Uncoupling Protein-1 Modulates Anxiety-Like Behavior in a Temperature-Dependent Manner

Abstract

A strong bidirectional link between metabolic and psychiatric disorders exists; yet, the molecular basis underlying this interaction remains unresolved. Here we explored the role of the brown adipose tissue (BAT) as modulatory interface, focusing on the involvement of uncoupling protein 1 (UCP-1), a key metabolic regulator highly expressed in BAT, in the control of emotional behavior. Male and female constitutive UCP-1 knock-out (KO) mice were used to investigate the consequences of UCP-1 deficiency on anxiety-related and depression-related behaviors under mild thermogenic (23°C) and thermoneutral (29°C) conditions. UCP-1 KO mice displayed a selective enhancement of anxiety-related behavior exclusively under thermogenic conditions, but not at thermoneutrality. Neural and endocrine stress mediators were not affected in UCP-1 KO mice, which showed an activation of the integrated stress response alongside enhanced fibroblast-growth factor-21 (FGF-21) levels. However, viral-mediated overexpression of FGF-21 did not phenocopy the behavioral alterations of UCP-1 KO mice and blocking FGF-21 activity did not rescue the anxiogenic phenotype of UCP-1 KO mice. No effects of surgical removal of the intrascapular BAT on anxiety-like behavior or FGF-21 levels were observed in either UCP-1 KO or WT mice. We provide evidence for a novel role of UCP-1 in the regulation of emotions that manifests as inhibitory constraint on anxiety-related behavior, exclusively under thermogenic conditions. We propose this function of UCP-1 to be independent of its activity in the BAT and likely mediated through a central role of UCP-1 in brain regions with converging involvement in energy and emotional control. SIGNIFICANCE STATEMENT In this first description of a temperature-dependent phenotype of emotional behavior, we propose uncoupling protein-1 (UCP-1), the key component of the thermogenic function of the brown adipose tissue, as molecular break controlling anxiety-related behavior in mice. We suggest the involvement of UCP-1 in fear regulation to be mediated through its expression in brain regions with converging roles in energy and emotional control. These data are important and relevant in light of the largely unexplored bidirectional link between metabolic and psychiatric disorders, which has the potential for providing insight into novel therapeutic strategies for the management of both conditions.

SLC25A28 Overexpression Promotes Adipogenesis by Reducing ATGL

“…BAT activation is triggered by exposure to cold, commencing a process termed nonshivering thermogenesis, which entails dissipation of energy as heat. The aforementioned process is mediated by uncoupling protein-1 (UCP-1) [11], which is located at the inner mitochondrial membrane of brown adipocytes, where it functions to uncouple chemical energy [12]. Concerning its role in enhancing energy expenditure, there exists an inverse correlation between BAT mass and activity with obesity and body mass index [13].…”

The open field assay is influenced by room temperature and by drugs that affect core body temperature

“… 5 , 6 Additionally, mice deficient in uncoupling protein 1 (UCP-1), a key metabolic regulator highly expressed in brown adipose tissue, were reported to display selective enhancement of anxiety-related behavior exclusively under thermogenic conditions (23°C), but not at thermoneutrality (29°C). 7 …”

The open field assay is influenced by room temperature and by drugs that affect core body temperature

“…5,6 Additionally, mice deficient in uncoupling protein 1 (UCP-1), a key metabolic regulator highly expressed in brown adipose tissue, were reported to display selective enhancement of anxiety-related behavior exclusively under thermogenic conditions (23°C), but not at thermoneutrality (29°C). 7 Environmental temperature sensation and perception is also influenced by core body temperature (CBT). Alterations to CBT can be a consequence of physiological changes associated with disease state, exercise, metabolic function, and hormonal changes.…”