Streptozotocin-induced diabetes disrupts the body temperature daily rhythm in rats
© Ramos-Lobo et al.; licensee BioMed Central. 2015
Received: 24 November 2014
Accepted: 16 April 2015
Published: 29 April 2015
In mammals, the temperature rhythm is regulated by the circadian pacemaker located in the suprachiasmatic nuclei, and is considered a “marker rhythm”. Melatonin, the pineal gland hormone, is a major regulator of the endogenous rhythms including body temperature. Its production is influenced by many factors, such as type 1 diabetes mellitus. In rats, diabetes leads to hypothermia and reduced melatonin synthesis; insulin treatment reestablishes both.
To study the body temperature daily rhythm of diabetic animals and the effects of insulin and/or melatonin treatment on its structure.
We studied the effects of streptozotocin-induced diabetes (60 mg/kg) on the body temperature rhythm of Wistar rats and the possible modifications resulting from early and late treatments with insulin (6U/day) and/or melatonin (daily 0.5 mg/kg). We monitored the daily body temperature rhythm, its rhythmic parameters (MESOR, amplitude and acrophase), glycemia and body weight for 55 days. Data were classified by groups and expressed as mean ± SEM. One-way ANOVA analysis was performed followed by Bonferroni posttest. Statistical significance was set at p < 0.05.
Diabetes led to complete disruption of the temperature rhythm and hypothermia, which were accentuated over time. All early treatments (insulin or/and melatonin) prevented the temperature rhythm disruption and hypothermia. Insulin plus melatonin restored the body temperature rhythm whereas insulin alone resulted less efficient; melatonin alone did not restore any of the parameters studied; however, when supplemented close to diabetes onset, it maintained the temperature rhythmicity. All these corrective effects of the early treatments were dependent on the continuous maintenance of the treatment.
Taken together, our findings show the disruption of the body temperature daily rhythm, a new consequence of insulin-dependent diabetes, as well as the beneficial effect of the complementary action of melatonin and insulin restoring the normal rhythmicity.
KeywordsDaily rhythms Type 1 diabetes mellitus Insulin Melatonin
Circadian rhythms play a central role in both mental and physical health . As all the circadian rhythms, body temperature is under the control of the circadian oscillatory system. Due to its robustness and the relative continuous monitoring easiness, body temperature has been established as a “marker rhythm” of the circadian pacemaker [2-4]. Scheer et al., described a dual effect of the suprachiasmatic nuclei (SCN) in thermoregulation in rats, i.e., daily synchronization and mediating the masking effect of light . Besides that, the SCN are fundamental for the circadian timing of metabolic rhythms such as plasma glucose changes, cortisol and melatonin levels [6-11].
Evidence in literature shows a strong connection between circadian disruption and metabolic pathologies, and that the relationship is bidirectional [12,13]. Previous studies show that both experimental animals as well as patients with metabolic pathologies, such as obesity and type 2 diabetes mellitus also present circadian abnormalities [14,15]. On the other hand, mice with disrupted clock function develop metabolic pathologies, such as diabetes and obesity [16,17]. In spite of being a well-structured rhythm, body temperature is susceptible to chronic shifts in mealtime resulting in pathological changes of carbohydrate and lipid metabolisms daily rhythms . These effects could be due to a misalignment of the body temperature, melatonin, and sleeping rhythms .
Melatonin is the main hormone produced by the pineal gland in mammals. Its synthesis is high during the night and low during the day, signaling to the body the daily and seasonal environmental photoperiod. It is known that melatonin synchronizes the body temperature rhythm in humans setting up the acrophases to the same hour every day . Several studies show the importance of melatonin in the regulation of energy metabolism. The decrease or absence of endogenous melatonin secretion in rats may alter energy metabolism, resulting in increased body weight and visceral adiposity associated with glucose intolerance, insulin resistance, diabetes, dyslipidemia, and cardiovascular disease; melatonin administration in those animals is capable of reverting all the effects mentioned above [7,21-25].
It is not clear yet how melatonin modulates directly the body temperature rhythm; melatonin has a peripheral vasodilator effect and thus increases heat loss and decreases temperature in the dark phase in humans , and given its close relationship with energy metabolism, it might also be involved in body temperature regulation. It is known that body temperature is altered in metabolic pathologies, especially in diabetes mellitus. Type 1 diabetes mellitus (T1DM) is an autoimmune disease leading to the destruction of the insulin-producing pancreatic beta cells in the islets of Langerhans. This alteration can lead to serious diseases affecting the heart and blood vessels, eyes, kidneys, and nerves, together with a higher risk of developing infections. The disease can affect people of any age, but is most commonly diagnosed in children and young adults, and by the time of diagnosis, patients have very little endogenous insulin production; every year 78,000 children develop type-1 diabetes worldwide (IDF, 2011, [27,28]). Data in literature show that experimental diabetes, induced by streptozotocin (STZ)  or alloxan  reduces 24 h body temperature, leading to hypothermia and intolerance to cold temperatures . Insulin treatment restores normal temperature [30,32,33]. This effect could be explained by the decreased brown adipose tissue thermogenesis, decreased shivering activity and lack of glucose uptake by muscle and adipose tissues, characteristic of diabetes [34-36]. When addressing melatonin synthesis in STZ-induced diabetic rats data in literature are discrepant. In spite of some contradictory evidence in the literature , data from our group, show a strong reduction (up to 50%) in melatonin synthesis in the pineal gland  and retina  of diabetic rats, and this effect is reversed by exogenous insulin. Moreover, in human T1DM there is a strong negative correlation between hyperglycemia and 6-sulphatoximelatonin production . In any case, these findings indicate that melatonin plays an important role in metabolic alterations, especially diabetes mellitus .
