Non-shivering thermogenesis activation and maintenance in the aging gray mouse lemur (Microcebus murinus)
Introduction
Non-shivering thermogenesis (NST), which mainly depends on the thermogenic metabolism of brown-adipose tissue (BAT), is widely used in heterothermic mammals (Himms-Hagen, 1984). BAT and NST are also assumed to be functional in humans, but only at fetal and neonatal stages (Symonds and Lomax, 1992). Until recently, there was no evidence for a functional activity of such thermogenesis in adult humans, while other thermogenic pathways (shivering, behaviors…) seemed to be preferred (Leppaluoto et al., 2005). However, a growing interest raised a few years ago on BAT metabolism, since the potential metabolic role of this thermogenic tissue has been recently described in adult humans (Christensen et al., 2006, Crisan et al., 2008, Cypess et al., 2009, Nedergaard et al., 2007, van Marken Lichtenbelt et al., 2009, Virtanen et al., 2009).
NST consists in a huge production of body heat originated from activation of mitochondrial activity in BAT (Cannon and Nedergaard, 2004, Ricquier, 2006, Sell et al., 2004). Indeed, brown adipocytes are constituted of multilocular lipid storing cells containing a massive amount of mitochondria and densely innervated by the sympathetic nervous system. Beta-adrenergic receptors are activated by noradrenaline release induced by the sympathetic influx. A cascade of metabolic events occurs, leading to the activation of uncoupling protein 1 (UCP-1). Free fatty acids are released from lipolysis of triglyceride droplets and are then used by UCP-1. This aerobic process is very demanding in oxygen implying that the respiratory metabolism is also highly increased. Body heat production through BAT metabolism is particularly efficient and allows a rapid rewarming, and prompt arousal from torpid state in small mammals (Klingenspor, 2003). In addition, when environmental conditions become harsher, for example when ambient temperatures (Tas) drop to low values, NST is used to avoid hypothermia. Thus, cold exposure has been shown to enhance NST activation at different levels (for review, see Klingenspor, 2003, Watanabe et al., 2008). Typically, brown adipocytes are massively recruited after cold exposure. These cells become hypertrophic and hyperplasic, while UCP-1 synthesis increases in association with thermogenic mitochondrial biogenesis.
Aging has been described to potentially impair the NST response in rodents, by reducing the amount of functional BAT and its thermogenic capacity by 50–60% (Horan et al., 1988, McDonald and Horwitz, 1999). However, the age-related decrease in NST capacity does not seem to be related to a decrease in sympathetic signalling (Gabaldon et al., 2003, McDonald et al., 1991, McDonald et al., 1993), but rather to a decrease in glucose utilization efficiency (McDonald et al., 1994) or in UCP-1 presence (Florez-Duquet and McDonald, 1998). Alternatively, an age-related impairment in fuel mobilization could explain the decrease in NST capacity during aging, at least in rodents (Florez-Duquet and McDonald, 1998, Kontani et al., 2005, Ueno et al., 1998), but this remains to be demonstrated in other species. In the case of non-human primate species, available data on the effects of aging on BAT function are scarce, whereas such data could bring valuable information on the potential role of BAT in humans.
In this context, the gray mouse lemur (Microcebus murinus, Primates) appears to be a biological model particularly interesting. The life span of this species is about 8 years in captivity (Perret, 1997), what is rare for such a small-sized species. This nocturnal primate originating from Madagascar exhibits daily heterothermia, which is characterized by the occurrence of a daily phase of low core temperature (Tc) during the first hours of daytime (Perret and Aujard, 2001). This physiological mechanism is particularly well adapted to compensate for small energy stores (Aujard and Vasseur, 2001) and leads to energy savings during the phase of Tc decrease. However, daily arousals imply the enhancement of NST and BAT metabolism in this species (Genin et al., 2003) and might induce high energy costs for rewarming. In captive gray mouse lemurs, daily modulations of Tc vary according to photoperiod and ambient temperature (Aujard et al., 1998, Seguy and Perret, 2005). More especially, it has been recently demonstrated that the daily phase of low Tc was strongly deepened during winter in aged mouse lemurs exposed to cold (Terrien et al., 2008). This was associated with impaired energy balance during aging, and we suggested that the energy costs of NST could be related to such impairment. For instance, no data is available on the effects of aging on NST function in the mouse lemur. Based on these findings, age-related effects on NST capacity were investigated in the mouse lemur by first investigating the effects of aging on cold-stimulated BAT to assess whether aging was associated with a modulation in BAT cell morphology or contents. Then, NST was pharmacologically stimulated to assess whether aging impaired NST activation in the mouse lemur.
Section snippets
Animals and housing conditions
All the gray mouse lemurs studied were males, born in the laboratory breeding colony of UMR 7179 (CNRS/MNHN, France, license approval No. A91.114.1) and were pathogen free. Before the experiment, general conditions of captivity were maintained constant: Ta (24–26 °C), relative humidity (55%). Food and water were available ad libitum. In captivity, seasonal variations of physiological functions can be entrained by alternating 6-month periods of summer-like long photoperiod (14 h of light/day) and
Short-term Tc response to cold
Fig. 1 represents the time-course of Tc recorded at the transition period between 25 °C and 12 °C. Adult and aged animals exhibited similar levels of Tc at 25 °C, before cold exposure. During the 2-day exposure to 12 °C, the patterns of daily Tc differed between the animals according to age. More particularly, time-course was significantly modified by age*Ta interaction (LME: F(2,18) = 3.5, p < 0.05). Indeed, although decreased from 35.8 ± 0.3 °C to 34.6 ± 0.5 °C between 25 °C and the first day at
Discussion
The main goal of this study was to investigate whether aging impaired the potentiality of non-shivering thermogenesis (NST) in the mouse lemur. The results showed that NST function was apparently conserved during aging and that its activation remained possible. However, in the case of strong need in NST function, e.g. during cold exposure, preliminary data on brown-adipose tissue (BAT) morphology revealed that energetic maintenance of such a thermogenesis process could be impaired during aging.
Acknowledgements
This work was carried out with the financial support of the «Institut de la Longévité et du Vieillissement», the «Fondation pour la Recherche Médicale (FRM)» and the «ANR – Agence Nationale de la Recherche – The French National Research Agency» under the «Programme National de Recherche en Alimentation et nutrition humaine», Project «ANR-06-PNRA-010-01».
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