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Adipose tissue depots develop specific functions in a location dependent manner. In humans, this for example includes thermogenic capacity in the brown adipose supraclavicular, deep neck and perirenal depots, healthy lipid storage primarily in the gluteofemoral subcutaneous depot, and immunogenic support in the visceral omental depot. These distinct functions are at some point programmed into adipose progenitor cells, which retain some of the phenotype from the depot they originated from upon isolation and differentiation in vitro. Cardiometabolic diseases associate with body fat distribution, with an accumulation of lipids in the visceral depot accompanied by low grade inflammation and insulin resistance as a typical phenotype. However, well-functioning subcutaneous adipose tissue and brown adipose tissue contribute to a metabolically healthy phenotype, and it is therefore worth understanding the function and regulation of these adipocytes. In this review, we will discuss the dysregulations in distinct human adipose tissue depots associated with cardiometabolic disease, some of the consequences this has on whole body metabolism, and how depot-specific dysregulations might affect other adipose depots to progress a cardiometabolic disease condition.