The effect of insulin-dependent diabetes on the circadian profile of body temperature (BT) is still unknown. Giving that physiological temperature rhythm is essential to maintain normal body functions and that STZ-induced diabetic rats show a significant loss of endogenous melatonin; and considering the tight relationship between melatonin, insulin and metabolism, it is highly important to study the effect of this pathological state on the body temperature daily rhythm .
In the present study, we aimed to describe the daily rhythm of BT in STZ-induced diabetic animals through telemetric analysis. We also aimed to study the potential effects of insulin treatment, melatonin supplementation or a combination of both hormones on the rhythmic structure of temperature in diabetic animals.
Material and methods
The Committee of Ethics in Animal Experimentation of the Institute of Biomedical Sciences, University of São Paulo, granted ethics approval for this study. All animal procedures were approved by the Ethics Committee on the Use of Animals of the Institute of Biomedical Sciences at the University of São Paulo, and were performed according to the ethical guidelines adopted by the Brazilian College of Animal Experimentation.
Male Wistar rats (250 g) were obtained from the Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil. The animals were kept under a constant 12 h: 12 h light–dark cycle (lights on at 7 AM; Zeitgeber Time [ZT] 0), in a temperature-controlled room (21 ± 2°C), with food and water ad libitum and housed in individual cages equipped with body temperature and locomotor activity recording.
Surgical procedure and data acquisition
Body temperature recordings were obtained by telemetry (Mini Mitter, Bend, OR, USA). A small transponder (ER400 E-Mitter® Respironics – Mini Mitter, Bend, OR, USA) was implanted in the abdominal cavity of each rat. Briefly, animals were anaesthetized with a ketamine/xylazine solution (3:1). The ventral surface of the abdomen was shaved and a 2 cm incision was performed along the linea abla 1 cm below the diaphragm. The body of the E-Mitter was slipped into the abdominal cavity along the sagittal plane and dorsal to the digestive organs, then the abdominal cavity was massaged gently to allow the internal organs to settle. The animals were allowed 7 days to recover following surgery  and all efforts were made to minimize suffering. The data acquisition was performed by the software VitalView™ recording every 30 seconds during 55 days. Animal’s body weight and glycemia were measured weekly.
STZ-induced diabetes, insulin and melatonin treatment
Diabetes was induced by a single intraperitoneal injection of STZ (60 mg/kg body weight; Sigma- Aldrich, St. Louis, MO) freshly diluted in citrate buffer (10 mM, Na citrate; pH 4.5). Tail blood was collected for glucose levels determination using a glucometer (Optium Xceed; Medisense, Abingdon, UK) 24 hours after the induction. Animals with glycemia > 200 mg/dL were considered diabetic. Insulin treated diabetic animals received 2 U subcutaneous long-action insulin (Glargina/Lantus; Sanofi-Aventis, Paris, France) at sunrise and 2 U regular insulin (Humulin R; Eli Lilly, Paris, France) plus 2 U long-acting insulin (Glargina/Lantus; Sanofi- Aventis) at sunset . Melatonin was administrated in drinking water (0.5 mg/mL; pure melatonin was first dissolved in ethanol and added to distilled water to achieve the melatonin solution) only in the dark phase for the time determined in the experimental design.
Analysis of rhythmic parameters
Temporal series were obtained with VitalView software (Mini Mitter, Bend, OR, USA) and individual thermograms were obtained from raw data using the El Temps® software (Diez-Noguera, Barcelona, Spain). For rhythmic analyses we used the Cosinor method using the COSANA software (Benedito Silva, São Paulo, Brazil). To generate the daily pattern, raw data was averaged in 1 h bins and analyzed as 24 h bins. The Cosinor method allows the daily rhythm of body temperature to be described in a simple cosine wave, which is typically characterized in terms of acrophase (measure of the crest time of a rhythm from the cosine wave), MESOR (the value midway between the highest and lowest values of the cosine wave), and amplitude (the difference between the maximum height of the wave and the rhythm-adjusted mean [MESOR] of the wave form). We obtained values for the rhythmic parameters: MESOR, amplitude and acrophase for each day (when the distribution was adjusted to a cosine wave with a period of 24 h). The periodograms (distribution of all periods in the temporal series to determine the presence of a predominant period) were generated from each period (control, diabetic and different treatments) using the Sokolov-Bushell method (El Temps® software).
Data were classified by groups and expressed as mean ± SEM. One-way ANOVA analysis was performed to determine variation in data throughout 24 h. Statistical significance was set at p < 0.05. The temporal series were globally analyzed and rhythmic statistics performed using COSANA software applying the Cosinor method for rhythmic analyses. MESOR, amplitude and acrophase were only considered for linear analysis in days where one-way ANOVA were significant. Statistical analyses were performed using the GraphPad PRISM software (GraphPad Software, CA, USA).
