Stress prompts brown fat into combustion

Abstract

Activation of dorsomedial hypothalamic-rostral medullary raphe neural signaling promotes brown fat thermogenesis, leading to elevated body temperature. In this issue, Kataoka et al. (2014) establish an important role for this brain-brown fat thermogenic action in psychological stress-induced hyperthermia in rats, implying a potential mechanism behind human psychogenic fever.

Psychological stress-induced hyperthermia (PSH) or “psychogenic fever” resulting from various types of psychological stress has long been noted (Falcon-Lesses and Proger, 1930; Oka et al., 2001), but the neural mechanism linking psychological stress to an acute or chronic elevation of body temperature (hyperthermia or fever) remains unclear. Brown adipose tissue (BAT) is a non-shivering thermogenic organ in mammals and acts to dissipate chemical energy to produce heat for protection against a cold environment (Cannon and Nedergaard, 2004). BAT thermogenesis also contributes to pyrogen-induced fever (Jepson et al., 1988; Szekely et al., 1973), a febrile response of the body that aims to increase immune cell activity and suppress pathogen growth for fighting against infections. The sympathetic nervous system (SNS) stimulates BAT thermogenesis in response to cold or pyrogenic stimulus, and this stimulation is regulated by the central nervous system (Morrison et al., 2014). Although detailed central regulation of BAT thermogenesis and body temperature remains in completely defined, recent evidence has indicated a critical role for the hypothalamic-medullary signaling pathway in thermoregulation (Dimicco and Zaretsky, 2007; Morrison et al., 2014; Saper et al., 2012). Specifically, the hypothalamic preoptic area (POA) contains temperature-sensitive neurons that integrate central and peripheral thermal signals, which are then relayed via the dorsomedial hypothalamus (DMH) to the rostral medullary raphe (RMR) in order to activate the SNS and regulate body temperature (Figure 1). In this issue, Kataoka et al.(2014) provide evidence that the DMH-RMR-BAT thermogenic system contributes to psychological stress-induced hyperthermia.

Figure 1. The hypothalamic-rostral medullary raphe (RMR) pathway in the regulation of brown adipose tissue (BAT) thermogenesis and body temperature.

The hypothalamic preoptic area (POA) contains temperature-sensitive neurons that are primarily GABAergic and elicit inhibitory effects on neurons in the dorsomedial hypothalamus (DMH). DMH neurons innervate sympathetic premotor neurons glutamatergically in the RMR that modulate sympathetic nervous system (SNS) stimulation of BAT thermogenesis. Cold exposure or pyrogenic infection causes decreased GABAergic signaling from the POA to the DMH. The resulting disinhibition (excitation) of neurons in the DMH promotes RMR neuronal activity, which increases sympathetic nervous activity to BAT, leading to increased BAT thermogenesis and body temperature. Psychological stress causes neuronal activation in the DMH via a yet to be identified neural signaling pathway(s), and such activation promotes BAT thermogenesis though increasing the RMR-SNS-BAT activity.

To explore a potential neural mechanism underlying PSH, Kataoka and colleagues (2014) exposed rats to social stress by placing “intruder” rats into the cages of dominant resident rats. They found that the defeated intruders had significant elevations of inter scapular BAT (IBAT) and core body temperature, demonstrating that social defeat stress induces hyperthermia in rats. Since the SNS mediates BAT thermogenesis via β3-adrenergic receptors (Cannon and Nedergaard, 2004), the authors next pharmacologically blocked sympathetic signaling to assess whether social defeat stress-induced hyperthermia is mediated through sympathetic BAT thermogenesis. In support of their view, intravenous injection of the non-selective β-blocker propranolol into the intruders prior to the stress exposure significantly eliminated stress-induced increases in IBAT and body temperature. Thus, the results from this study and their β3-receptor-specific antagonist indicate a primary role for BAT thermogenesis in social defeat stress-induced hyperthermia (Kataoka et al, 2014).

