Black dog barks at brown fat

Abstract

CRY2 genetic variants associate with the depressive episodes in a range of mood disorders. Expression of core clock genes is highly responsive to stimuli in brown fat. Brown fat clocks might synchronize clocks in other tissues through their control of heat production and core body temperature. Among the repressors within the clocks, CRY2 is hypothesized to a key to the resetting of clocks throughout and play a leading role in the antidepressant effect of total sleep deprivation.

Key words::

• Adipocyte
• circadian
• CRY2
• depressive
• temperature

Key messages

• CRY2 associates with the depressed mood in a range of mood disorders.

• CRY2 in brown fat is hypothesized to a key to the resetting of oscillators throughout.

• Annals of Medicine publishes a special section on brown adipose tissue.

It is dark outside, the fall has fallen, it is once again one of those grey Wednesday mornings, and … wait a second … is it the Black Dog closing up on me from there? Sightings of black dogs as an omen of death, have been known in the folklores in the British Isles for long, and ever since the expression “Black Dog” has coined to a metaphor of major depressive disorder.

Recently, in humans, genetic variants in CRY2 (Cryptochrome 2) were discovered to associate with winter depression or seasonal affective disorder (1), with rapid cycling bipolar disorder (2), with chronic depressive symptoms in major depressive and bipolar disorders (3), and with persistent depressive disorder or dysthymia (4). Winter depression is characterized by recurrent major depressive episodes, time spent in major depressive episodes outweighs that spent in manic episodes in bipolar disorders, and patients with dysthymia often suffer from deepenings into major depressive episodes. On the basis of these data, it appears that CRY2 is a mood gene, or a key gene contributing to the depressed mood in specific.

Mechanisms for the core circadian clock functions of CRY2 have been elucidated (5–8). Among the repressors within circadian timing transcription-translation feedback loops, the cryptochrome proteins seem to be the actual repressors, and they act during the night (5). Here, CRY2 plays a leading role (6). The nuclear ratio of CRY1 to CRY2 proteins may be of key importance (7), and CRY2 has a critical role in tuning the circadian period by opposing the action of CRY1 and thereby denying CRY1 from accessing to DNA targets too early (8). The nuclear ratio of CRY1 to CRY2 proteins bears an inhibitory effect on the functions of the G_sα subunit of heterotrimeric G proteins (9). If it does inhibit, then a sustained change in this ratio may result in impairment of the functions of the dopamine D2 receptors in the retina. It may affect adaptation to light and compromise the effects of these receptors on the control of circadian clocks (10), and release the inhibition of heat production in brown adipose tissue (11). Such release might underlie some key features of the phenotype in depressed individuals, e.g. defects in thermoregulation, blunted circadian amplitudes and elevated core body temperatures during the night, a marked loss of weight, and abnormalities in the theta oscillation during wakefulness and during sleep. It is not known, whether these phenotypic characteristics, if any, are due to the over-activated brown adipose tissue in the depressed.

Currently, it is not known, whether the knock-out or the knock-down of the CRY2 gene in the whole organism or specific to a tissue produces any change in the activity of brown adipose tissue or in anxiety-like or depressive-like behaviors. However, CRY2 expression is abnormal, when inbred-strain mice with the intrinsic level of high anxiety are deprived of sleep (12), and when patients with bipolar type 1 disorder do not respond to but remain depressed after the antidepressant total sleep deprivation (1). A hypothesis has been put forward that total sleep deprivation corrects the dysfunctions of core clock genes, resets the circadian rhythms and alleviates the circadian abnormalities, and thereby improves mood in the depressed (13). To extend it, I hypothesize herein that the starting point of this healing process is brown fat whose over-activity is normalized during total sleep deprivation.

Fluctuations in core body temperature are guided by the suprachiasmatic nuclei and may serve a universal resetting cue for the intrinsic clocks (14). In agreement with Kleitman (15) saying that “a physiological rhythm, specifically the diurnal rhythm, is essentially a metabolic cycle”, the circulating blood is a carrier of heat generated by brown adipose tissue and carries “heat waves” or oscillations in body temperature throughout. These ultradian oscillations may thus be the universal resetting cue for the intrinsic clocks and drive the rhythms of longer periods. Indeed, changes in the activity of brown adipose tissue guide the overall maintenance of the circadian rhythm of core body temperature (16).

Brown adipose tissue may be a site of interaction between metabolic and circadian systems, as suggested earlier (17). In the brown fat clock (18), expression of core clock genes is highly responsive to stimuli, such as cold exposure, and may serve to synchronize oscillators in other tissues through its control of heat production and core body temperature (19). Whether this function of the brown fat clock is universal throughout or restricted to only a set of responsive tissues, it is not known.

Annals of Medicine has not so far published original research findings on brown adipose tissue or CRY2 genetic variants. However, there is one review on the adipocyte differentiation (20), and the edition of a special section on brown fat is currently on its way to be published. With publication of this special section we in Annals of Medicine hope to stimulate interest in and elucidate the roles of the cryptic tissue of brown adipocytes from which the Black Dog might draw strength.

Declaration of interest: The author reports no conflicts of interest. The author alone are responsible for the content and writing of the paper.