Role of Inflammatory Signaling in the Differential Effects of Saturated and Poly-unsaturated Fatty Acids on Peripheral Circadian Clocks

Abstract

Inflammatory signaling may play a role in high-fat diet (HFD)-related circadian clock disturbances that contribute to systemic metabolic dysregulation. Therefore, palmitate, the prevalent proinflammatory saturated fatty acid (SFA) in HFD and the anti-inflammatory, poly-unsaturated fatty acid (PUFA), docosahexaenoic acid (DHA), were analyzed for effects on circadian timekeeping and inflammatory responses in peripheral clocks. Prolonged palmitate, but not DHA, exposure increased the period of fibroblast Bmal1-dLuc rhythms. Acute palmitate treatment produced phase shifts of the Bmal1-dLuc rhythm that were larger in amplitude as compared to DHA. These phase-shifting effects were time-dependent and contemporaneous with rhythmic changes in palmitate-induced inflammatory responses. Fibroblast and differentiated adipocyte clocks exhibited cell-specific differences in the time-dependent nature of palmitate-induced shifts and inflammation. DHA and other inhibitors of inflammatory signaling (AICAR, cardamonin) repressed palmitate-induced proinflammatory responses and phase shifts of the fibroblast clock, suggesting that SFA-mediated inflammatory signaling may feed back to modulate circadian timekeeping in peripheral clocks.

Inhibition of p38 MAPK activity leads to cell type-specific effects on the molecular circadian clock and time-dependent reduction of glioma cell invasiveness

“…The period difference observed between the PER2::LUC rhythms in SCN cells (Fig. 4a ) and Bmal1-dluc oscillations in fibroblasts is consistent with our published data [ 34 , 47 ] and reflects differences in cell types and clock gene reporters. In Per2 Luc SCN cells or Bmal1-dLuc fibroblasts treated with 10 μM or 20 μM VX-745, rhythms of bioluminescence persisted for 3–4 cycles similar to the control.…”

“…All DMSO-treated Per2 Luc SCN and Bmal1-dLuc fibroblast cultures exhibited circadian rhythms of bioluminescence that persisted for at least 3–4 cycles with circadian periods of 23.4 h and 25.5 h, respectively. The peak of SCN PER2::LUC expression occurred at ~36 h after the initiation of bioluminescence analysis, and the peak of Bmal1-dLuc in fibroblasts occurred at ~24 h following serum shock, similar to published data [ 34 , 47 ]. The period difference observed between the PER2::LUC rhythms in SCN cells (Fig.…”

Circadian Rhythms and Mitochondria: Connecting the Dots

“…CRY protein stability is crucial for defining the pattern of expression of mammalian clock genes ( Zhang et al, 2010 ) and consequently, the destabilization of CRY1 by AMPK affects the overall clock gene expression, notably by promoting CLOCK and BMAL1 expression ( Lamia et al, 2009 ). Indeed, AICAR-induced AMPK activation in fibroblasts induces a phase shift of BMAL1 ( Kim et al, 2016 ). This is potentially part of an important metabolic cross-talk, since AICAR-stimulated glucose uptake in skeletal muscle is reduced in BMAL1 deficient mice ( Harfmann et al, 2016 ).…”

Non-obesogenic doses of palmitate disrupt circadian metabolism in adipocytes

“…While palmitate is associated with the development of obesity, and Type 2 diabetes, lipotoxicity and oxidative stress, oleate has been shown to prevent or alleviate the toxic effect of saturated free fatty acids and to be protective against insulin resistance and metabolic disorders [27]. Palmitate has been associated with circadian dysregulation in different cell lines [28][29][30][31][32]. In a recent study, non-obesogenic doses of the fatty acids palmitate and oleate showed different effects on circadian rhythms and metabolism both in vitro in hepatocytes and in vivo in mouse liver.…”