For each group (n = 3) a representative animal is shown in rhythmic analyses, given that each one acted as its own control. Thermograms for all the animals are shown in Additional file 1 (late treatment) and Additional file 2 (early treatment). It should be stressed that all the effects described for the representative animal were observed in the whole group (Additional files 1 and 2).
STZ- induced diabetes disrupts the body temperature daily rhythm
Average rhythmic parameters in insulin, melatonin and insulin plus melatonin late-treated diabetic animals
Insulin treated group
37.59 ± 0.01487
36.48 ± 0.07885***
37.22 ± 0.07453aaa
0.2300 ± 0.02289
0.5556 ± 0.03913***
0.5521 ± 0.05900**
13.45 ± 0.9341
10.58 ± 0.4889*
9.762 ± 0.6649**
Melatonin supplemented group
37.47 ± 0.01503
36.75 ± 0.07445***
36.48 ± 0.07706***
0.2357 ± 0.01950
0.555 ± 0.06827*
0.5917 ± 0.06674*
14.59 ± 0.4758
11.04 ± 0.7539
11.59 ± 0.9328
Insulin + melatonin treated group
Insulin + Melatonin
37.62 ± 0.01857
36.96 ± 0.06499***
37.38 ± 0.05622aaa
0.3057 ± 0.02103
0.5291 ± 0.05421*
0.4533 ± 0.03055
14.65 ± 0.4103
13.65 ± 0.4664
13.90 ± 0.2138
After long-term diabetes insulin treatment restores BT rhythm and is more efficient when combined with melatonin
Early treatments prevent the disruption of the BT rhythm caused by diabetes; melatonin supplementation maintains BT rhythm synchronized. Insulin and melatonin combined is most efficient. Beneficial effects are suppressed when the treatment stops
Average rhythmic parameters in insulin, melatonin and insulin plus melatonin early-treated diabetic animals
Insulin treated group
37.55 ± 0.01850
37.59 ± 0.02640
37.18 ± 0.06034***bbb
37.41 ± 0.05469aab
0.2814 ± 0.01969
0.3546 ± 0.0248
0.3915 ± 0.042
0.4329 ± 0.0908*
15.46 ± 0.4256
14.31 ± 0.2471
15.18 ± 0.6522
14.27 ± 0.4303
Melatonin supplemented group
38.15 ± 0.01875
37.84 ± 0.02414***
37.57 ± 0.05185***bbb
37.84 ± 0.03808***aaa
0.3157 ± 0.02467
0.3460 ± 0.02156
0.3473 ± 0.02697
0.3477 ± 0.02822
16.57 ± 0.5227
16.66 ± 0.6569
14.60 ± 1.400
16.57 ± 0.2733
Insulin + Melatonin treated group
1st Insulin + Melatonin
2nd Insulin + Melatonin
37.55 ± 0.01672
37.58 ± 0.01696*
37.29 ± 0.08757bb
37.44 ± 0.04681
0.2543 ± 0.02553
0.3740 ± 0.02801
0.4218 ± 0.03670*
0.4127 ± 0.03099*
18.08 ± 0.4162
14.89 ± 0.1850***
14.63 ± 0.7259***
15.06 ± 0.4708**
To study whether the preventive effects showed above are dependent on the continuity of the treatments, after 15 days they were interrupted for two weeks and the rhythmic effects were evaluated.
All animals presented a 24 h period of the temperature rhythm; however, they presented a decreased potency (Qp) on their periodograms (Qp = 150–200 during early treatments vs 80–100 when treatments were interrupted) (Additional file 9 second column for treated period and third for interrupted period). The interruption of the treatments led to a severe alteration in the rhythm (Figure 3D-F). All three groups showed a delay in the onset of the alterations following the interruption, and it was more evident in early-INS + MEL group, probably due to a protective effect of the early treatments (Figure 2D-F). Early-INS and MEL rats showed alterations in their acrophase maps being more evident in early-MEL; however this alteration did not reach statistical difference (Table 2). Despite the altered acrophases (phase delays and advances), they were mostly in the dark period (Figure 4D-F). MESOR was reduced progressively (Additional file 5D-F and Table 2) and amplitude showed no significant alteration when compared to the previous period (Additional file 6D-F and Table 2). During the interruption BT was significantly reduced in all three groups, although in a minor magnitude when compared with long-term diabetic animals, indicating that all early treatments in some way prevented a bigger reduction of body temperature (Figure 6). Also, during the interruption, hyperglycemia was rapidly established and the animals lost weight (Additional files 7 and 8). In conclusion, the interruption of the treatments led to the loss of their effects on the rhythm; however during that period the rhythm was not as disrupted as seen in long-term diabetic animals. The most efficient early treatment was INS + MEL; it preserved the structure of the rhythm for 5 days before the effects of diabetes were established (Figure 3D-F).
