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

• The saturated fatty acid (SFA) palmitate differentially modulates the circadian timekeeping mechanism in peripheral clocks;
• Palmitate induces time-dependent phase shifts that coincide with its rhythmic induction of inflammatory signaling;
• Time-dependent nature of the palmitate-induced phase shifts and inflammatory signaling is cell specific;
• Inhibitors of inflammatory signaling repress the proinflammatory and phase shifting effects of palmitate;
• Inflammatory signaling plays a role in the mechanism by which palmitate alters circadian timekeeping in peripheral clocks.Circadian or 24-hour clocks throughout the body mediate the local temporal coordination of tissue- or cell-specific processes necessary for normal inflammatory responses and metabolic homeostasis. Dysregulation of peripheral clocks and their timekeeping function contribute to obesity-related metabolic disorders (e.g., type 2 diabetes). Our data unveil a novel mechanism by which mutual interactions between peripheral clocks and inflammatory signaling pathways dysregulate circadian timekeeping, and exacerbate proinflammatory responses to saturated fatty acids. These studies will guide the development of chronotherapeutic drug and/or dietary omega-3 fatty acid treatments for managing and preventing metabolic disorders and other inflammation-related pathologies (e.g., cardiovascular disease, stroke, arthritis).

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.