Discovery and therapeutic development of 'lean genes': characterisation of a novel gain-of-function adipose tissue lean gene, thiosulfate sulfur transferase .

Obesity is a leading unmet global health problem associated with life-threatening chronic disease complications (Type 2 diabetes, hypertension, atherosclerosis and certain cancers). There are no effective therapies for obesity apart from invasive surgery. Importantly, recent direct measure surveys for obesity indicate a plateau at, or below, ~40% prevalence. Thus, the majority of humans remain intrinsically lean, arguably even when exposed to the modern obesogenic environment. Whilst the mechani sms remain elusive, I contend that understanding the molecular basis of this obesity-resistance will provide fundamental insight into the development of new therapeutic approaches. I have identified a novel gain-of-function adipose-specific lean gene, thiosulfate sulfur transferase (TST) using a Systems Biology approach (physiology, transcriptomics, genetics) in a unique polygenic model of selected contrasting adiposity in mice. The finding translates to humans. Exploring this exciting discove ry will unlock novel biological mechanisms and offers a distinct therapeutic target. This New Investigator application aims to provide the experimental infrastructure and collaborative critical mass to broadly realise the promise of lean gene research as a source of new target mechanisms in the fight against metabolic disease. The research platform will be established initially to definitively test Tst as an example 'par excellence' for my overarching vision - but Tst represents one of many pre dicted lean genes. I will establish gold-standard methodologies for determining insulin sensitivity and energy expenditure in vivo, as well as an arsenal of cutting edge cellular and molecular methodologies to define the mechanistic impact of manipulation of the 'lean gene' TST.