Moderate SIRT1 overexpression protects against brown adipose tissue inflammation

Abstract

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 demanding to find strategies to protect BAT against the effects of inflammation in energy balance. In this study we have explored the impact of moderate Sirtuin 1 (SIRT1) overexpression in insulin sensitivity and β-adrenergic responses in BAT and brown adipocytes (BA) under pro-inflammatory conditions. Methods: The effect of inflammation in BAT functionality was studied in obese db/db mice and lean wild-type (WT) mice or mice with moderate overexpression of SIRT1 (SIRT1Tg+) injected a low dose of bacterial lipopolysaccharide (LPS) to mimic endotoxemia. We also conducted studies in differentiated BA (BA-WT and BA-SIRT1Tg+) exposed to a macrophagederived pro-inflammatory conditioned medium (CM) to evaluate the protection of SIRT1 overexpression in insulin signaling and glucose uptake, mitochondrial respiration, fatty acid oxidation (FAO), as well as norepinephrine (NE)-mediated-modulation of uncoupling protein-1 (UCP-1) expression. Results: BAT from db/db mice was susceptible to metabolic inflammation manifested by 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 lean WT mice upon LPS injection. By contrast, BAT from mice with moderate overexpression of SIRT1 (SIRT1Tg+) was protected against LPSinduced activation of pro-inflammatory signaling, insulin resistance and defective thermogenicrelated responses upon cold exposure. Importantly, the drop of triiodothyronine (T3) levels both in circulation and intra-BAT after exposure of WT mice to LPS and cold was markedly attenuated in SIRT1Tg+ mice. In vitro experiments in BA from the two genotypes revealed that upon differentiation with a T3-enriched medium and subsequent exposure to a macrophagederived pro-inflammatory CM, only BA-SIRT1Tg+ fully recovered insulin and noradrenergic responses. Conclusion: This study has unraveled the benefit of moderate overexpression of SIRT1 to confer protection against defective insulin and β-adrenergic responses caused by inflammation in BAT. Our results have potential therapeutic value proposing combinatorial therapies of BATspecific thyromimetics and SIRT1 activators to combat metainflammation in this tissue.