Endocrine Abstracts

Our goal is to elucidate mechanisms underpinning developmental programming of disease. Focusing on non-genetic and non-environmental triggers, we’ve identified Trim28 and Nnat as novel ‘probabilistic’ regulators of disease outcomes. Loss-of-function mutations, in either gene triggers a unique developmental phenomenon known as ‘polyphenism’, in which genetically identical animals take on one of several meta-stable phenotypic programs, during development. These models represent the first formal demonstrations of mammalian polyphenism and carry profound implications for our understanding of the origins of disease risk in that they suggest that each individual may have several preferred multi-trait disease susceptibility states. I will share data that (i) characterize the phenotypic and epigenetic distinctions between these states in mice, in the contexts of cancer, obesity and food-addiction; (ii) first dissections of the mechanisms underpinning the developmental disease susceptibility state decision; (iii) provide evidence for alternate developmental trajectories in humans, including a high-dimensional analyses of monozygotic twin discordance and a panUKBB deconvolution that reveals human obesity endotypes. Collectively, these data alter our understanding of the fundamentals of the origins of metabolic disease heterogeneity.