Goal: Thermogenic (brown and beige) adipocytes can catabolize stored energy to generate heat. This capacity for thermogenesis holds tremendous promise as a therapy for metabolic diseases like obesity, type 2 diabetes, and many cancers. The major focus of the Kazak lab is to identify the molecular mechanisms that drive adipocyte thermogenesis. By elucidating the genetic and metabolic pathways that control thermogenesis, we aim to recapitulate the positive effects of brown fat energy expenditure on health.
The Kazak lab is currently focused on the following research aims:
1. Determine the metabolic intermediates controlling creatine-dependent thermogenesis. Creatine drives energy expenditure in adipose tissue by stimulating a futile cycle of mitochondrial ATP turnover (Kazak L et al., Cell, 2015), and this process powerfully combats obesity in pre-clinical models (Kazak L et al., Cell Metabolism, 2017). However, the metabolic intermediates that drive creatine cycling are unknown. The Kazak lab is utilizing mass spectrometry-based metabolic tracing to identify creatine-dependent metabolite signatures in thermogenic fat. We are combining this approach with genetic manipulations and bioenergetic analyses in primary adipocytes and mouse models to determine the effects of these novel metabolites on thermogenic respiration and body mass/composition.
2. Identify the composition of the creatine-dependent thermogenic protein complex. Mitochondrial synthesis of phosphocreatine and its use in ATP-requiring reactions involves a close physical association between mitochondrial creatine kinase (Mi-CK) and the enzymes that generate and consume ATP. Given the unique function for creatine in thermogenic adipose tissue, we hypothesize that Mi-CK physically interacts with proteins that support creatine cycling. We are using unbiased quantitative proteomics to discover novel MiCK-interacting partners, which can be studied in vivo and may potentially be exploited therapeutically to combat obesity.
3. Determine the role of thermogenic effectors on combating obesity. We have shown that the constitutive uncoupling protein 1 knockout mouse (UCP1KO) acquires a substantial number of downstream alterations that make it an unsuitable model to study the role of UCP1 in physiology (Kazak L et al., PNAS, 2017). To continue our work on elucidating the role of adipocyte thermogenesis (UCP1 and beyond) in combating obesity and metabolic disease, we are generating new genetically-engineered mouse models where we can inactivate thermogenic genes selectively in fat, in an inducible manner.
4. Identify the role of creatine in tumorigenesis. Creatine is intimately linked with mitochondrial metabolism and is critical for cell types that require rapid energetic sensing for diverse biological outcomes. Genes of creatine metabolism drive malignancies such as breast cancer, colorectal cancer, pancreatic cancer, and acute myeloid leukemia. However, the molecular mechanism underlying this pro-cancer property of creatine is unknown. We are generating biochemical and genetic tools to systematically examine the molecular mechanisms underlying the role of creatine energetics in cancer metabolism.