Members

Nutrient Sensing and Diabetes: Mammalian 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), the deacetylase SIRT1 (responds to NAD+ levels) and components of the canonical cAMP pathway, and insulin/amino acid cell cycle components (Lee et al. 2014). We have also identified small molecules that control “acetylation” components with anti-diabetic effects (Sharabi et al. 2017). In the context of cell cycle components linked to obesity/diabetes, we have recently identified a specific vulnerability (Cyclin D1/CDK4) in liver tumors formed in obese/diabetic conditions (Luo et al. 2020). We have also identified NADPH regulatory pathways that are controlled by metabolic enzymes such ME1 (Balsa et al. 2020). 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 and signaling kinases including Clk2 (Verdeguer et al. 2015; Hattings et al. 2017) and PERK (Balsa et al 2019; Latorre-Muro et al. 2021). In addition, we uncouvered new mechanisms whereby tetracyclines and mitochondrial translation rescue mitochondrial dysregulation and mutations in cells and mouse pre-clinical models (Perry et al. 2021).

Our lab is focused on the regulation of energy homeostasis in mammals, primarily at the level of gene transcription. This includes the problems of fat cell development, control of metabolic rates and the pathways of glucose and lipid metabolism. These studies have applications to the development of new therapies for diabetes, obesity, muscular and neurodegenerative diseases.

1. Regulation Of Fat Cell Development. We are deeply interested in the development and function of adipose cells, white, brown and beige. Our group identified the master regulator of fat development in 1994: the nuclear receptor PPARγ. Since then a major focus of our group has been to understand the pathways that control PPARγ function: its ligands, its coactivators and other transcription factors that modify its function. Since synthetic ligands to PPARγ are used clinically as anti-diabetic drugs, we are taking biochemical approaches to understanding the identity of endogenous ligands that control this receptor in vivo. We have also explored the transcriptional control of brown fat differentiation; this led to the identification of a futile cycle of creatine phosphorylation and dephosphoryation as being a critical component of adaptive thermogenesis. We have recently identified the critical creatine kinase (CKB) and creatine phosphate hydrolase (TNAP) involved in this pathway.

2. Metabolic Control Through The PGC-1 Coactivators. Biological control via gene transcription was thought to occur mainly through changes in amounts or activities of transcription factors. However, the PGC-1 coactivators have illustrated the regulation of critical metabolic programs is controlled largely via transcriptional coactivation. Brown fat-mediated thermogenesis muscle fiber type switching and hepatic gluconeogenesis are all induced via expression of PGC-α, then docks on a variety of transcription factor targets. PGC1α mRNA undergoes much control at the level of mRNA translation and we are currently exploring factors involved in this process.

3. Function and Regulation of Irisin. Irisin is a PGC1α-dependent myokine secreted into the blood of mice and humans. It influences bone development and osteoporosis in female mice; its function in motor nerves and the CNS is under study in our lab and others. We are currently studying the effects of irisin in muscular dystrophies, where diabetes is common and in ALS.