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Cardiovascular disease (CVD) remains the leading global cause of mortality, with heart failure (HF) as its terminal manifestation. While intensive glycemic and lipid control strategies have shown limited success in mitigating cardiovascular complications in metabolic disorders such as obesity and diabetes, a growing body of evidence points to the crucial role of adipocytes, the largest endocrine organ, in modulating cardiovascular outcomes. My presentation explores a translational research paradigm focused on targeting adipocyte dysfunction to improve cardiac health, particularly under conditions of metabolic stress.

Adipose tissue secretes a diverse array of bioactive molecules, including adipokines (e.g., adiponectin, leptin, resistin, CTRPs), cytokines, hormones, and metabolites, all of which influence cardiovascular function. In health, these factors maintain metabolic balance and vascular integrity. However, in obesity and diabetes, adipocyte endocrine function becomes dysregulated, leading to systemic inflammation, oxidative/nitrative stress, lipotoxicity, and ultimately cardiac injury. Diabetic cardiomyopathy is characterized by structural changes such as left ventricular hypertrophy and fibrosis, as well as functional abnormalities including systolic and diastolic dysfunction.

Among adipokines, adiponectin has emerged as a pivotal cardioprotective factor. It exerts its effects through AdipoR1-mediated signaling pathways involving AMPK, APPL1, and neutral ceramidase (nCDase), contributing to anti-inflammatory, anti-oxidative, and insulin-sensitizing responses. However, post-infarction or metabolic stress impairs adiponectin signaling via GRK2-mediated receptor phosphorylation, disrupting pro-survival cascades and accelerating cardiac dysfunction. Recent studies from our lab further revealed that adipocytes communicate with cardiomyocytes via extracellular vesicles (EVs), and myocardial ischemia/reperfusion (MI/R) injury can suppress adipocyte function and downstream signaling.

Efforts to enhance adipocyte function, particularly through the restoration of adiponectin pathways and activation of adipocyte-derived CTRPs such as CTRP3 and CTRP9, have shown promise in mitigating myocardial injury and improving angiogenesis and cell survival. These mechanistic insights support the therapeutic targeting of adipose tissue to buffer against the progression from metabolic syndrome to ischemic heart failure.

An intriguing aspect discussed is the “obesity paradox”, the observation that while obesity increases the risk for HF development, higher BMI is paradoxically associated with improved survival in patients with established HF. Our recent experimental results provided clear evidence that adipocyte insufficiency, rather than excess, may compromise cardiac resilience in HF. Enhancing adipogenesis and promoting the browning of white adipose tissue (via β3-adrenergic stimulation or cold exposure) may augment energy expenditure and metabolic efficiency, thereby offering cardiometabolic benefits.

In summary, adipocyte dysfunction is both a driver and a consequence of metabolic cardiovascular disease. Targeting adipocyte signaling and endocrine capacity, particularly through adiponectin and CTRP-mediated pathways and adipogenesis, offers a novel and promising strategy to attenuate HF progression and improve outcomes in obesity- and diabetes-related CVD. This adipocyte-centric approach represents a paradigm shift from treating downstream cardiovascular symptoms to addressing upstream metabolic derangements and may redefine prevention and therapeutic strategies in the 21st-century battle against chronic cardiometabolic diseases.