Finally, we studied if the interruption leaves consequences in the daily BT rhythm when the treatments are reinstituted. After reinstitution, daily rhythmicity was rapidly restored in all groups (Figure 2D-F), and the acrophases returned to the dark phase, being more synchronized in those groups where melatonin was administered (Figure 4D-F and Table 2). The potency of the 24 h period was restored as in control and early treated period (Additional file 9D, H, and L). After reestablishment of the treatments, only those groups where insulin was administered showed a restored MESOR. In early-MEL rats MESOR attained the pattern and values of the early supplementation (Additional file 5D-F and Table 2). The amplitude remained increased in early-INS and early-INS + MEL rats but not in early-MEL rats, where it remained unaltered (Additional file 6D-F and Table 2). In conclusion, the pattern of the daily rhythm of BT was restored, with higher temperatures at nighttime and lower temperature at daytime; however, early-MEL rats showed improved synchronization of the rhythm, when compared with early-INS rats. Finally, early-INS + MEL rats had the most synchronized rhythm among the three, but the restitution was not as efficient as the early treatment (Figure 3D-F). As expected, body weight and glycemia were normalized with restitution in early-INS and early-INS + MEL groups but not early-MEL (Additional files 7 and 8).
STZ-induced diabetes disrupts body temperature daily rhythm, and alters all its rhythmic parameters (MESOR, amplitude and acrophase). Given its structure, BT is known and widely considered one of the “marker rhythms” of the biological clock. Its complex chronobiological, neural, endocrine, metabolic and molecular regulation involves several metabolic elements, such as thyroid hormone, brown adipose tissue (BAT), leptin and hypothalamic neural structures, in particular, the suprachiasmatic nuclei.
It is well documented that STZ-induced diabetes causes a significant decrease in mean BT [29,32,33], and that exogenous insulin treatment is able to restore it . In this study we describe for the first time, to our knowledge, the daily profile of BT in a insulin-deficient diabetic animal, and we demonstrate that diabetes not only causes a significant reduction in BT, but also the disruption of its daily rhythm (no rhythms with period between 20 and 28 hours), disturbance that intensifies with time, showing alterations in all rhythmic parameters, such as decreased MESOR, increased amplitude and shifted acrophases.
In the present experimental design, the results of the rhythmic analysis came from the same animal as its own control, given that each individual has a particular daily profile and range of BT, which would be lost if a pool of animals were used instead.
Diabetes is a metabolic pathology directly related to energy metabolism and, consequently, temperature regulation. The thyroid gland is an important gland for thermoregulation, and it is reported the occurrence of hypothyroidism associated with most common experimental type 1 diabetes models (STZ and alloxan), [42-47]. More recent data shows that STZ- induced diabetes leads to a true hypothyroidism (decreased free T3 and T4 levels, along with clinical signals for hypothyroidism, and increased Q-T interval). Exogenous insulin treatment prevents all signs of hypothyroidism and restores normal free T3 and T4 levels; T3 treatment alone normalizes BT, heart rate and Q-T interval, but has no effect on glycemia [48,49], therefore the reduction of the mean body temperature observed in our work would probably be result of a hypothyroidism secondary to STZ-induced diabetes.
Other studies demonstrate the importance of BAT in regulation of BT. BAT thermogenesis contributes to the increase of core BT during the dark phase, indicating that circadian changes of BAT thermogenesis does indeed play significant role in the overall maintenance of the circadian rhythm of core BT .
Another important consequence of insulin dependent diabetes in rodents is leptin deficiency . It has been demonstrated that diabetic animals also have decreased leptin, and that insulin treatment is able to restore it. Since leptin is a major regulator of thermoregulation and energy metabolism through the balance of body weight and adipose tissue , an important feature of the loss of thermoregulation in STZ-induced diabetic animals could be the reduction of leptin levels. It would be important to assess the leptin levels in both groups, in short-term and long-term to determine leptin’s part in regulating the body temperature rhythm.
Previous work shows that in experimental diabetes, a significant decrease of BT occurs only eight weeks after STZ injection and that two weeks are not enough to observe this change . These data differs from other in literature [29,33], and from the present work, where a significant decrease in core BT is evident two weeks after diabetes induction. This discrepancy is probably due to methodological differences, given that Zhang et al. measured rectal BT only twice (two and eight weeks after STZ), instead of monitoring it continuously, as was done in the present study. Moreover, as it was shown in the temporal analysis of the present data, even though the BT rhythm is disrupted and, in average, temperature is decreased, at some points temperature still reaches normal values and therefore few samples of rectal BT would not necessarily detect the mean reduction in BT caused by diabetes, already seen at the onset of the disease.
