Involvement of connexin 43 in brown adipose tissue dysfunction in type 2 diabetes
T Egan Benova, M Sykora, M Soltesova Prnova, V Farkasova, K Ondrejak Andelova, M Ferko, N Tribulova, B Szeiffova BacovaAbstract
Background
Brown adipose tissue (BAT) may influence cardiac function through metabolic and paracrine mechanisms, but the pathways in type 2 diabetes (T2D) remain unclear. Connexin 43 (Cx43), a gap junction channel protein essential for both BAT and cardiac function, may link BAT dysfunction to early diabetic cardiac impairment. Therefore, purpose of this study was to investigate these processes comprehensively in T2D.
Methods
Forty adult four-month-old male Zucker Diabetic Fatty (ZDF) rats were used in a study. Obese diabetic rats carried a leptin receptor mutation (fa/fa), while non-obese, non-diabetic rats without the mutation (fa/+) served as controls. Animals were divided into four groups: lean controls, lean treated with Cemtirestat (2.5 mg/kg/day), obese T2D rats and obese T2D rats treated with Cemtirestat (2.5 mg/kg/day). Treatment lasted six months. Body weight, heart weight and selected metabolic parameters were measured. BAT was analyzed for Cx43 expression, thermogenic markers and inflammatory cytokines. Cardiac function was evaluated by echocardiography, focusing on diastolic parameters.
Results
Obese T2D rats exhibited diastolic dysfunction, increased body and heart weight, as well as hyperglycemia. Notably, BAT whitening was associated with reduced Cx43 expression and a shift to unilocular adipocytes. Thermogenic and metabolic markers (UCP1, UCP3, FGF21, GDF15, PPARγ) were downregulated, while inflammatory cytokines (IL-6, IL-10, TNF-α) were elevated. Cemtirestat partially restored BAT Cx43, attenuated inflammatory markers and selected metabolic and stress-related regulators and ameliorated diastolic dysfunction.
Conclusion
Downregulation of Cx43 in BAT is associated with whitening and its functional impairment in obese T2D rats, linking BAT impairment to early cardiac dysfunction. Targeting BAT Cx43 may represent a novel approach to prevent diabetic heart failure.