Central and Peripheral Clock Control of Circadian Feeding Rhythms

Abstract

Many behaviors exhibit ~24-h oscillations under control of an endogenous circadian timing system that tracks time of day via a molecular circadian clock. In the fruit fly, Drosophila melanogaster, most circadian research has focused on the generation of locomotor activity rhythms, but a fundamental question is how the circadian clock orchestrates multiple distinct behavioral outputs. Here, we have investigated the cells and circuits mediating circadian control of feeding behavior. Using an array of genetic tools, we show that, as is the case for locomotor activity rhythms, the presence of feeding rhythms requires molecular clock function in the ventrolateral clock neurons of the central brain. We further demonstrate that the speed of molecular clock oscillations in these neurons dictates the free-running period length of feeding rhythms. In contrast to the effects observed with central clock cell manipulations, we show that genetic abrogation of the molecular clock in the fat body, a peripheral metabolic tissue, is without effect on feeding behavior. Interestingly, we find that molecular clocks in the brain and fat body of control flies gradually grow out of phase with one another under free-running conditions, likely due to a long endogenous period of the fat body clock. Under these conditions, the period of feeding rhythms tracks with molecular oscillations in central brain clock cells, consistent with a primary role of the brain clock in dictating the timing of feeding behavior. Finally, despite a lack of effect of fat body selective manipulations, we find that flies with simultaneous disruption of molecular clocks in multiple peripheral tissues (but with intact central clocks) exhibit decreased feeding rhythm strength and reduced overall food intake. We conclude that both central and peripheral clocks contribute to the regulation of feeding rhythms, with a particularly dominant, pacemaker role for specific populations of central brain clock cells.

Inducible Reporter Lines for Tissue-specific Monitoring of Drosophila Circadian Clock Transcriptional Activity

“…This result is particularly striking for flies in which we monitored fat body luciferase signals while selectively expressing Clk DN within these cells (Figure 6). As these flies retain feeding rhythms (Xu et al, 2008; Fulgham et al, 2021), the results help to rule out the possibility that luciferase rhythms arise secondary to rhythmic consumption of luciferin-containing food.…”

“…To-GAL4 is relatively selectively expressed in the fat body (Dauwalder et al, 2002), a peripheral metabolic tissue that functions similar to mammalian liver and adipose tissue, with some additional expression in other parts of the gastrointestinal tract (Xu et al, 2008). We were particularly interested in the effect of constant environmental conditions on fat body circadian clock activity, as it has been previously reported that per expression in the abdomen of Drosophila quickly dampens in DD based on experiments conducted with a lucifierase reporter (Stanewsky et al, 1997), RNA extraction (Xu et al, 2011), or antibody staining (Fulgham et al, 2021), suggesting that fat body clocks are not sustained without light cues.…”

“…In these flies, the molecular clock is functional in non-GAL4-expressing tissue. Furthermore, we and others have found that flies in which circadian clock function has been selectively abrogated in fat body cells retain locomotor activity and feeding rhythms (Xu et al, 2008;Fulgham et al, 2021). Thus, any systemic cues that derive indirectly from these behavioral cycles should remain intact.…”

Time series transcriptome analysis uncovers regulatory networks and a role for the circadian clock in theDrosophila melanogasterfemale’s response to Sex Peptide

“…The metabolic gene regulatory network that we identified, and expression changes of fit, suggest that the fat body clock is altered in response to SP. The fat body clock regulates feeding behavior and glucose metabolism, but synchronization between the fat body clock and the clock in neuronal cells is important, and desynchronization has been shown to negatively impact egg laying (Zheng and Sehgal 2008;Fulgham et al 2021;Erion et al 2016;Xu et al 2011). This, in addition to the expression changes we observed in neuronal genes that follow a circadian expression pattern in virgin females (such as aru, retn, sand), indicate that circadian changes in response to SP are not likely to be limited to the fat body.…”

Effects of Food Availability Cycles on Phase and Period of Activity-rest Rhythm in Drosophila melanogaster

“…Fruit flies also feed rhythmically with a peak in the morning in light-dark cycles and early subjective day in constant conditions (Xu et al, 2008). While most of these rhythms are controlled by either peripheral clocks (Xu et al, 2008, Krishnan et al, 1999; Chatterjee et al, 2010) or central clocks (Helfrich-Forster, 1998), or both (Fulgham et al, 2021; Barber et al, 2021), whether and how food availability affects any of these rhythms is unknown.…”