Melatonin is the hormone that signalizes exterior daytime and nighttime to the body, and is also important to maintain internal synchronization . Previous work form our lab demonstrated that during T1DM rats have significant reduction of melatonin synthesis both in the pineal gland  and in the retina . In the present study, short-term diabetes was sufficient to disturb the BT rhythmicity even though the 24 h period remained, indicating that three-day diabetes is enough to produce circadian alterations. In accordance with these evidence, and because melatonin is a major regulator of BT rhythm in humans ; we supplemented diabetic animals with melatonin, in physiological doses. Melatonin alone did not restore the rhythmic parameters, or reverse the reduction of BT in long term diabetic animals. When administered early, melatonin partially maintained BT rhythmicity although it was not as efficient as insulin, since MESOR was significantly reduced, and animals remained hyperglycemic and stopped gaining weight. However, melatonin had an effect on the regulation of BT since a further decrease was observed when the supplementation was interrupted. Some characteristics of the long-term diabetic animals appeared. After the reinstitution of the supplementation all animals returned to the same state as they were during the first supplementation. Based on these results, early melatonin ameliorates the effects of diabetes on BT rhythm. Melatonin seems to have a stronger effect on rhythmicity, while insulin seems to act both on the metabolic and chronobiological effects of diabetes. Still, we demonstrated here that melatonin early treatment is important to prevent the disruption in the BT rhythm caused by diabetes. In fact, it was demonstrated that in STZ-diabetic animals pineal melatonin production is reduced by more than 50%  and that melatonin is important for the integrity and function of the BAT  as well as for the daily distribution of thermogenic processes . The absence of melatonin reduces nighttime energy expenditure and temperature. Taking together these data, it should be postulated that the reduction in melatonin associated to the STZ-induced diabetes is responsible at least partially for the rhythmic disturbances observed in body temperature. This result in some way diverges from data in literature showing a hypothermic effect of melatonin treatment , where they used pharmacological doses (30-120 mg/kg i.p.) in healthy animals whereas this study studied a near physiological dose (0.5 mg/kg in drinking water) in diabetic animals.
A combination of melatonin plus insulin restored normal BT and its rhythm, including daily allocation of the acrophases at night and normal MESOR and amplitudes. These results show a complementary action of insulin and melatonin to restore BT, body weight, glycemia and the daily rhythm in long-term diabetic animals. The early treatment of diabetic animals with insulin plus melatonin increased BT above control values and maintained its rhythm. This could be explained by a combined action of melatonin and insulin on BT, since they both act increasing it. When the treatments were interrupted, some of the effects observed during the treatments were lost. Reinstituting treatments restored MESOR, but not amplitude nor acrophases. These results suggest that 15 days of diabetes, even after receiving treatment, lead to persistent alterations of BT rhythm and all rhythmic parameters, along with body weight loss and hyperglycemia, and the reinstitution of the treatments does not result as effective as treating the animals after an early onset. They also suggest a possible interaction between insulin and melatonin in diabetic animals that leads to a more efficient treatment of the disruption in the daily rhythm of BT. Since body temperature is a marker rhythm of the state of internal synchronization of the body, the alteration of its structure probably leads to a strong alteration in the synchronization of the entire body. Another factor to be considered is a progressive and severe, insulin resistance .
We still need to study the mechanisms underlying this phenomenon; however, we suppose that melatonin potentializes insulin action in BT rhythmicity acting centrally  or peripherally . In this way, it could be of great importance to include melatonin as a complement in insulin treatment of diabetes, given that disruption of the BT rhythm, and probably other rhythms in the organism are not completely reverted by insulin alone.
Despite the alterations in the rhythmic parameters seen after 3 and 15 days of diabetes, neither of them was sufficient to cause the loss of the 24 h period, differently from what was observed with 33 days, where the all periods - from 20 to 28 h - were lost. All treatments were able to prevent the loss of the 24 h predominant period; however a reduction in the potency of the predominance of the 24 h period was evident in every case. It seems that the 24 h period is a characteristic of the circadian system that persists even when other rhythmic parameters are disrupted and, different from MESOR, amplitude and acrophase, it was completely restored by all late treatments.
This study shows for the first time, to our knowledge, the alterations in the daily rhythm of BT, one of the most important rhythms, caused by STZ-induced diabetes. It is important to know that diabetes not only causes metabolic damages, but it also damages the circadian system; this information is relevant for a wider approach when designing new therapies for treating this disease, considering a new system that results significantly altered and is not fully restored by therapies in use. More studies are needed to understand the mechanisms behind these observations, such as the role of BAT and thyroid gland on the BT rhythm in this model, and integrate the chronobiological, metabolic, neural systems.
In conclusion, we describe a new consequence of insulin dependent diabetes: the disruption of the BT rhythm; when the disease is treated, insulin can restore MESOR and amplitude, but with peaks of BT in the light phase; melatonin is not able to either restore the rhythm or reverse the decreased BT; joint treatment of insulin and melatonin restores average BT and its normal daily rhythm. Early treatments can prevent the disruption of the rhythm. Melatonin as an early treatment, acts partially increasing BT. Insulin and melatonin appear to act in a complementary way restoring the rhythm. All beneficial effects observed are dependent on the continuous maintenance of the treatments and; reinstituting treatments do not result as effective as the early ones. Melatonin seems to improve insulin action restoring the endogenous rhythm of body temperature after long-term diabetes. Therefore, melatonin could be a new complement of insulin treatment improving its action on the energy metabolism.
Type 1 diabetes mellitus
Midline estimating statistic of rhythm
- INS + MEL:
Insulin and melatonin
Light and dark cycle
Brown adipose tissue
We are thankful to Julieta Scialfa for technical assistance during the experiments and animal handling, Prof. Luiz S. Menna-Barreto for lending us the El Temps software and the discussions regarding the present work, and Marcio Fernandes, for English review of this manuscript.
This study was supported by the São Paulo Research Foundation [FAPESP-Brazil, 2011/ 15462–4 (AMRL), 09/52920-0 (JCN)] and CAPES (AMRL).
