soluble frizzle related receptors (SFRP) are negative regulators of wnt signaling [27].…”

Polyacetylenes from carrots (Daucus carota) improve glucose uptake in vitro in adipocytes and myotubes

“…Retention time, UV and MS data of falcarinol and falcarindiol were identical with those of authentic reference compounds obtained from previous research. 17 NMR data ( 1 H, 13 C, DEPT, COSY, and HSQC) were acquired on a Bruker 400 MHz spectrometer in CDCl 3 (δ H 7.26/δ C 77.7) with tetramethylsilane as internal standard and optical rotation was recorded on an ADP440+ digital polarimeter (Bellingham + Stanley Ltd, UK). The complete spectroscopic and spectrometric data set of the isolated polyacetylenes were in accordance with literature values for (3R,9Z)-heptadeca-1,9-dien-4,6-diyn-3-ol (falcarinol) and (3R,8S,9Z)-heptadeca-1,9-dien-4,6-diyn-3,8-diol (falcarindiol).…”

“…11,12 This may explain why full and partial agonists recruit different sets of co-activators, and exhibit different pharmacological activities. 11,13 Plants have a long history in the traditional treatment of diabetes, and are therefore a promising source of natural products with potential antidiabetic effects and improved modes of action. 14,15 Using a screening platform for identification of plant extracts with potential bioactivity related to insulindependent GU and fat accumulation we recently demonstrated that the dichloromethane (DCM) extract of carrot roots (Daucus carota, Apiaceae) is able to activate PPARγ and to stimulate insulin-dependent GU in 3T3-L1 adipocytes and porcine myotubes.…”