Defective and augmented extracellular matrix, a process termed neurofibrosis, develops around neurons within the arcuate nucleus of the hypothalamus (ARC) during the progression of metabolic diseases. Once established, the defective neurofibrotic extracellular environment within the ARC promotes cellular insulin resistance resulting in significant whole-body metabolic dysfunction. Currently, there are no therapeutics targeting defective neurofibrosis for treating metabolic disease.
Leveraging on this novel disease mechanism, we have identified a “first-in-class” small molecule neurofibrosis inhibitor, PZ6005 and we sought to evaluate its efficacy in promoting the remission of diet-induced obesity. To do this, we centrally administered PZ6005 (intracerebroventricularly) to diet-induced obese C57BL/6J mice. We found that 10-day administration of PZ6005 to obese mice attenuated neurofibrosis and reinstated insulin receptor signalling in the ARC. This pharmacological attenuation of neurofibrosis in obese mice resulted in a profound weight loss accompanied by enhanced energy expenditure and improved glycaemic control. We reasoned that the actions of PZ6005 on metabolism are mediated through insulin receptor signalling in agouti-related peptide (AgRP) neurons in the ARC. Using CRISPR-Cas9 mediated genetic manipulation, we selectively ablated insulin receptors in AgRP neurons in mice after the onset of diet-induced obesity. We found that the protective effects of PZ6005 on energy homeostasis and glycaemic control were dependent upon functional insulin receptor signalling in AgRP neurons. We further substantiated the validity and efficacy of the therapeutic mechanism using both structural (PZ6103) and functional (PZ6065) analogues of PZ6005. Taken together, these findings demonstrate a novel disease mechanism and class of therapeutics to alleviate brain insulin resistance for the treatment of metabolic disease.