Brown Adipose Tissue Connexin-43 Dysfunction as a Novel Determinant of Cardioprotection in Obesity and Type 2 Diabetes

Objective: Obesity and type 2 diabetes (T2D) markedly increase cardiovascular risk, particularly hypertension, cardiac hypertrophy, and diastolic dysfunction. Brown adipose tissue (BAT) is an active endocrine and metabolic organ with cardioprotective effects mediated by energy expenditure, glucose and lipid metabolism, and regulation of systemic inflammation. In obesity and T2D, BAT undergoes functional impairment and whitening, but mechanisms linking BAT dysfunction to hypertension-related cardiac remodeling remain unclear. Connexin 43 (Cx43), a key gap junction channel protein, is essential for electrical and metabolic coupling in cardiomyocytes and is also expressed in BAT, where it supports thermogenic and metabolic activity. We hypothesized that dysregulation of BAT Cx43 contributes to cardiometabolic imbalance and cardiac dysfunction in obesity-related T2D. Design and method: Forty four-month-old male Zucker Diabetic Fatty rats (lean fa/+ and obese diabetic fa/fa) were divided into control or Cemtirestat-treated groups (2.55 mg/kg/day). After six months of treatment, cardiac structure and function were assessed by echocardiography with emphasis on diastolic function. Selected biometric and biochemical parameters were measured, and BAT and left ventricular (LV) myocardium were collected for analysis of Cx43 expression, inflammatory markers and related signaling pathways. Results: Obese T2D rats exhibited increased body and heart weight, visceral adiposity, BAT mass, hyperglycemia, hyperinsulinemia, and dyslipidemia. Cx43 expression was increased in the LV but markedly reduced in BAT, accompanied by BAT whitening and a shift toward white-like adipocytes. Thermogenic and metabolic regulators (UCP1, UCP3, FGF21, GDF15, PPAR-gamma) were downregulated, while inflammatory mediators (IL-6, IL-10, TNF-alfa) were elevated. PKC epsilon was reduced and PKC delta increased in both BAT and LV tissue. Cemtirestat improved selected metabolic and inflammatory parameters and attenuated diastolic dysfunction without significantly affecting ventricular Cx43 expression. Conclusions: Impaired BAT Cx43 signaling is associated with loss of BAT thermogenic and anti-inflammatory capacity and is associated with cardiac hypertrophy and diastolic dysfunction - hallmarks of hypertensive heart disease - in obesity-related T2D. BAT and Cx43 represent potential cardiometabolic and antihypertensive targets. This study was supported by VEGA 2/0133/24, APVV 21-0410 and VV-MVP-24-0278 grants.