**3. Diurnal variation of human body temperature – A manifestation of our circadian rhythm**

From unicellular organisms to complex mammals like humans, a circadian rhythm exists, whose role revolves around optimizing the function of the organism relative to an approximately 24-hour-long diurnal period [16–20]. While there are many bodily functions that appear to be governed by the circadian rhythm such as sleep, cardiovascular function, respiration, coagulation, and others, as detailed in other chapters of this book, body temperature is one of if not the most easily accessible manifestation of the circadian rhythm. Body temperature can be measured with both good accuracy [21] and at high frequency [22], thus allowing for relatively inexpensive experimental designs in the fields of circadian rhythm and chronotherapy research.

The relationship between body temperature diurnal oscillations and the circadian rhythm was first reported in the 1800s by Davy [23] and Ogle [24]. Currently, we know that in healthy humans the minimum body temperature (the bathyphase) occurs in the early morning about 2 hours before wakening (i.e., 5–7 AM) and the maximum body temperature (the acrophase) occurs in the evening about 2 hours before falling asleep (i.e., 8–10 PM) [25–28]. The body temperature diurnal cycle can be approximated by a sinusoidal curve, whose amplitude is one-half of the total diurnal temperature change (acrophase minus bathyphase), and whose mesor is the rhythm-adjusted mean. The reader can refer to **Figure 3** for an illustration of this cycle. In humans, the amplitude had been measured to be around 0.2–0.8°C [16, 26, 27, 29]. There appear to be certain sex-based differences in the diurnal body temperature cycle just like there were differences in average body temperature between the sexes, as was described in the previous section of this chapter. For instance, Cain et al. [27] showed that on average the bathyphase in healthy women occurred earlier (at 4:46 AM) compared with healthy males (at 6:11 AM). The same study also measured a statistically smaller diurnal amplitude among women (0.43°C) versus men (0.55°C). Mallette et al. [28] also found an earlier bathyphase for women (at 4:48 AM) compared with men (at 6:04 AM) and also measured a much later

**Figure 3.** *Body temperature circadian rhythm schematic.*

#### *Human Body Temperature Circadian Rhythm in Health and Disease DOI: http://dx.doi.org/10.5772/intechopen.1003852*

acrophase for women (at 10:49 PM) compared with men (at 8:49 PM). The authors of these studies hypothesized that the measured differences in the timing of acrophases and bathyphases could be related to the different timing of melatonin peak between the sexes. However, a highly controlled study by Gunn et al. [30] showed that although melatonin production and subsequently serum concentrations were higher in women, the circadian rhythm of melatonin, i.e., the timing of peak and trough, were statistically identical for both sexes. On the other hand, it was hypothesized that sex hormone-related differences could account for the lower diurnal change but not for the above detailed differences in acrophase and bathyphase timing [31, 32].

Further, age seems to be affecting the circadian rhythm as well. Czeisler et al. [29] showed that among healthy subjects the diurnal body temperature amplitude was significantly higher among younger individuals (average of 0.28°C) compared with older adults (average of 0.2°C). The authors proposed that there are age-related changes in the mammalian intrinsic pacemaker (the suprachiasmatic nucleus (SCN) in the hypothalamus) that could account for the smaller amplitudes among people and animals of advanced age. This is supported by the finding that other circadian rhythm indicators such as the sleep-wake cycle are also shorter in older people [33, 34]. Further, as humans age, the SCN decreases in size, likely due to age-related microvascular disease that leads to the overall shrinkage of the human brain with age, with the total number of SCN cells decreasing as well [35, 36]. Perhaps the most striking evidence stems from animal models using rodents, where the sleep-wake cycle period and the amplitude of the body temperature oscillation were shown to be directly proportional to the size of the remaining volume of the SCN in animals with partial lesions inflicted in that brain region [37, 38], with total loss of the circadian rhythm of body temperature upon complete surgical removal of the SCN [39]. However, it should be pointed out that traumatic brain injury in rats not involving the SCN specifically also had been shown to induce downregulation of circadian clock gene expression and associated animal behavioral changes [40], thus pointing to a more complex regulatory process of the mammalian circadian rhythm.

