SR59230A, a beta-3 adrenoceptor antagonist, inhibits ultradian brown adipose tissue thermogenesis and interrupts associated episodic brain and body heating

Abstract

Brown adipose tissue (BAT) thermogenesis occurs episodically in an ultradian manner approximately every 80-100 min during the waking phase of the circadian cycle, together with highly correlated increases in brain and body temperatures, suggesting that BAT thermogenesis contributes to brain and body temperature increases. We investigated this in conscious Sprague-Dawley rats by determining whether inhibition of BAT thermogenesis via blockade of beta-3 adrenoceptors with SR59230A interrupts ultradian episodic increases in brain and body temperatures and whether SR59230A acts on BAT itself or via sympathetic neural control of BAT. Interscapular BAT (iBAT), brain, and body temperatures, tail artery blood flow, and heart rate were measured in unrestrained rats. SR59230A (1, 5, or 10 mg/kg ip), but not vehicle, decreased iBAT, body, and brain temperatures in a dose-dependent fashion (log-linear regression P < 0.01, R(2) = 0.3, 0.4, and 0.4, respectively, n = 10). Ultradian increases in BAT, brain, and body temperature were interrupted by administration of SR59230A (10 mg/kg ip) compared with vehicle, resuming after 162 ± 24 min (means ± SE, n = 10). SR59230A (10 mg/kg ip) caused a transient bradycardia without any increase in tail artery blood flow. In anesthetized rats, SR59230A reduced cooling-induced increases in iBAT temperature without affecting cooling-induced increases in iBAT sympathetic nerve discharge. Inhibition of BAT thermogenesis by SR59230A, thus, reflects direct blockade of beta-3 adrenoceptors in BAT. Interruption of episodic ultradian increases in body and brain temperature by SR59230A suggests that BAT thermogenesis makes a substantial contribution to these increases.

The integrated ultradian organization of behavior and physiology in mice and the contribution of orexin to the ultradian patterning

“…Our findings are similar to those reported previously in rats (Ootsuka et al, 2009, Blessing et al, 2012. Thus, the present data is consistent with the view that the ultradian alternation of rest-active states is a fundamental part of animal life (Aschoff and Gerkema, 1985, Ootsuka et al, 2011, Blessing et al, 2012, 2013.Previous studies, using EEG-based wake-sleep scoring, show robust changes in behavioural and physiological parameters upon waking (Mochizuki et al, 2006, Zhang et al, 2007, Bastianini et al, 2011, Lo Martire et al, 2012, Silvani et al, 2014, Bastianini et al, 2015. Zhang and colleagues performed simultaneous recording of different behavioural and physiological parameters in mice, including EEG and food intake, observed that eating occurs approximately 15 min after waking (Zhang et al, 2007).…”

“…It is proposed that, in addition to circadian patterning, ultradian (<24 hour) alternation between active interaction with the external environment and rest is a fundamental part of animal life (Aschoff and Gerkema, 1985, Ootsuka et al, 2011, Blessing et al, 2012, 2013, Blessing and Ootsuka, 2016. The ultradian pattern, also referred to as the basic-rest activity cycle (Kleitman, 1982), is particularly prominent when the circadian pattern is eliminated by destruction of the suprachiasmatic nucleus (Baker et al, 2005).…”

“…Notably, the integrated ultradian pattern continues even under food-depravation (Blessing et al, 2012). These observations suggest that the ultradian pattern is centrally coordinated as opposed to a secondary phenomenon driven by external events, or by afferent signals originating peripherally.Although the ultradian pattern is likely to be a fundamental biological rhythm across animal species (Aschoff and Gerkema, 1985, Ootsuka et al, 2011, Blessing et al, 2012, 2013, so far there are no reports of the integrated ultradian behavioural and physiological pattern in animals other than rats. Previous mice studies, which measured locomotor activity, body temperature, oxygen consumption, respiratory rhythm and arousal level not simultaneously but individually in the majority of cases, have shown 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 5 that these parameters increase in an ultradian episodic manner (Stupfel et al, 1985, Stupfel et al, 1990, Mazzucchelli et al, 1995, Stupfel et al, 1995, Poon et al, 1997, D'Olimpio and Renzi, 1998, Mochizuki et al, 2006, Dowse et al, 2010, Blum et al, 2014, Ono et al, 2015.…”

Brown adipose tissue thermogenesis contributes to emotional hyperthermia in a resident rat suddenly confronted with an intruder rat

“…In the present study we observed the resident rat for at least 24 h, recording the coordinated behavioral and physiological events that occur when the rat engages with the external environment as part of the basic rest-activity cycle (2,3,46,47). This enabled us to introduce the intruder rat when temperatures were at a basal level.…”

“…To further assess the possible contribution of BAT thermogenesis to emotional hyperthermia, we determined whether SR59230A, a ␤3 adrenoceptor antagonist (33,43,47), reduces the increases in BAT, body, and brain temperatures in resident rats suddenly confronted with an intruder rat. In all resident rats we also monitored the thermoregulatory vascular bed by continuously measuring tail artery blood flow with a chronically implanted Doppler ultrasonic flow probe.…”