Resistin activity in mice and humans affecting obesity, insulin resistance and T2DM: Blocking resistin action by resistin antagonis

Abstract

Resistin, that was originally discovered in 2001 is named for its capacity to resist insulin action shown mainly in mice. However, there is a controversial history regarding its role in the pathogenesis of insulin resistance and type 2 diabetes mellitus (T2DM) in humans as most of the research was based on association between resistin blood levels and T2DM or other pathologies and so far the pharmacological effect of recombinant resistin has not been tested in humans or even in primates. Resistin is a 12 kD cysteine-rich small protein acting as covalent dimer. Although human and mouse resistin genes and protein sequences share only approximately 60% homology, which is less than most hormones conserved across species, the genes are syntenic, with the mouse gene encoding resistin being located at a similar distance from the insulin receptor gene. Unlike mouse resistin which is mainly expressed in adipocytes, human resistin is synthesized predominantly in monocytes and macrophages, especially in the visceral adipose tissue. Resistin`s effects are mediated via paracrine and endocrine mechanisms of action through a receptor on the surface of target cells that remains controversial. Others and our study has shown that resistin interacts with the Toll-like receptor 4 (TLR4), however other putative receptors such as an isoform of decorin, mouse receptor tyrosine kinase-like orphan receptor 1 (ROR1) and adenylyl cyclase-associated protein 1 (CAP1) have been also proposed. Downstream targets of resistin provide indirect evidence for its function in intracellular pathways, involving impairment of insulin signaling, response to inflammation and proliferation. Despite the lack of in vivo data concerning the resistin receptor and signaling in primates or humans, there is a need to explore the inflammatory, metabolic and oncogenic effects of resistin on human diseases. To address this challenge we have recently developed resistin mutant (C6A), acting as resistin antagonist which in several in vitro bioassays inhibited resistin action and in mice fed high fat diet (HFD) reduced weight, visceral fat, restored insulin sensitivity and attenuated HFD-induced neuro inflammation.