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Brown adipose tissue plays a central role in systemic inflammation-induced sleep responses.

ABSTRACT: We previously identified brown adipose tissue (BAT) as a source of sleep-inducing signals. Pharmacological activation of BAT enhances sleep while sleep loss leads to increased BAT thermogenesis. Recovery sleep after sleep loss is diminished in mice that lack uncoupling protein 1 (UCP-1), and also in wild-type (WT) mice after sensory denervation of the BAT. Systemic inflammation greatly affects metabolism and the function of adipose tissue, and also induces characteristic sleep responses. We hypothesized that sleep responses to acute inflammation are mediated by BAT-derived signals. To test this, we determined the effects of systemic inflammation on sleep and body temperature in UCP-1 knockout (KO) and WT mice. Intraperitoneal injections of lipopolysaccharide, tumor necrosis factor-?, interleukin-1 beta and clodronate containing liposomes were used to induce systemic inflammation. In WT animals, non-rapid-eye movement sleep (NREMS) was elevated in all four inflammatory models. All NREMS responses were completely abolished in UCP-1 KO animals. Systemic inflammation elicited an initial hypothermia followed by fever in WT mice. The hypothermic phase, but not the fever, was abolished in UCP-1 KO mice. The only recognized function of UCP-1 is to promote thermogenesis in brown adipocytes. Present results indicate that the presence of UCP-1 is necessary for increased NREMS but does not contribute to the development of fever in systemic inflammation.

SUBMITTER: Szentirmai E

PROVIDER: S-EPMC5945014 | biostudies-other | 2018

REPOSITORIES: biostudies-other

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Brown adipose tissue plays a central role in systemic inflammation-induced sleep responses.

Szentirmai Éva É Kapás Levente L

PloS one 20180510 5

We previously identified brown adipose tissue (BAT) as a source of sleep-inducing signals. Pharmacological activation of BAT enhances sleep while sleep loss leads to increased BAT thermogenesis. Recovery sleep after sleep loss is diminished in mice that lack uncoupling protein 1 (UCP-1), and also in wild-type (WT) mice after sensory denervation of the BAT. Systemic inflammation greatly affects metabolism and the function of adipose tissue, and also induces characteristic sleep responses. We hypo ...[more]

PMID: 29746591

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Project description:ObjectiveMetainflammation is a chronic low-grade inflammatory state induced by obesity and associated comorbidities, including peripheral insulin resistance. Brown adipose tissue (BAT), a therapeutic target against obesity, is an insulin target tissue sensitive to inflammation. Therefore, it is necessary to find strategies to protect BAT against the effects of inflammation in energy balance. In this study, we explored the impact of moderate sirtuin 1 (SIRT1) overexpression on insulin sensitivity and β-adrenergic responses in BAT and brown adipocytes (BA) under pro-inflammatory conditions.MethodsThe effect of inflammation on BAT functionality was studied in obese db/db mice and lean wild-type (WT) mice or mice with moderate overexpression of SIRT1 (SIRT1Tg+) injected with a low dose of bacterial lipopolysaccharide (LPS) to mimic endotoxemia. We also conducted studies on differentiated BA (BA-WT and BA-SIRT1Tg+) exposed to a macrophage-derived pro-inflammatory conditioned medium (CM) to evaluate the protection of SIRT1 overexpression in insulin signaling and glucose uptake, mitochondrial respiration, fatty acid oxidation (FAO), and norepinephrine (NE)-mediated-modulation of uncoupling protein-1 (UCP-1) expression.ResultsBAT from the db/db mice was susceptible to metabolic inflammation manifested by the activation of pro-inflammatory signaling cascades, increased pro-inflammatory gene expression, tissue-specific insulin resistance, and reduced UCP-1 expression. Impairment of insulin and noradrenergic responses were also found in the lean WT mice upon LPS injection. In contrast, BAT from the mice with moderate overexpression of SIRT1 (SIRT1Tg+) was protected against LPS-induced activation of pro-inflammatory signaling, insulin resistance, and defective thermogenic-related responses upon cold exposure. Importantly, the decline in triiodothyronine (T3) levels in the circulation and intra-BAT after exposure of the WT mice to LPS and cold was markedly attenuated in the SIRT1Tg+ mice. In vitro BA experiments in the two genotypes revealed that upon differentiation with a T3-enriched medium and subsequent exposure to a macrophage-derived pro-inflammatory CM, only BA-SIRT1Tg+ fully recovered insulin and noradrenergic responses.ConclusionsThis study has ascertained the benefit of the moderate overexpression of SIRT1 to confer protection against defective insulin and β-adrenergic responses caused by BAT inflammation. Our results have potential therapeutic value in combinatorial therapies for BAT-specific thyromimetics and SIRT1 activators to combat metainflammation in this tissue.

Dataset Information

Brown adipose tissue plays a central role in systemic inflammation-induced sleep responses.

Publications

Brown adipose tissue plays a central role in systemic inflammation-induced sleep responses.

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