The impact of saturated fatty acids and glucose on Toll-like receptor activated inflammatory pathways in human adipose tissue, in vitro
Alison Harte1, Elham Youssef-Elabd2, Kirsty McGee1, Gyanendra Tripathi1, Esmat Ashour2, Mogha Aballah3, Hayat Sharada3, Ashraf Amin4, Antonio Ceriello1, Paul OHare1, Sudhesh Kumar1 & Philip McTernan1
Chronic elevation of saturated fatty acids (SFAs) and glucose (Glc) appears to activate an inflammatory response; compounded by habitual feeding. Restoration of physiological SFAs and Glc levels post-prandially may not attenuate the original insult; a concept termed metabolic memory. Therefore we investigated (1) the effect of chronic and oscillating SFAs and Glc on the inflammatory pathway in human abdominal subcutaneous (AbdSc) adipose tissue (AT) and adipocytes (Ads) and (2) whether Ads are subject to metabolic memory.
AbdSc AT (age 45±3.3 years; BMI: 21.9±2.4 kg/m2; n=6) was obtained with ethics approval. Explants and Ads were treated with chronic low glucose (L-Glc): 5.6 mM and high glucose (H-Glc): 7.5 mM, with low (0.2 mM) and high (2 mM) doses of a palmitate:stearic tri-mix (SFA) for 48 h. Further, AbdSc AT explants and Ads were also exposed to the aforementioned treatment regimen for 12 h periods, with alternating rest periods of 12 h in L-Glc. Western blot and ELISAs were utilised to examine components of the NFκB pathway.
Chronic treatment with H-Glc and high SFAs up-regulated key proteins of the NFκB pathway in AbdSc AT explants and Ads (TLR4, NFκB, P<0.05) whilst down-regulating MyD88 protein levels. Oscillating treatment with Glc and SFAs increased TLR4, NFκB, IKKβ and MYD88 in explants and Ads (P<0.05). Downstream TNFα, resistin and IL-6 (P<0.05) secretion were markedly increased in chronically treated explants and Ads whilst, with oscillating treatments, a sustained inflammatory effect was noted in absence of treatment.
This study implicates elevated SFAs as a key instigator of the inflammatory response in both AT and Ads, via NFκB, and suggests that short-term exposure of cells to uncontrolled levels of SFAs and Glc leads to a longer-term inflammatory insult within the Ads. These findings indicate the importance of maintaining a low fat diet to reduce inflammatory risk in patients with obesity and T2DM.