Although the complexity of body temperature regulation in man is great, ultimately a specific body temperature is the result of a balance between heat production via body metabolism and heat loss via processes such as heat radiation from and air convection at the body surface. Like we mentioned in the previous paragraph, the master pacemaker for all circadian cycles of the mammalian body, including body temperature, is believed to be located in the suprachiasmatic nucleus (SCN) of the hypothalamus, with abundant evidence thereof recently reviewed by Hastings et al. [41]. In a most simplistic description, body temperature information needs to be captured from the periphery, e.g., the extremities and the internal organs, then transported to the SCN, where it is processed, compared to the expected pre-set body temperature goal for the current location along the diurnal circadian cycle, then instructions for adjustments in heat production need to be sent from the SCN to the periphery and executed at the cellular level, with the ultimate result being a rise or fall in body temperature. To aid this temperature "normalization" process, there are also behavioral adaptations that animals exhibit such as seeking shade when the environment is too hot or moving to a warmer place when it is too cold. Certainly, the majority of modern humans have many more behavioral adaptations at their disposal compared with mammals living in the wild.

The specific mechanisms for some of these steps are well understood while others are still being investigated, with several recently published reviews available in the

literature [17, 41, 42]. In mammals, including humans, temperature is sensed by TRP (transient receptor potential) family of ion channels [43–45]. The TRPs are expressed in sensory neurons throughout the body, with the biggest contributors to the signal being the skin, spinal cord, abdominal viscera, and the brain [46]. Different subtypes of TRPs are activated at different temperature thresholds [47] and the temperature information from the various sources is believed to be collected and processed by the SCN [48]. The SCN then communicates with the neurons in the preoptic area of the hypothalamus, which initiate the downstream signaling to achieve a "correction" in the organism's body temperature via the physiologic effectors that control thermogenesis, shivering, skin blood flow, and evaporative cooling as well as via thermoregulatory behaviors [49, 50]. The details regarding the various signaling cascades involved in the downstream signaling are still an area of active research. How the master pacemaker in the SCN operates is also being debated. There is some evidence pointing toward synchronization (a.k.a., entrainment) of the SCN by the ambient day-night lightening pattern [51–53]. Other studies provide evidence for hormonal regulation via melatonin feedback loops [54, 55] and via fluctuations in the serum serotonin levels [56, 57].

Regarding the circadian clock signaling mechanisms on the cellular level of multicellular organisms, these are being detailed in other chapters of this book. But briefly, in nearly all cells, including the SCN neurons, there is a clock-like mechanism in the form of an auto-regulatory transcriptional negative feedback loop as follows: The proteins CLOCK and BMAL1 (brain and muscle Arnt-like protein-1) form a dimer, which serves as a transcription factor and activates the transcription of the period and cryptochrome genes, which are then translated into the PER and CRY proteins. The PER and CRY proteins then interact with CLOCK and BMAL1, preventing them from further activating the period and cryptochrome genes' transcription. The CLOCK:BMAL1 transcription factor had been shown to also facilitate the expression of the clock-controlled genes (Ccgs), which are believed to control about 30% of the mammalian genome expression, thus controlling physiologic functions involved in metabolism, immunity, and many others [58]. To offer an example relevant to the circadian rhythm of body temperature, one of the downstream effects of this transcription loop involves the generation of oscillations in the mitochondrial oxidative capacity in mice via rhythmic changes of NAD+ biosynthesis [59]. These oscillations lead to changes in metabolic rate on the cellular level, which could potentially lead to a change in body temperature on the organismal level. All in all, at the current stage of scientific knowledge, the mechanisms that link the metabolic circadian rhythm at the cellular level to the circadian rhythm on the organismal level remain largely uncertain. What is curious however is the finding that even though an organism's body temperature diurnal cycling is governed by the circadian rhythm generated by the SCN, the diurnal temperature cycling itself is sufficient to sustain peripheral circadian clocks. This had been demonstrated by Brown et al. [60] in experiments where peripheral tissues from mammals were cultured *ex vivo*. The authors showed that by simulating the *in vivo* body temperature cycling inside the incubator, the tissues were able to maintain the proper circadian gene expression patterns. This points toward the existence of interdependence between the master clock in the SCN and body temperature. Beyond doubt, more research needs to be carried out before we can have a complete mechanistic picture for the maintenance of our body temperature. In parallel, knowledge regarding the clinical implications of disturbance in the body temperature diurnal rhythmicity had been accumulating and is explored in the next chapter section.
