Oleic Acid Protects Against Insulin Resistance by Regulating the Genes Related to the PI3K Signaling Pathway

Abstract

Background: The effects of different types of fatty acids on the gene expression of key players in the IRS1/PI3K signaling pathway have been poorly studied. Material and Methods: We analyzed IRS1, p85α, and p110β mRNA expression and the fatty acid composition of phospholipids in visceral adipose tissue from patients with morbid obesity and from non-obese patients. Moreover, we analyzed the expression of those genes in visceral adipocytes incubated with oleic, linoleic, palmitic and dosahexaenoic acids. Results: We found a reduced IRS1 expression in patients with morbid obesity, independent of insulin resistance, and a reduced p110β expression in those with lower insulin resistance. A positive correlation was found between p85α and stearic acid, and between IRS1 and p110β with palmitic and dosahexaenoic acid. In contrast, a negative correlation was found between p85α and oleic acid, and between IRS1 and p110β with linoleic, arachidonic and adrenic acid. Incubation with palmitic acid decreased IRS1 expression. p85α was down-regulated after incubation with oleic and dosahexaenoic acid and up-regulated with palmitic acid. p110β expression was increased and decreased after incubation with oleic and palmitic acid, respectively. The ratio p85α/p110β was decreased by oleic and dosahexaenoic acid and increased by palmitic acid. Conclusions: Our in vitro results suggest a detrimental role of palmitic acid on the expression of gene related to insulin signaling pathway, with oleic acid being the one with the higher and more beneficial effects. DHA had a slight beneficial effect. Fatty acid-induced regulation of genes related to the IRS1/PI3K pathway may be a novel mechanism by which fatty acids regulate insulin sensitivity in visceral adipocytes.

Differential effects of single fatty acids and fatty acid mixtures on the phosphoinositide 3-kinase/Akt/eNOS pathway in endothelial cells

“…We report for the first time the effects of OA on the mRNA expression of the regulatory (p85α) and catalytic (p110β) subunits of PI3K in endothelial cells, in addition to confirming previous observations of this fatty acid on p85α [ 8 ] and PTEN expression [ 36 ]. These findings may, in the case of some of the reported effects, appear counter intuitive or contrary to what may have been predicted.…”

“…Interestingly, our observations for OA of a decrease in p85α and p110β expression suggest a co-ordinated down-regulation of these two subunits by OA and may indicate a direct effect of this fatty acid on PI3K. In agreement, opposing effects of 100 µM OA and PA on the mRNA expression of p85α have been reported in visceral adipose tissue biopsies from morbidly obese individuals, albeit the reduction in p110β expression was only evident at 25 µM but not 100 µM OA in this cell type [8]. Differences in the responsiveness of p110β to the actions of OA between studies may reflect the cell types used (endothelial cells versus visceral adipose tissue) and the phenotype of the adipose tissue donors (obese participants).…”

“…As far as the authors are aware, this study is the first to determine the effects of fatty acids on the expression of both the catalytic (p110α and β) and regulatory subunits (p85α and β) of the Class 1A PI3K, which are proposed to have opposing effects on insulin signalling [ 24 ]. Studies in knock-out mice suggest that the regulatory subunits may have negative effects on insulin action [ 25 ], with increased expression of p85α also observed in mouse models of gestational diabetes [ 26 ] and in obese humans [ 8 , 27 ]. Conversely, reductions in p85α (and to a lesser extent p85β) have been shown to enhance insulin sensitivity [ 24 , 28 ] and lead to a decrease in the catalytic subunits p110α and p110β in the insulin sensitive tissues of these knock-out animals [ 25 ].…”

“…Studies in endothelial cells examining the impact of dietary fat composition have reported more detrimental effects of SFA (palmitic acid (PA)) than MUFA (oleic acid (OA)) and n-6 PUFA (linoleic acid (LA)) on the phosphorylation status of the PI3K pathway and nitric oxide production [4][5][6][7] following insulin stimulation. In visceral adipocytes, OA has been shown to protect against insulin resistance by regulating the expression of genes in the PI3K signalling pathway [8], suggesting that a similar mechanism may also operate in the endothelium.…”

Phytochemical Profiling in Conjunction with In Vitro and In Silico Studies to Identify Human α-Amylase Inhibitors in Leucaena leucocephala (Lam.) De Wit for the Treatment of Diabetes Mellitus

“…Accordingly, further in vitro and in vivo experimental studies , are required to confirm and validate the possible α-amylase enzyme inhibitory activity of hexadecanoic acid and oleic acid. As nutraceuticals, hexadecanoic acid and oleic acid could serve for nonpharmacological strategies for treating T2DM. − However, possible detrimental side effects (e.g., fatty liver, insulin resistance, atherosclerosis, or other cardiovascular diseases) of long-term treatment at higher doses must be considered and would require further animal and human studies. − Moreover, although L. leucocephala leaves could be a reasonable alternative medicine in the form of a food supplement for relief of T2DM, , isolated and purified fatty acids from different plant origins and with proven inhibitory activity of key enzymes related to T2DM − would require optimized production processes at an industrial scale and would have to pass through the entire drug development process, including clinical trials. − …”