- Karatsoreos IN, Bhagat S, Bloss EB, Morrison JH, McEwen BS. Disruption of circadian clocks has ramifications for metabolism, brain, and behavior. Proc Natl Acad Sci U S A. 2011;108(4):1657–62.View ArticlePubMed CentralPubMedGoogle Scholar
- Minors DS, Folkard S, Waterhouse JM. The shape of the endogenous circadian rhythm of rectal temperature in humans. Chronobiol Int. 1996;13(4):261–71.View ArticlePubMedGoogle Scholar
- Hanneman SK. Measuring circadian temperature rhythm. Biol Res Nurs. 2001;2(4):236–48.View ArticlePubMedGoogle Scholar
- Kelly G. Body temperature variability (Part 1): a review of the history of body temperature and its variability due to site selection, biological rhythms, fitness, and aging. Altern Med Rev. 2006;11(4):278–93.PubMedGoogle Scholar
- Scheer FA, Pirovano C, Van Someren EJ, Buijs RM. Environmental light and suprachiasmatic nucleus interact in the regulation of body temperature. Neuroscience. 2005;132(2):465–77.View ArticlePubMedGoogle Scholar
- la Fleur SE, Kalsbeek A, Wortel J, Fekkes ML, Buijs RM. A daily rhythm in glucose tolerance: a role for the suprachiasmatic nucleus. Diabetes. 2001;50(6):1237–43.View ArticlePubMedGoogle Scholar
- la Fleur SE, Kalsbeek A, Wortel J, van der Vliet J, Buijs RM. Role for the pineal and melatonin in glucose homeostasis: pinealectomy increases night-time glucose concentrations. J Neuroendocrinol. 2001;13(12):1025–32.View ArticlePubMedGoogle Scholar
- Reiter RJ, Tan DX, Korkmaz A. The circadian melatonin rhythm and its modulation: possible impact on hypertension. J Hypertens Suppl. 2009;27(6):S17–20.View ArticlePubMedGoogle Scholar
- Peschke E, Frese T, Chankiewitz E, Peschke D, Preiss U, Schneyer U, et al. Diabetic Goto Kakizaki rats as well as type 2 diabetic patients show a decreased diurnal serum melatonin level and an increased pancreatic melatonin-receptor status. J Pineal Res. 2006;40(2):135–43.View ArticlePubMedGoogle Scholar
- Peschke E, Stumpf I, Bazwinsky I, Litvak L, Dralle H, Muhlbauer E. Melatonin and type 2 diabetes - a possible link? J Pineal Res. 2007;42(4):350–8.View ArticlePubMedGoogle Scholar
- Goncharova ND, Vengerin AA, Khavinson V, Lapin BA. Pineal peptides restore the age-related disturbances in hormonal functions of the pineal gland and the pancreas. Exp Gerontol. 2005;40(1–2):51–7.View ArticlePubMedGoogle Scholar
- Scheer FA, Hilton MF, Mantzoros CS, Shea SA. Adverse metabolic and cardiovascular consequences of circadian misalignment. Proc Natl Acad Sci U S A. 2009;106(11):4453–8.View ArticlePubMed CentralPubMedGoogle Scholar
- Boden G, Chen X, Polansky M. Disruption of circadian insulin secretion is associated with reduced glucose uptake in first-degree relatives of patients with type 2 diabetes. Diabetes. 1999;48(11):2182–8.View ArticlePubMedGoogle Scholar
- Scott EM, Carter AM, Grant PJ. Association between polymorphisms in the Clock gene, obesity and the metabolic syndrome in man. Int J Obes (Lond). 2008;32(4):658–62.View ArticleGoogle Scholar
- Woon PY, Kaisaki PJ, Braganca J, Bihoreau MT, Levy JC, Farrall M, et al. Aryl hydrocarbon receptor nuclear translocator-like (BMAL1) is associated with susceptibility to hypertension and type 2 diabetes. Proc Natl Acad Sci U S A. 2007;104(36):14412–7.View ArticlePubMed CentralPubMedGoogle Scholar
- Marcheva B, Ramsey KM, Buhr ED, Kobayashi Y, Su H, Ko CH, et al. Disruption of the clock components CLOCK and BMAL1 leads to hypoinsulinaemia and diabetes. Nature. 2010;466(7306):627–31.View ArticlePubMed CentralPubMedGoogle Scholar
- Turek FW, Joshu C, Kohsaka A, Lin E, Ivanova G, McDearmon E, et al. Obesity and metabolic syndrome in circadian Clock mutant mice. Science. 2005;308(5724):1043–5.View ArticlePubMed CentralPubMedGoogle Scholar
- Yoon JA, Han DH, Noh JY, Kim MH, Son GH, Kim K, et al. Meal time shift disturbs circadian rhythmicity along with metabolic and behavioral alterations in mice. PLoS One. 2012;7(8), e44053.View ArticlePubMed CentralPubMedGoogle Scholar
- Hasler BP, Buysse DJ, Kupfer DJ, Germain A. Phase relationships between core body temperature, melatonin, and sleep are associated with depression severity: further evidence for circadian misalignment in non-seasonal depression. Psychiatry Res. 2010;178(1):205–7.View ArticlePubMed CentralPubMedGoogle Scholar
