Fatty fish and winter depression (II) – Interplay of omega-3s with clock genes

The «Fat­ty fish and win­ter depres­sion» inves­ti­ga­tion com­pris­es two parts. This arti­cle is the sec­ond part. Read the first part first: Fat­ty fish and win­ter depres­sion (I) – An Ice­landic para­dox.

The Ice­landic para­dox, if indeed there is one, might reside in good dietary habits. Ice­landers con­sume a lot of fish – 85.39kg per capi­ta in 2022 vs. 22.07kg per capi­ta in the USA.

Sea­son­al affec­tive dis­or­der seems to equate to a cir­ca­di­an mis­match – a mis­match between cir­ca­di­an biol­o­gy, marked by the evening mela­tonin rise, and sleep/wake cycles. Do omega-3s from fat­ty fish pos­sess the pow­er to reset our inter­nal clocks?

In this sec­ond episode, we first review how clocks work at a mol­e­c­u­lar lev­el. We then study more close­ly those clocks at work in brain func­tion. And final­ly, we will be able to under­stand the mol­e­c­u­lar effect of omega‑3 fat­ty acids on clock genes and, ulti­mate­ly, on cog­ni­tion and mood.

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The molecular clockwork

Cir­ca­di­an clocks all seem to be gov­erned by the same basic prin­ci­ples; their peri­od, ampli­tude, and phase are deter­mined by the inter­play of spe­cif­ic genes (clock genes) and their pro­tein prod­ucts, along feed­back loops that delin­eate dai­ly rhythms.

Recall the pro­tein fac­to­ry. Pro­teins are large bio­mol­e­cules assem­bled from amino acids based on infor­ma­tion encod­ed in the DNA of genes. Genes are first tran­scribed into mes­sen­ger RNA (mRNA). mRNA then serves as a tem­plate in the syn­the­sis of pro­teins, or trans­la­tion. Some spe­cif­ic pro­teins con­trol pro­tein syn­the­sis; so-called tran­scrip­tion fac­tors bind to spe­cif­ic DNA sequences to con­trol tran­scrip­tion. Essen­tial­ly, they upreg­u­late or down­reg­u­late genes – they turn them on or off.

A cru­cial transcriptional/translational feed­back loop (TTFL) defin­ing cir­ca­di­an rhythms fea­tures a duo of tran­scrip­tion fac­tors: the apt­ly named CLOCK, and BMAL1. This duo per­forms a tire­less cir­ca­di­an chore­og­ra­phy.

Dur­ing the day, the BMAL1:CLOCK com­plex translo­cates to the cel­l’s nucle­us, where it pro­motes the expres­sion of Peri­od (PER1, PER2, PER3) and Cryp­tochrome (CRY1, CRY2) genes. PER and CRY pro­teins grad­u­al­ly accu­mu­late in the cyto­plasm. After sev­er­al hours, they translo­cate back into the nucle­us, where they inhib­it the BMAL1:CLOCK com­plex: PER and CRY pro­tein syn­the­sis sub­sides, their con­cen­tra­tion drops, and by the end of the night BMAL1:CLOCK is free to pro­mote tran­scrip­tion anew: the clock restarts. Some sec­ondary TTFLs sta­bi­lize the core TTFL, notably includ­ing tran­scrip­tion­al repres­sors (REV-ERB α/β) or pro­mot­ers (ROR α/β) of BMAL1 expres­sion. (Checa-Ros, 2022)

We have now intro­duced the prin­ci­pal mol­e­c­u­lar pro­tag­o­nists of cir­ca­di­an clocks. What, then, of the mol­e­c­u­lar clocks dri­ving brain func­tion?