The authors then sought to characterize the neural circuit underlying this phenomenon. They found that both inhibition of neurons in the RMR with a GABA_A receptor agonist and blockade of glutamate receptors in the RMR by glutamate receptor antagonists significantly reduced social stress-induced increases in IBAT and body temperature (Kataoka et al, 2014). These results establish that glutamatergic inputs into RMR neurons play a crucial role in the development of social stress-induced hyperthermia.

Given that DMH neurons are known to innervate the RMR and regulate BAT thermogenesis, the authors used a technique of retrograde tracing combined with c-Fos as a marker of neuronal activation to determine whether the DMH-RMR signaling pathway mediates social defeat stress-induced hyperthermia. They detected a cluster of neurons in the dorsal part of the DMH that were activated by social defeat stress, which were also labeled with the retrograde tracer cholera toxin B subunit injected into the RMR (Kataoka et al, 2014), confirming that social stress activates DMH neurons with projection to the RMR. Most strikingly, a functional role for this projection was demonstrated. In vivo optogenetic stimulation of DMH-nerve endings in the RMR resulted in increases in sympathetic nervous activity (SNA) and temperature in IBAT. While optogenetic stimulation of DMH neurons consistently provoked these increases, such effects were prevented by antagonism of glutamate activity in the RMR. Although DMH neurons also project to the parventricular nucleus (PVN) and the ventrolateral part of the caudal periaqueductal gray (vlcPAG), which have both been proposed to affect BAT thermogenesis, DMH modulation of BAT thermogenesis was not mediated by these two areas as optogenetic stimulation of DMH-nerve endings in the PVN or vlcPAG did not affect IBAT SNA and temperature.

The POA plays a key role in thermoregulation via a tonic inhibitory action on the DMH-RMR-BAT thermogenic system (Figure 1). Cold exposure or pyrogenic infection results in inhibition of GABAergic signaling from the POA, and the resulting disinhibition of neurons in the DMH and RMR causes increased BAT thermogenesis and body temperature. Whereas pyrogenic prostaglandin E2 (PGE2) induces fever via the POA, alterations in PGE2 signaling do not affect psychological stress-induced fever, suggesting that the POA is unlikely to mediate stress-induced hyperthermia (Saper et al., 2012; Vinkers et al., 2008). Thus, the critical question remains - what is the upstream pathway(s) of the DMH in stress-induced hyperthermia? There are several potential regulatory nuclei, such as the bed nucleus of the striaterminalis and the lateral septal nucleus as (1) both nucleisend GABAergic inhibitory inputs to the DMH, and (2) they have been linked to behavioral and sympathetic responses to psychological stress. The other is the medial amygdala as it has been implicated in stress-induced fever (Vinkers et al., 2008), but whether it also innervates DMH neuronal activity remains unclear. Nevertheless, the findings of such pathway(s) would advance our overall understanding of how the DMH integrates three different stimuli (cold, pyrogen, and stress) to produce the same thermogenic action via the common RMR-SNS-BAT pathway (Figure 1).

In addition, although active BAT has recently been found in adult humans and the importance of BAT in thermogenesis and obesity in humans has been overwhelmingly investigated, whether human BAT contributes to stress-induced hyperthermia has yet to be explored, which will bean other challenge for researchers. Since other factors have been shown to participate inhuman thermogenesis including shivering thermogenesis, cutaneous vasoconstriction, sweating, and neuroendocrine actions, roles for these factors in stress-induced hyperthermia in humans also merit evaluation. Furthermore, clinical evidence has shown that psychogenic fever could be suppressed by anxiolytic, neuroleptic, and anti-depressive drugs, and altered body temperature has been found in psychiatric disorders including schizophrenia, depressive disorders, and insomnia (Oka et al., 2001; Vinkers et al., 2008), implying that other neuromodulators or signaling pathways also contribute to psychogenic fever.

Overall, the current results highlight the importance of the DMH-RMR-BAT thermoregulatory system in the development of PSH in rats and imply a potential role for this system in the etiology of psychogenic fever, a “mysterious”, most commonly psychosomatic disorder in humans.