Abstract
<jats:p>Cardiometabolic diseases associated with obesity are continuously increasing worldwide. Yet, current therapeutic strategies remain insufficient to improve patient outcomes. The beta3-adrenergic receptor (β3AR) promotes lipolysis in adipose tissue (AT) and thermogenesis specifically in brown adipose tissue (BAT). In mice, BAT activation also improves systemic metabolism and limits cardiometabolic damage. While BAT is limited in humans (e.g., with ageing and obesity), β3AR activation induces beige adipocytes within white adipose depots with similar thermogenic properties. To study the role of adipocyte β3AR in the regulation of cardiac metabolism and remodeling, mice with/without adipocyte-specific β3AR genetic deletion were fed a high-fat-sucrose (HF-S) diet and treated with the selective β3AR agonist CL316,243 (CL). The metabolic and cardiac protection following β3AR activation was abrogated upon β3AR deletion in adipocytes, together with the beiging of the epididymal (visceral) AT, highlighting a critical role of adipose β3AR signalling in mediating these benefits. Multi-omic analysis of AT and cardiac samples identified CL-induced secreted mediators of the crosstalk between AT and the heart. Therefore, adipocyte β3AR is critical for the adipose-cardiac communication and supports the therapeutic potential of targeting β3AR for the management of obesity-related cardiometabolic diseases.</jats:p>