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Brain clocks

The afore­men­tioned stud­ies doc­u­ment­ing the suc­cess of light ther­a­py (the pre­pon­der­ant time cue) and mela­tonin admin­is­tra­tion (a key cir­ca­di­an mark­er) in treat­ing sea­son­al depres­sion con­firm that the cir­ca­di­an sys­tem is deeply inter­twined with brain func­tion. Ani­mal mod­els deep­en our under­stand­ing. A wealth of stud­ies shows the inter­con­nec­tion between the bio­log­i­cal clock and path­ways impli­cat­ed in mem­o­ry con­sol­i­da­tion, neu­ro­ge­n­e­sis, and ulti­mate­ly, the onset of neu­ro­log­i­cal dis­eases. (Checa-Ros, 2022)

Stud­ies in the rich lit­er­a­ture review by Checa-Ros notably demon­strates: In BMAL1-defi­cient mice, the impair­ment of «con­tex­tu­al fear and spa­tial mem­o­ry» via an clear­ly iden­ti­fied mol­e­c­u­lar path­way; in mice with some BMAL1 deficit in the hip­pocam­pus, «dis­rup­tions in mem­o­ry retrieval […] relat­ed to dys­reg­u­la­tion in dopamine […] recep­tors»; in mice with PER2 muta­tions, «reduc­tions in hip­pocam­pal neu­ronal plas­tic­i­ty» and «decreased acti­va­tion of the tran­scrip­tion fac­tor CREB […] involved in mem­o­ry for­ma­tion by rein­forc­ing glu­ta­mater­gic synaps­es». Tweak the clock genes and pro­teins, and mice lose their minds.

BMAL1 dele­tion increas­es epilep­sy fre­quen­cy or excitabil­i­ty in mice, and a mol­e­c­u­lar causal chain has been iden­ti­fied. When arti­fi­cial­ly induc­ing seizures in rodents, the «anti­con­vul­sant effects of mela­tonin and adreno­cor­ti­cotrop­ic hor­mone (ACTH)» are linked to «sig­nif­i­cant­ly increased expres­sions of BMAL1, CLOCK, PER1, PER2, CRY1, and CRY2.» Fur­ther­more, BMAL1 defi­cien­cy in mice seems to exac­er­bate the «deposit of β‑amyloid plaques in the hip­pocam­pus» that is symp­to­matic of Alzheimer’s dis­ease. Tweak the clock genes and pro­teins, and mice fall neu­ro­log­i­cal­ly ill. (Checa-Ros, 2022)

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Omega-3s and circadian clocks

Lit­er­a­ture amply attests to the crit­i­cal role of omega‑3 fat­ty acids in brain func­tion – cog­ni­tion and mood. This in itself points to them as a poten­tial key to our «Ice­landic mys­tery» – and to fat­ty fish as an adju­vant against Sea­son­al Affec­tive Dis­or­der.

Yet, we aim high­er; evi­dence is accu­mu­lat­ing that omega‑3 fat­ty acids affect neu­ro­log­i­cal process­es via cir­ca­di­an path­ways and, at the mol­e­c­u­lar lev­el, via clock genes.

First, dietary fat­ty acids appear to inter­act with the bio­log­i­cal clock. Sec­ond, omega‑3 fat­ty acids seem to reg­u­late mela­tonin pro­duc­tion – a key cir­ca­di­an mark­er. Third, at least one study direct­ly sup­ports an effect of omega‑3 fat­ty acids on brain func­tion via clock genes. And final­ly, sev­er­al stud­ies sup­port an anti-inflam­ma­to­ry effect of omega‑3 fat­ty acids via clock genes – neu­roin­flam­ma­tion being a process involved in cog­ni­tive and mood impair­ment as well as neu­rode­gen­er­a­tive dis­eases such as Alzheimer’s.

This all makes fat­ty acids strong can­di­dates for being «non-phot­ic zeit­ge­bers and cir­ca­di­an clock syn­chro­niz­ers,» as the study by Checa-Ros phras­es it. (Checa-Ros, 2022) Now that we have acquaint­ed our­selves with the bio­mol­e­c­u­lar mech­a­nisms of cir­ca­di­an clocks, let’s focus on the evi­dence for the inter­ac­tion between omega‑3 fat­ty acids and clock genes.

