Alterações metabólicas induzidas pelo isolamento social: Papel do tecido adiposo marrom.

Abstract

Maintaining social bonds is so critical for survival that social isolation has been reported as a challenge to homeostasis, comparable to hunger and thirst. Mammals use social interaction to maintain thermal homeostasis, allowing them to conserve energy. This phenomenon is particularly critical for small animals, such as laboratory mice. We have previously demonstrated that isolated mice maintain their circadian peak in core body temperature (Tc) at the expense of reduced body weight gain compared to group-housed mice. However, it is unclear how energy metabolism is affected by isolation conditions in these animals. Brown adipose tissue (BAT) is a unique tissue capable of generating heat through the action of uncoupling protein 1 (UCP1). Based on this, we hypothesized that social isolation induces metabolic changes through adaptations in BAT to maintain the daily rhythm of Tc throughout the day in isolated mice. The present study aimed to evaluate whether the effects of social isolation on energy metabolism and circadian variations in Tc involve BAT participation and/or modulation of environmental temperature. For this purpose, adult C57BL/6-UNI mice were used. Mice were maintained either in isolation or in groups (4 animals per cage – Control Group) for 28 days under a 12-hour light/dark cycle (lights on at 7:00 AM) in two thermal conditions: one closer to the thermoneutral zone (28 ± 2 °C) and another outside this temperature zone (25 ± 1 °C). Tc and spontaneous locomotor activity (SLA) were monitored by intra-abdominal telemetry probes. Body mass and food intake were tracked throughout the protocol, and at the end, metabolic rate was assessed using indirect calorimetry. On the 28th day of the protocol, the animals were euthanized at zeitgeber time (ZT) 1 and 10 to obtain intrascapular BAT for gene expression analysis by qRT-PCR. Tc was lower in the middle of light phase in isolated mice at 25 ± 1 °C, while the circadian peak in Tc shown by isolated mice was comparable to grouped mice. Isolated mice at 25 ± 1 °C showed lower respiratory Exchange ratio (RER) and higher energy expenditure (EE), which may have contribuited to the lower body weight gain during the protocol. These differences in Tc rhythm and metabolic responses between grouped and isolated mice were not observed at 28 ± 2 °C. Next, we challenged the BAT with an i.p. injection of a type-3 adrenergic receptor agonist (B3ADR) at 25 ± 1 °C to mimic the BAT response to cold exposure. In grouped animals, as expected, there was an increase in the expression of Ucp1 and the hormone-sensitive lipase (Hsl) gene, whereas in isolated animals, we observed an increase in the expression of the Rev-erbα gene and the Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-Alpha (PGC1α). It is known that Rev-erbα is part of the accessory loop of molecular clock regulation and negatively regulates UCP1. Based on this result, we investigated other clock genes as well as the effect of isolation at two different times of day. Socially isolated animals at 28 ± 2 °C showed lower expression of Ucp1 and PGC1α at ZT1 (the beginning of the light phase), whereas at ZT10, no differences in the expression of these genes were observed between grouped and isolated animals. At ZT1, isolation also reduced the expression of Per2 without altering the expression of Per1 or Bmal1. Based on these results, we suggest that the social isolation-induced changes in metabolism to maintain the daily Tc rhythm can be explained by alterations in the transcriptional programming of BAT, which appear to be determined by the time of day and ambient temperature.