Dermal adipocytes have emerged as active participants in cutaneous host defense. In parallel, adipocyte hypertrophy and hyperplasia–driven obesity has become a global public health priority and is strongly associated with increased risk and severity of bacterial infections. Here, we established and optimized two complementary S. aureus infection models—epidermal and subcutaneous—and in combination with diet-induced (HFD) and genetic ( ob/ob ) obesity, to systematically evaluate cathelin-related