Melatonin-Omega‑3 Interplay

We know the clear inter­play of cir­ca­di­an clocks with brain func­tion path­ways. Just the same way, we know their inter­play with innate and adap­tive immu­ni­ty path­ways, as well as the devel­op­ment of chron­ic inflam­ma­to­ry dis­eases. For instance, «patients suf­fer­ing from [rheuma­toid arthri­tis] were report­ed to reach mela­tonin peak con­cen­tra­tions around 2 h ear­li­er than healthy con­trols»; and inflam­ma­to­ry decreas­es in rodents with induced arthri­tis point to an «inhibito­ry effect of CRY1 and CRY2 on inflam­ma­tion with­in fibrob­last-like syn­ovio­cytes.»

And sev­er­al stud­ies suc­ceed in con­nect­ing the anti-inflam­ma­to­ry changes induced by an omega‑3 fat­ty acid-enriched diet with mod­i­fi­ca­tions in BMAL1, REV-ERBα, and RORα expres­sion – where, as we recall, the nuclear recep­tors REV-ERBα/β and RORα/β act as tran­scrip­tion­al repres­sors and pro­mot­ers of BMAL1 expres­sion, respec­tive­ly. (Checa-Ros, 2022; Lavialle, 2008)

Since there is a strong (neuro)inflammatory com­po­nent in brain func­tion defi­cien­cies and impair­ments, clock genes become good can­di­dates for medi­at­ing the reg­u­la­to­ry and pro­tec­tive effects of omega-3s on mem­o­ry, cog­ni­tion, mood, and chron­ic brain dis­eases.

But there is also direct evi­dence that omega-3s work on the brain via clock reg­u­la­tion. Demon­stra­tive­ly, a large cohort study in type 2 dia­bet­ic patients finds that omega‑3 con­sump­tion damp­ens sleep impair­ment via an upreg­u­la­tion of the clock genes CLOCK, BMAL2, PER2, and BMAL1-pro­mot­ing RORα, lead­ing to the restora­tion of hypo­thal­a­m­ic clock oscil­la­tions. «Recep­tor-lig­and mol­e­c­u­lar dock­ing sim­u­la­tion unveiled a potent affin­i­ty between the active pock­et of RORα and DHA/EPA [omega‑3]. Fur­ther RORα-based loss-of-func­tion assay fur­ther sup­port­ed a piv­otal role of RORα in [omega-]3 PUFA-induced mas­ter reg­u­la­tion of mol­e­cule clock oscil­la­tions.» (Zhuang, 2025)

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Omega‑3 a dietary zeitgeber?

A cir­ca­di­an time cue has the pow­er to reset the clock. The first light of dawn starts a new cycle. To what extent might omega-3s pos­sess a sim­i­lar reset capac­i­ty?

As we have seen, there is strong evi­dence for an inter­play between omega‑3 fat­ty acids and clock genes, whose dai­ly bal­let rep­re­sents the ele­men­tary cir­ca­di­an pace­mak­er. In this regard, we might already call them, in a sense, mol­e­c­u­lar zeit­ge­bers. But are they capa­ble of act­ing on the entire bio­log­i­cal tim­ing sys­tem, as a phot­ic sig­nal does? Their demon­strat­ed effect on mela­tonin pro­duc­tion is per­haps the most elo­quent argu­ment for such a hypoth­e­sis.

Melatonin-omega‑3 interplay

Sig­nif­i­cant­ly, omega‑3 defi­cien­cy in rodents dras­ti­cal­ly damp­ens the rhythm of mela­tonin release at night, down 52%. There is sound evi­dence of the whole causal chain at work. Cell mem­brane phos­pho­lipids become par­tic­u­lar­ly defi­cient in DHA in the pineal gland, the pri­ma­ry fac­to­ry for cir­cu­lat­ing mela­tonin. There­by, their AA:DHA ratio becomes about 5 times high­er than in the con­trol group. (DHA and AA are types of omega‑3 and omega‑6 fat­ty acids, respec­tive­ly.) A high­er AA con­tent in the pineal gland is known to cor­re­late with a decrease in endoge­nous pineal 12-HETE, an acid pro­duced by the oxy­gena­tion of non-ester­i­fied (free-float­ing) AA, while 12-HETE is known to stim­u­late mela­tonin pro­duc­tion. (Lavialle, 2008)

