Pere Puigserver, PhD
Control of Nutrient and Energy Metabolism
Nutrient Sensing and Diabetes
Mamalian cells sense nutrients signals to reprogram energetic metabolism and trigger tissue specific responses within the context of whole animal physiology. For example, nutrient fluctuations during fed/fasting or diabetic conditions define specific metabolic functions in central and peripheral tissues. We have used the family of PGC-1 coactivators, key proteins in remodeling glucose and lipid metabolism, as a “scaffold” bait to identify nutrient sensing components. We have identified a new regulatory nutrient/metabolite pathway that impinges on the hyperacetylation of PGC-1s. Central sensing components within this pathway include metabolite sensitive enzymes such as the acetyl transferase GCN5 (responds to Acetyl-CoA levels), (Dominy et al. 2012) the deacetylase SIRT1 (responds to NAD+ levels), components of the canonical cAMP pathway, and insulin/amino acid cell cycle components (Rodgers et al. 2005; Gerhart-Hines et al. 2011; Tabata el al. 2014; Lee et al. 2014). Studies in cells and mouse models have shown that manipulation of these pathways is dysregulated in type 2 diabetes linked to obesity.
Mitochondrial Biology and Energy Metabolism
Energy expenditure is a key component of energy balance that, at the cellular level, requires oxidative metabolism through mitochondrial respiratory activities. We are interested in defining the regulatory control of how mitochondrial mass is formed, assembled and activated to generate energy and heat dissipation. We use traditional approaches in biochemistry, cellular biology and physiology in combination with new screening technologies, genetic/epigenetic and disease models. We have applied bioinformatic and genetic/proteomic tools to identify transcription factors that are pivotal to mitochondrial biology including the zinc finger YY1 and the co-activator PGC-1s (Dominy and Puigserver, 2013; Blättler et al. 2012).
Together, our goal is to identify new therapeutic targets to treat metabolic diseases including diabetes and obesity.