Both aging and a high-fat diet (HFD) dampen circadian gene transcription rhythms and promote chronic inflammation. How aging and HFD interact to affect peripheral molecular clocks and circadian behavior remains unclear. Using Drosophila melanogaster , we showed that aging and HFD additively dampened circadian behavior, with their adverse effects converging on the fat body (FB), a tissue that regulates systemic metabolism and innate immunity. Applying longitudinal in vivo bioluminescence recording in small, genetically defined cell populations, we found that molecular clocks in the FB were uniquely vulnerable to aging- and HFD-induced dampening of rhythm amplitude, whereas those in the clock neurons declined with age but were resistant to dietary stress. To test the consequences of this FB clock decline, we disrupted individual components of the core molecular clock specifically in the FB. We found that only CLOCK (CLK) disruption shortened lifespan on HFD, whereas disrupting its binding partner CYCLE (CYC), or the repressors PERIOD and TIMELESS, did not. Furthermore, CLK, but not CYC, disruption upregulated antimicrobial peptide expression in the FB, dampened behavioral rhythms, and suppressed locomotor activity, even though both CLK and CYC disruption comparably dampened clock gene oscillation in the FB. Together, these results indicate that FB CLK has a unique role in suppressing pro-inflammatory signals independently of CYC. Our findings provide insight into how stressors such as aging and HFD selectively disrupt the peripheral metabolic clock, and into the distinct roles of individual clock components, with implications for age-related inflammation and metabolic disease.
