Importantly, we found a high correlation between the kinetics of circulating FFA increase and expression of PPARα and several of its target genes. Moreover, treatment with a β3-adrenergic receptor agonist further enhanced this response in vivo through PPARα but did not induce detrimental FFA-sensitive response driven by toll-like receptor 4 (TLR4). This is likely due to the mixture of FFA released from the adipose stores. Indeed, fatty acids that accumulated in the liver of Pparαhep−/− mice during fasting were mostly oleic (C18:1n–9) and linoleic acids (C18:2n–6), and not only saturated fatty acids such as palmitic acid (C16:0). Interestingly, it has been shown that palmitic acid cannot activate TLR4 in the presence of unsaturated FFA.37