- Gubin DG, Gubin GD, Waterhouse J, Weinert D. The circadian body temperature rhythm in the elderly: effect of single daily melatonin dosing. Chronobiol Int. 2006;23(3):639–58.View ArticlePubMedGoogle Scholar
- Wolden-Hanson T, Mitton DR, McCants RL, Yellon SM, Wilkinson CW, Matsumoto AM, et al. Daily melatonin administration to middle-aged male rats suppresses body weight, intraabdominal adiposity, and plasma leptin and insulin independent of food intake and total body fat. Endocrinology. 2000;141(2):487–97.PubMedGoogle Scholar
- Alonso-Vale MI, Anhe GF, Borges-Silva C, Andreotti S, Peres SB, Cipolla-Neto J, et al. Pinealectomy alters adipose tissue adaptability to fasting in rats. Metab Clin Exp. 2004;53(4):500–6.View ArticlePubMedGoogle Scholar
- Alonso-Vale MI, Borges-Silva CN, Anhe GF, Andreotti S, Machado MA, Cipolla-Neto J, et al. Light/dark cycle-dependent metabolic changes in adipose tissue of pinealectomized rats. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme. 2004;36(7):474–9.View ArticlePubMedGoogle Scholar
- Muhlbauer E, Gross E, Labucay K, Wolgast S, Peschke E. Loss of melatonin signalling and its impact on circadian rhythms in mouse organs regulating blood glucose. Eur J Pharmacol. 2009;606(1–3):61–71.View ArticlePubMedGoogle Scholar
- Cipolla-Neto J, Amaral FG, Afeche SC, Tan DX, Reiter RJ. Melatonin, energy metabolism, and obesity: a review. J Pineal Res. 2014;56(4):371–81.View ArticlePubMedGoogle Scholar
- Krauchi K, Cajochen C, Wirz-Justice A. A relationship between heat loss and sleepiness: effects of postural change and melatonin administration. J Appl Physiol (1985). 1997;83(1):134–9.Google Scholar
- Whiting DR, Guariguata L, Weil C, Shaw J. IDF diabetes atlas: global estimates of the prevalence of diabetes for 2011 and 2030. Diabetes Res Clin Pract. 2011;94(3):311–21.View ArticlePubMedGoogle Scholar
- King AJ. The use of animal models in diabetes research. Br J Pharmacol. 2012;166(3):877–94.View ArticlePubMed CentralPubMedGoogle Scholar
- Howarth FC, Jacobson M, Naseer O, Adeghate E. Short-term effects of streptozotocin-induced diabetes on the electrocardiogram, physical activity and body temperature in rats. Exp Physiol. 2005;90(2):237–45.View ArticlePubMedGoogle Scholar
- Howarth FC, Jacobson M, Shafiullah M, Ljubisavljevic M, Adeghate E. Heart rate, body temperature and physical activity are variously affected during insulin treatment in alloxan-induced type 1 diabetic rat. Physiological research / Academia Scientiarum Bohemoslovaca. 2011;60(1):65–73.PubMedGoogle Scholar
- Kilgour RD, Williams PA. Diabetes affects blood pressure and heart rate responses during acute hypothermia. Acta Physiol Scand. 1998;162(1):27–32.View ArticlePubMedGoogle Scholar
- Howarth FC, Jacobson M, Shafiullah M, Adeghate E. Long-term effects of streptozotocin-induced diabetes on the electrocardiogram, physical activity and body temperature in rats. Exp Physiol. 2005;90(6):827–35.View ArticlePubMedGoogle Scholar
- Howarth FC, Jacobson M, Shafiullah M, Adeghate E. Effects of insulin treatment on heart rhythm, body temperature and physical activity in streptozotocin-induced diabetic rat. Clin Exp Pharmacol P. 2006;33(4):327–31.View ArticleGoogle Scholar
- Seydoux J, Chinet A, Schneider-Picard G, Bas S, Imesch E, Assimacopoulos-Jeannet F, et al. Brown adipose tissue metabolism in streptozotocin-diabetic rats. Endocrinology. 1983;113(2):604–10.View ArticlePubMedGoogle Scholar
- Kilgour RD, Williams PA. Effects of diabetes and food deprivation on shivering activity during progressive hypothermia in the rat. Comp Biochem Physiol A Physiol. 1996;114(2):159–65.View ArticlePubMedGoogle Scholar
- Smith OL, Davidson SB. Shivering thermogenesis and glucose uptake by muscles of normal or diabetic rats. Am J Physiol. 1982;242(1):R109–15.PubMedGoogle Scholar
- Peschke E, Bahr I, Muhlbauer E. Melatonin and pancreatic islets: interrelationships between melatonin, insulin and glucagon. Int J Mol Sci. 2013;14(4):6981–7015.View ArticlePubMed CentralPubMedGoogle Scholar
- Amaral FG, Turati AO, Barone M, Scialfa JH, do Carmo Buonfiglio D, Peres R, et al. Melatonin synthesis impairment as a new deleterious outcome of diabetes-derived hyperglycemia. J Pineal Res. 2014;57(1):67–79.View ArticlePubMedGoogle Scholar
- do Carmo Buonfiglio D, Peliciari-Garcia RA, do Amaral FG, Peres R, Nogueira TCA, Afeche SC, et al. Early-stage retinal melatonin synthesis impairment in streptozotocin-induced diabetic wistar rats. Invest Ophthalmol Vis Sci. 2011;52(10):7416–22.View ArticlePubMedGoogle Scholar
