SGLT2 inhibitor canagliflozin reduces visceral adipose tissue in db/db mice by modulating AMPK/KLF4 signaling and regulating mitochondrial dynamics to induce browning.

Qu, Jingru; Tian, Lei; Zhang, Man; Sun, Bei; Chen, Liming

Qu, Jingru; Tian, Lei; Zhang, Man; Sun, Bei; Chen, Liming.

Afiliação

Qu J; NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, 300134, People's Republic of China.
Tian L; NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, 300134, People's Republic of China.
Zhang M; NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, 300134, People's Republic of China.
Sun B; NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, 300134, People's Republic of China. Electronic address: sun_peipei220@hotmail.com.
Chen L; NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, 300134, People's Republic of China. Electronic address: xfx22081@vip163.com.

Mol Cell Endocrinol ; 592: 112320, 2024 Oct 01.

Article em En | MEDLINE | ID: mdl-38964727

ABSTRACT

ABSTRACT

Obesity is characterized by excessive accumulation of adipose tissue (mainly visceral). The morphology and function of mitochondria are crucial for regulating adipose browning and weight loss. Research suggests that the SGLT2 inhibitor canagliflozin may induce weight loss through an unknown mechanism, particularly targeting visceral adipose tissue. While Krueppel-Like Factor 4 (KLF4) is known to be essential for energy metabolism and mitochondrial function, its specific impact on visceral adipose tissue remains unclear. We administered canagliflozin to db/db mice for 8 weeks, or exposed adipocytes to canagliflozin for 24 h. The expression levels of browning markers, mitochondrial dynamics, and KLF4 were assessed. Then we validated the function of KLF4 through overexpression in vivo and in vitro. Adenosine monophosphate-activated protein kinase (AMPK) agonists, inhibitors, and KLF4 si-RNA were employed to elucidate the relationship between AMPK and KLF4. The findings demonstrated that canagliflozin significantly decreased body weight in db/db mice and augmented cold-induced thermogenesis. Additionally, canagliflozin increased the expression of mitochondrial fusion-related factors while reducing the levels of fission markers in epididymal white adipose tissue. These consistent findings were mirrored in canagliflozin-treated adipocytes. Similarly, overexpression of KLF4 in both adipocytes and db/db mice yielded comparable results. In all, canagliflozin mitigates obesity in db/db mice by promoting the brown visceral adipocyte phenotype through enhanced mitochondrial fusion via AMPK/KLF4 signaling.

Assuntos

Proteínas Quinases Ativadas por AMP; Tecido Adiposo Marrom; Canagliflozina; Gordura Intra-Abdominal; Fator 4 Semelhante a Kruppel; Fatores de Transcrição Kruppel-Like; Dinâmica Mitocondrial; Transdução de Sinais; Inibidores do Transportador 2 de Sódio-Glicose; Animais; Dinâmica Mitocondrial/efeitos dos fármacos; Canagliflozina/farmacologia; Camundongos; Transdução de Sinais/efeitos dos fármacos; Masculino; Inibidores do Transportador 2 de Sódio-Glicose/farmacologia; Fatores de Transcrição Kruppel-Like/metabolismo; Fatores de Transcrição Kruppel-Like/genética; Gordura Intra-Abdominal/efeitos dos fármacos; Gordura Intra-Abdominal/metabolismo; Proteínas Quinases Ativadas por AMP/metabolismo; Tecido Adiposo Marrom/metabolismo; Tecido Adiposo Marrom/efeitos dos fármacos; Camundongos Endogâmicos C57BL; Termogênese/efeitos dos fármacos; Mitocôndrias/metabolismo; Mitocôndrias/efeitos dos fármacos; Peso Corporal/efeitos dos fármacos

Palavras-chave

Browning; KLF4; Mitochondrial dynamics; Sodium-glucose co-transporter-2 inhibitor; Visceral adipose tissue

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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Tecido Adiposo Marrom / Transdução de Sinais / Gordura Intra-Abdominal / Fatores de Transcrição Kruppel-Like / Proteínas Quinases Ativadas por AMP / Dinâmica Mitocondrial / Canagliflozina / Inibidores do Transportador 2 de Sódio-Glicose / Fator 4 Semelhante a Kruppel Limite: Animals Idioma: En Revista: Mol Cell Endocrinol Ano de publicação: 2024 Tipo de documento: Article País de publicação: Irlanda

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