Role of Adiponectin in the Metabolic Syndrome: Current Perspectives on its Modulation as a Treatment Strategy

Adiponectin, a secretory protein specifically expressed by adipose tissue, has been shown to play a critical role in the maintenance of metabolic homeostasis. A deficiency of adiponectin has been linked to a wide variety of metabolic abnormalities, including obesity and associated disorders such as insulin resistance, hyperglycemia, dyslipidemia, hypertension and nonalcoholic fatty liver disease, collectively referred to as the "metabolic syndrome". Conversely, increased expression of adiponectin corrects these abnormalities, as revealed by the positive metabolic effects observed in genetic over expression studies or by administration of recombinant adiponectin. This has led to widespread interest in its role as a therapeutic target for treatment of a range of metabolic disorders such as diabetes mellitus, obesity, inflammatory and cardiovascular diseases. Various therapeutic approaches targeted at increasing adiponectin levels, or its activity, are being explored. These consist of increasing expression of adiponectin or its receptors by inducers, increasing circulating levels of adiponectin by administering recombinant protein, peptide mimetic approaches, or increasing expression/activity of its downstream effectors such as AMPK or PPAR alpha. Many of these approaches have achieved therapeutic benefits in animal models of metabolic diseases. Despite the profusion of research on adiponectin and ways to modulate it, there are limited number of studies focused on small-molecule based-therapeutic approaches. In this review, we summarize what is currently known with respect to the therapeutic potential of adiponectin and discuss the challenges in designing small molecule-based therapies.