Excess lipid accumulation in non-adipose tissues is associated with lipotoxicity — cellular dysfunction and cell death that is linked to the pathogenesis of complications of diabetes and obesity. Our goal is to understand ways in which environmental cues shape metabolic physiology and to identify novel therapeutic targets for improving human metabolic fitness.

 

Our work is focused in three areas in which metabolic stress responses are linked to RNA biology. First, disruption of intronic small nucleolar RNAs (snoRNAs) upregulates mitochondrial oxidative metabolism. We are elucidating mechanistic links between snoRNAs and metabolic regulation, and we seek to determine whether metabolic phenotypic variability in humans can be related to expression of the more than 2000 snoRNAs across the human genome. Second, haploinsufficiency of the lysosomal RNase, RNASET2, abrogates lipid-induced oxidative stress. Here, our aim is to identify RNA targets of RNASET2 and the mechanism by which these RNAs are delivered to the lysosome for degradation. Third, our snoRNA discoveries have led to studies in which we are testing the hypothesis that remodeling of ribosomes in tissues generates rapid changes in the proteome and serves as a mechanism for metabolic plasticity in response to nutrient exposures and exercise.