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Moderate SIRT1 overexpression protects against brown adipose tissue inflammation
Carmen Escalona-Garrido1, Patricia Vázquez1, Paula Mera2
1Instituto de Investigaciones Biomédicas Alberto Sols (Centro Mixto CSIC-UAM), 28029 Madrid, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERdem), 28029 Madrid, Spain.
Moderate sirtuin 1 (SIRT1) overexpression protects brown adipose tissue (BAT) from obesity-induced inflammation. This finding offers potential therapeutic strategies for metabolic inflammation by enhancing insulin sensitivity and adrenergic responses in BAT.
Area of Science:
- Metabolic inflammation
- Obesity and Comorbidities
- Brown Adipose Tissue (BAT) Biology
Background:
- Metainflammation, a chronic inflammatory state linked to obesity, impairs insulin sensitivity and affects tissues like brown adipose tissue (BAT).
- BAT is crucial for energy balance and thermogenesis, but its function is compromised by inflammation, necessitating protective strategies.
- Sirtuin 1 (SIRT1) plays a role in metabolic regulation, and its impact on BAT's inflammatory response requires investigation.
Purpose of the Study:
- To investigate the protective effects of moderate sirtuin 1 (SIRT1) overexpression on brown adipose tissue (BAT) and brown adipocytes (BA) under pro-inflammatory conditions.
- To assess the impact of SIRT1 on insulin sensitivity and beta-adrenergic responses in BAT and BA during inflammation.
- To explore potential therapeutic strategies for combating metainflammation in BAT.
Main Methods:
- Studied obese (db/db) and lean wild-type (WT) mice, alongside SIRT1-overexpressing (SIRT1Tg+) mice, exposed to lipopolysaccharide (LPS) to induce inflammation.
- Utilized differentiated brown adipocytes (BA-WT and BA-SIRT1Tg+) exposed to pro-inflammatory conditioned medium (CM) to evaluate cellular responses.
- Assessed insulin signaling, glucose uptake, mitochondrial respiration, fatty acid oxidation, and UCP-1 expression, along with triiodothyronine (T3) levels.
Main Results:
- Obese mouse BAT exhibited inflammation, insulin resistance, and reduced UCP-1 expression, while LPS induced similar impairments in lean mice.
- SIRT1Tg+ mice showed protection against LPS-induced inflammation, insulin resistance, and defective thermogenic responses.
- In vitro studies confirmed that SIRT1 overexpression in BA restored insulin and noradrenergic responses following inflammatory challenge.
Conclusions:
- Moderate SIRT1 overexpression confers significant protection against BAT inflammation, preserving insulin and beta-adrenergic signaling.
- These findings highlight the therapeutic potential of combining SIRT1 activators with thyromimetics for treating metainflammation in BAT.
- SIRT1 modulation represents a promising avenue for managing obesity-related metabolic dysfunction.
