Abstract: The classical role of adipocytokines is a negative feedback mechanism, providing information about bodily energy reserves to the brain, and thus controlling satiety and food intake (Campfield et al., 1995). Adipose tissue forms the largest endocrine organ of the body. After the initial description of leptin and its receptor, LEPR/OBR, with its main active isoform OBRb, there was an initial hope for a drugable pathway to counteract the increasing burden of overweight/adiposity, metabolic syndrome, and related disorders (Figure 1). Compensatory pathways and tolerance effects, however, preclude a metabolic intervention using recombinant adipocytokines in metabolic syndrome. Leptin, for example, is increased in adiposity and metabolic syndrome. Nevertheless, recombinant leptin has been approved for leptin deficiency-associated lipodystrophy in the US.