Molecular mechanisms of UCP1-independent pathways in metabolic health

Beth Israel Deaconess Medical Center, Boston MA

Investigators

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Abstract

PROJECT SUMMARY For over 30 years, a mitochondrial protein, uncoupling Protein 1 (UCP1), was thought to be the only protein responsible for non-shivering thermogenesis in mammals and all the metabolic benefits associated with active brown/beige fat. However, recent studies from our group and others show that UCP1-independent pathways also play a key role in thermogenesis and energy balance. An emerging question is to address the molecular mechanisms underlying the UCP1-independent pathways. A particular focus of this proposal is Ca2+ cycling thermogenesis in adipose tissue. We have recently identified an ER-anchored peptide that acts as a “molecular resistance” to Ca2+ cycling in the microsome. Our preliminary data suggest that this peptide is required for Ca2+ cycling thermogenesis and whole-body energy balance, particularly when UCP1-dependent thermogenesis is inactive. Accordingly, we aim to determine the structural basis, regulatory pathways, and pathophysiological roles of UCP1-independent Ca2+ cycling thermogenesis in adipose tissue. Successful completion of the proposed study will advance our fundamental understanding of how UCP1- independent thermogenesis functions at the molecular, cellular, and organismal levels. Significantly, this study will establish the hierarchy of UCP1-dependent and UCP1-independent pathways in physiology and disease.