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 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 (SIRT1 Tg+ ) injected with a low dose of bacterial lipopolysaccharide (LPS) to mimic endotoxemia. We also conducted studies on differentiated BA (BA-WT and BA-SIRT1 Tg+ ) 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 (SIRT1 Tg+ ) 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 (T 3 ) levels in the circulation and intra-BAT after exposure of the WT mice to LPS and cold was markedly attenuated in the SIRT1 Tg+ mice. In vitro BA experiments in the two genotypes revealed that upon differentiation with a T 3 -enriched medium and subsequent exposure to a macrophage-derived pro-inflammatory CM, only BA-SIRT1 Tg+ 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.

Metformin reduces macrophage HIF1α-dependent proinflammatory signaling to restore brown adipocyte function in vitro

“…HSL phosphorylation) and the lipolytic response as visualized by the higher size of the lipid droplets in brown adipocytes receiving CM-Lps and CL316243 compared to the controls. As expected from the impaired β-adrenergic signaling, Ppargc1a mRNA and UCP1 protein levels were significantly reduced in agreement with data in C3H10T1/2 (10T1/2) mouse mesenchymal stem cells [ 72 ] and our recent study [ 36 ]. Of relevance, herein we show that, in brown adipocytes, ectopic expression of HIF1α is sufficient to suppress their responses to CL316243.…”

“…Generation of brown preadipocyte cell lines and differentiation. Brown preadipocytes were isolated from the interscapular BAT of 20-day old suckling mice and immortalized as previously described [ 36 ]. Brown preadipocytes were also immortalized from Ampkα1 −/− mice [ 37 ] or mice containing loxP-flanked alleles of HIF1α previously described [ 38 ], referred as BA Ampkα1−/- and BA Hif1afl/fl , respectively.…”

Cecal Ligation and Puncture-Induced Sepsis Promotes Brown Adipose Tissue Inflammation Without Any Impact on Expression of Thermogenic-Related Genes

“…In fact, the impact of inflammation on BAT activity is currently discussed, as some studies in mice with obesity-associated chronic low-level inflammation reported that BAT inflammation is associated with decreased thermogenic activity ( Sakamoto et al, 2016 ; Escalona-Garrido et al, 2020 ), in other studies no correlation between BAT thermogenesis and inflammation was observed ( Cao et al, 2018 ; Boulet et al, 2021 ). To the best of our knowledge, the in vivo effects of acute inflammation mediated by CLP-induced sepsis in expression of BAT thermogenic- and metabolic-related genes have not been previously reported.…”

Effects of stem cells from inducible brown adipose tissue on diet-induced obesity in mice

“…Immunohistochemistry was done as described by Escalona-Garrido and colleagues 58 . Paraffin sections were heated for 20 min in 100 mM sodium citric buffer (pH 6.0) and 0.05% Tween-20 and then blocked for 10 min with a solution of 9% H 2 O 2 in 10% methanol.…”