Moderate SIRT1 overexpression protects against brown adipose tissue inflammation

Objective: Metainflammation 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. Methods: The 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. Results: BAT 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. Conclusions: This 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.
This study was funded by grants RTI2018-094052-B-100 (MICINN/AEI/FEDER, EU), S2017/BMD-3684 (Community of Madrid, Spain), the Ramón Areces Foundation (Spain), and CIBERdem (ISCIII) to A.M.V., grant S2010/BMD-2423 (Community of Madrid, Spain) to M.J.O. and A.M.V., grants SAF2017-83813-C3-1-R (MICINN/AEI/FEDER, EU) and CIBERobn (grant CB06/03/0001, ISCIII, Spain) to L.H. and D.S., grants 2017SGR278 (Government of Catalonia) and 201627-30 (Fundació La Marató of TV3) to D.S., grant RTI2018-095166-B-I00 (MICINN/AEI/FEDER, EU) to F.J.R., and grants SAF2017-86342-R (MICINN/AEI/FEDER, EU) and CIBERer (ISCIII, Spain) to A.G.-F. C.E. is a recipient of an FPU fellowship (Ministry of Universities, Spain) (FPU 15/00251). S.Z. is a recipient of an ANID fellowship from Chile.