From there, what kind of zeit­ge­ber is mela­tonin? Mela­tonin, «the dark­ness hor­mone», is no sim­ple mes­sen­ger relay­ing infor­ma­tion from a mas­ter light-sen­si­tive SCN pace­mak­er. The effect, it seems, goes both ways. Alter­ations in mela­tonin rhythms also «enhance cir­ca­di­an sen­si­tiv­i­ty to light syn­chro­niz­ers and reduce the resis­tance of the tim­ing sys­tem to pho­tope­ri­od vari­a­tions.» (Lavialle, 2008) Besides, mela­tonin pro­duc­tion is not lin­ear­ly trig­gered by dark­ness: dark­ness sim­ply unin­hibits its pro­duc­tion. Its syn­the­sis, as we have just seen, is con­trolled by much more than light – e.g., its cell mem­brane lipid com­po­si­tion. Ulti­mate­ly, the cor­rec­tion of cir­ca­di­an phase-shift delays through mela­tonin admin­is­tra­tion makes it the same poten­tial «exter­nal time cue» and «pho­to­bi­ot­ic» as light.

Ulti­mate­ly, omega-3s undoubt­ed­ly deserve the rank of a cir­ca­di­an sys­tem zeit­ge­ber – their reg­u­la­tion of and close inter­play with the non-phot­ic zeit­ge­ber mela­tonin speak for it.

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Fatty fish against winter depression

We must con­clude on the poten­tial of fat­ty fish to reset the clocks in win­ter.

Sea­son­al Affec­tive Dis­or­der is essen­tial­ly, as we have seen ear­li­er, a cir­ca­di­an mis­match. A delay of the cir­ca­di­an clocks with respect to the sleep/wake cycle. Omega-3s can be said to act as a time cue for cir­ca­di­an rhythms along mul­ti­ple path­ways. They pro­mote the pineal night secre­tion of mela­tonin, a cen­tral zeit­ge­ber of the cir­ca­di­an sys­tem. There is sound evi­dence that mol­e­c­u­lar (gene) clock reg­u­la­tion medi­ates their anti-inflam­ma­to­ry and pro­tec­tive effects on brain func­tions. Those include mood and sleep – two key vari­ables of win­ter depres­sion.

In light of these inves­ti­ga­tions, the syn­chrony of bio­log­i­cal clocks at all lev­els of phys­i­ol­o­gy seems piv­otal to good health, and their mis­match an impor­tant con­trib­u­tor in chron­ic dis­ease. Eat­ing ade­quate amounts of fat­ty fish seems like a sim­ple and savory way to oil the clock­work.

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References

Checa-Ros, A., & D’Mar­co, L. (2022). Role of omega‑3 fat­ty acids as non-phot­ic zeit­ge­bers and cir­ca­di­an clock syn­chro­niz­ers. Inter­na­tion­al Jour­nal of Mol­e­c­u­lar Sci­ences, 23(20), 12162. https://doi.org/10.3390/ijms232012162

Lavialle, M.., Cham­peil-Potokar, G., Alessan­dri, J. M., Bal­asse, L., Gues­net, P., Papil­lon, C., Pévet, P., Van­cas­sel, S., Vivien-Roels, B., &. Denis, I. (2008). An (n‑3) polyun­sat­u­rat­ed fat­ty acid-defi­cient diet dis­turbs dai­ly loco­mo­tor activ­i­ty, mela­tonin rhythm, and stri­atal dopamine in Syr­i­an ham­sters. The Jour­nal of Nutri­tion, 138(9), 1719–1724. https://doi.org/10.1093/jn/138.9.1719

Zhuang, P., Wu, Y., Yao, J., Wang, T., Zhang, Y., & Jia, J. (2025). Marine n‑3 polyun­sat­u­rat­ed fat­ty acids slow sleep impair­ment pro­gres­sion by reg­u­lat­ing cen­tral cir­ca­di­an rhythms in type 2 dia­betes. Cell Reports Med­i­cine, 6(5), 102128. https://doi.org/10.1016/j.xcrm.2025.102128