Investigating the effects of Orexin-A on thermogenesis in human deep neck brown adipose tissue.

Abstract

Despite successful preclinical testing, 85% of early clinical trials for novel drugs fail. Most futilities originate from molecular mechanisms of the drug(s) tested. It is critically important to develop validated human cell-based model systems in which animal-based research can be translated in order to complement the preclinical in vivo findings prior to implementation of a clinical trial. Obesity is associated with reduced circulating levels of Orexin-A (OX-A) in humans. OX-A increases thermogenesis in rodent brown adipose tissue (AT), yet this phenomenon has not been explored in humans. We established a cell-based model system of human brown and white adipocytes and tested the effects of OX-A on thermogenesis. Contrary to published in vivo and in vitro reports in rodents, OX-A treatment alone or in combination with an adrenergic stimulus did neither enhance thermogenesis nor its related transcriptional program in a human in vitro model of brown adipocytes or AT explants. Translating preclinical findings in human model systems poses a challenge that must be overcome for the development of effective therapeutic compounds and targets.