Heat Shock Factor 1 Deficiency Affects Systemic Body Temperature Regulation.
Heat shock factor 1 (HSF1) is a ubiquitous heat-sensitive transcription factor that mediates heat shock protein transcription in response to cellular stress, such as increased temperature, in order to protect the organism against misfolded proteins. In this study, we analysed the effect of HSF1 deficiency on core body temperature regulation.
MATERIALS AND METHODS:
Body temperature, locomotor activity, and food consumption of wild-type mice and HSF1-deficient mice were recorded. Prolactin and thyroid-stimulating hormone levels were measured by ELISA. Gene expression in brown adipose tissue was analysed by quantitative real-time PCR. Hypothalamic HSF1 and its co-localisation with tyrosine hydroxylase was analysed using confocal laser scanning microscopy.
HSF1-deficient mice showed an increase in core body temperature (hyperthermia), decreased overall locomotor activity, and decreased levels of prolactin in pituitary and blood plasma reminiscent of cold adaptation. HSF1 could be detected in various hypothalamic regions involved in temperature regulation, suggesting a potential role of HSF1 in hypothalamic thermoregulation. Moreover, HSF1 co-localises with tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis, suggesting a potential role of HSF1 in the hypothalamic control of prolactin release. In brown adipose tissue, levels of prolactin receptor and uncoupled protein 1 were increased in HSF1-deficient mice, consistent with an up-regulation of heat production.
Our data suggest a role of HSF1 in systemic thermoregulation.
Thermoregulation is a process that controls homeostasis of core body temperature. Under physiological conditions the core body temperature is regulated to a narrow window between 36.5°C and 37.4°C. Many factors can affect body temperature such as external hot or cold temperatures, infections, exercise, or metabolic conditions. Moreover, body temperature fluctuates in a time-of-day dependent manner providing a powerful signal for the time-keeping system in the entire body. The hypothalamus habors the master pacemaker of the time-keeping system as well as the control device for thermoregulation. Temperature sensors in the brain detect internal temperature changes and in response, the hypothalamus sends humoral and neuronal signals to the periphery in order to activate a variety of thermoregulatory mechanisms. For instance, in response to cold temperatures, the body activates heat producing and heat-saving mechanisms in order to increase core body temperature. For efficient energy homeostasis, this increase in core body temperature will be compensated by decreased overall locomotor activity. On the cellular level, exposure to high temperatures activates the thermosensitive transcription factor heat shock factor 1 (HSF1) which mediates cytoprotective signaling pathways. In cerebellar purkinje neurons, HSF1 plays a role in intracellular calcium homeostasis, and HSF1-deicient mice show an ataxia-like behavior (Ingenwerth et al. 2016a). In our here featured study (Ingenwerth et al. 2016b), we tested the hypothesis that HSF1 plays a role in systemic thermoregulation. In order to test this hypothesis we analyzed thermoregulation in a mouse with a targeted deletion of the HSF1 gene (HSF1-/-). Interestingly, HSF1-/- mice have an overall increased core body temperature (hyperthermia), indicating an increase in heat production reminiscent of adaptive thermogenesis in response to cold exposure. This was associated with an overall decrease in locomotor activity, indicating a compensatory mechanism to balance total energy expenditure. Thus, HSF1 plays a role in systemic thermoregulation. When we analyzed HSF1 in the hypothalamus, we found a co-localization with the neuronal enzyme tyrosine hydroxylase (TH), the rate limiting enzyme of dopamine production (Fig. 1). This suggets a potential role of HSF1 in thermosensing of the brain, especially by hypothalamic regions which are involved in autonomic and behavioral responses to temperature challenges. In the hypothalamus, dopamine regulates the release of the hormone prolactin form the pituitary gland which is tightly linked to adaptive thermoregulation. In HSF1–/– mice, we found a significant downregulation of prolactin levels consistent with conditions of cold adaptation. A key molecule for heat production is the uncoupling protein 1 (UCP1), also known as thermogenin, found in the mitochondria of brown adipose tissue. We found a significantly higher expression level of UCP1 and prolactin receptors in brown adipose fat tissue of HSF1–/– mice. In conclusion, hypothalamic HSF1 affects energy homeostasis and adaptive thermogenesis via prolactin-mediated UCP1 recruitment. Thus, further elucidation of HSF1-dependent mechanisms might be relevant to develop new approaches for the development of anti-obesity drugs.
Figure 1: Representative microphotographs show cytoplasmic TH-Ir (red) nuclear HSF1-Ir (green) and nuclear staining (DAPI, blue) in the dorsomedial arcuate nucleus (Arc). The TH-immunopostive fibres terminating in the median eminence (ME) release dopamine into the hypophyseal portal system and thus regulate prolactin release from the pituitary gland. Scale bar, 150 µm.
Figure 2: Loss of HSF1 affects systemic body temperature regulation. HSF1-deficieny leads to an increase in body temperature and BAT UCP1/PRLR gene expression as well as a decrease in locomotor activity and pituitary prolactin release.
Ingenwerth M, Estrada V, Stahr A, Müller HW, von Gall C (2016a) HSF1-deficiency affects gait coordination and cerebellar calbindin level. Behav Brain Res. 2016 Sep 1;310:103-8. doi: 10.1016/j.bbr.2016.05.015.
Ingenwerth M, Noichl E, Stahr A, Korf HW, Reinke H, von Gall C (2016b) Heat Shock factor 1 Deficiency Affects Systemic Body Temperature Regulation. Neuroendocrinology. 2016;103(5):605-15. doi: 10.1159/000441947.