- Nishida S. Metabolic effects of melatonin on oxidative stress and diabetes mellitus. Endocrine. 2005;27(2):131–6.View ArticlePubMedGoogle Scholar
- Harkin A, O'Donnell JM, Kelly JP. A study of VitalView for behavioural and physiological monitoring in laboratory rats. Physiol Behav. 2002;77(1):65–77.View ArticlePubMedGoogle Scholar
- Sochor M, Baquer NZ, Ball MR, McLean P. Regulation of enzymes of glucose metabolism and lipogenesis in diabetic rat liver by thyroid hormones. Biochem Int. 1987;15(3):619–27.PubMedGoogle Scholar
- Sundaresan PR, Sharma VK, Gingold SI, Banerjee SP. Decreased beta-adrenergic receptors in rat heart in streptozotocin-induced diabetes: role of thyroid hormones. Endocrinology. 1984;114(4):1358–63.View ArticlePubMedGoogle Scholar
- Rodgers RL, Davidoff AJ, Mariani MJ. Cardiac function of the diabetic renovascular hypertensive rat: effects of insulin and thyroid hormone treatment. Can J Physiol Pharmacol. 1991;69(3):346–54.View ArticlePubMedGoogle Scholar
- Rondeel JM, de Greef WJ, Heide R, Visser TJ. Hypothalamo-hypophysial-thyroid axis in streptozotocin-induced diabetes. Endocrinology. 1992;130(1):216–20.PubMedGoogle Scholar
- der Elst JP S-v, van der Heide D. Effects of streptozocin-induced diabetes and food restriction on quantities and source of T4 and T3 in rat tissues. Diabetes. 1992;41(2):147–52.View ArticleGoogle Scholar
- Katovich MJ, Marks KS, Sninsky CA. Effect of insulin on the altered thyroid function and adrenergic responsiveness in the diabetic rat. Can J Physiol Pharmacol. 1993;71(8):568–75.View ArticlePubMedGoogle Scholar
- Zhang L, Parratt JR, Beastall GH, Pyne NJ, Furman BL. Streptozotocin diabetes protects against arrhythmias in rat isolated hearts: role of hypothyroidism. Eur J Pharmacol. 2002;435(2–3):269–76.View ArticlePubMedGoogle Scholar
- Matsen ME, Thaler JP, Wisse BE, Guyenet SJ, Meek TH, Ogimoto K, et al. In uncontrolled diabetes, thyroid hormone and sympathetic activators induce thermogenesis without increasing glucose uptake in brown adipose tissue. Am J Physiol Endocrinol Metab. 2013;304(7):E734–46.View ArticlePubMed CentralPubMedGoogle Scholar
- Yang YL, Shen ZL, Tang Y, Wang N, Sun B. [Simultaneous telemetric analyzing of the temporal relationship for the changes of the circadian rhythms of brown adipose tissue thermogenesis and core temperature in the rat]. Zhongguo ying yong sheng li xue za zhi = Zhongguo yingyong shenglixue zazhi =Chinese journal of applied physiology. 2011;27(3):348–52.Google Scholar
- Havel PJ, Uriu-Hare JY, Liu T, Stanhope KL, Stern JS, Keen CL, et al. Marked and rapid decreases of circulating leptin in streptozotocin diabetic rats: reversal by insulin. Am J Physiol. 1998;274(5 Pt 2):R1482–91.PubMedGoogle Scholar
- Rezai-Zadeh K, Munzberg H. Integration of sensory information via central thermoregulatory leptin targets. Physiol Behav. 2013;121:49–55.View ArticlePubMedGoogle Scholar
- Cagnacci A, Elliott JA, Yen SS. Melatonin: a major regulator of the circadian rhythm of core temperature in humans. J Clin Endocrinol Metab. 1992;75(2):447–52.PubMedGoogle Scholar
- Teodoro BG, Baraldi FG, Sampaio IH, Bomfim LH, Queiroz AL, Passos MA, et al. Melatonin prevents mitochondrial dysfunction and insulin resistance in rat skeletal muscle. J Pineal Res. 2014;57(2):155–67.View ArticlePubMedGoogle Scholar
- Lin MT, Chuang JI. Melatonin potentiates 5-HT(1A) receptor activation in rat hypothalamus and results in hypothermia. J Pineal Res. 2002;33(1):14–9.View ArticlePubMedGoogle Scholar
- de Fronzo RA, Hendler R, Simonson D. Insulin resistance is a prominent feature of insulin-dependent diabetes. Diabetes. 1982;31(9):795–801.View ArticleGoogle Scholar
- Anhe GF, Caperuto LC, Pereira-Da-Silva M, Souza LC, Hirata AE, Velloso LA, et al. In vivo activation of insulin receptor tyrosine kinase by melatonin in the rat hypothalamus. J Neurochem. 2004;90(3):559–66.View ArticlePubMedGoogle Scholar
- Zanquetta MM, Seraphim PM, Sumida DH, Cipolla-Neto J, Machado UF. Calorie restriction reduces pinealectomy-induced insulin resistance by improving GLUT4 gene expression and its translocation to the plasma membrane. J Pineal Res. 2003;35(3):141–8.View ArticlePubMedGoogle Scholar
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