Regulation of hepatic lipid homeostasis by transcriptional co-factor complexes

• Applicant: Professor Dr. Stephan Herzig
• Subject Area: Endocrinology, Diabetology, Metabolism ; Pharmacology ; Cell Biology
• Term: from 2008 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 82204417

• Final Report Year: 2015

Final Report Abstract

A tight regulation of energy homeostasis is a prerequisite for the maintenance of bodyweight and metabolic adaptation to changing nutritional and (patho)-physiological conditions. In this context, the term “metabolic flexibility” describes the capability of an organism to adapt fuel usage to changes in availability and is thus a key determinant of functional energy homeostasis. On the other hand, its counterpart metabolic inflexibility is a contributing and predisposing factor to severe metabolic pathologies, including obesity and type 2 diabetes. Despite the general acceptance of the concept, the molecular mechanisms contributing to metabolic (in)flexibility remain elusive. Given that nutrients are nowadays continuously available in excess not only in industrialized countries, energy uptake and dissipation are in a permanent imbalance, with special implications for metabolic flexibility. Thus, a better understanding of molecular determinants of metabolic flexibility and thus, metabolic health, is urgently needed to combat the obesity pandemic. We have previously defined the role of distinct transcriptional co-factor complexes as critical checkpoints in the coordination of metabolic programs. Based on this work which was in part funded by the DFG, here, we identified and characterized two factors that are differentially expressed under specific conditions representing nutrient stress in organs coordinating whole-body energy homeostasis, namely adipose tissue and liver. Expression manipulation of either of these factors resulted in distinct metabolic phenotypes reflecting specific components of the metabolic syndrome, i.e. insulin resistance, hyperlipidemia and hepatosteatosis. Using patient cohorts at the University Hospitals of Heidelberg, Leipzig, and Vienna, we could confirm deregulated of the factors described here also in obese and/or diabetic patients, thereby highlighting clinical relevance of our findings. Taken together, our data indicate that these factors act as novel hubs in the regulation of metabolic flexibility through coordination of adaptive lipid and glucose metabolism in mice and men. Tissuespecific or systemic approaches targeting the factors identified and characterized in this project might help to counteract metabolic inflexibility under conditions of energy stress.

Publications

• (2013). Metabolic control through glucocorticoid hormones: an update. Mol Cell Endocrinol 380:65-78
  Rose, A.J. and Herzig, S.
  
• (2013). Transcriptional co-factor TBLR1 controls lipid mobilization in white adipose tissue. Cell Metab 17(4):575-585
  Rohm, M., Sommerfeld, A., Strzoda, D., Jones, A., Sijmonsma, T., Rudofsky, G., Wolfrum, C., Sticht, C., Gretz, N., Zeyda, M., Leitner, L., Nawroth, P.P., Stulnig, T.M., Berriel Diaz, M., Vegiopoulos, A., and Herzig, S.
  
• (2014). Rund und gesund? – Der Beitrag von Übergewicht zur Krebsentstehung und Implikationen für die Therapie. Deutsche Zeitschrift für Onkologie 46(04):167-174
  Rohm, M., Herzig, S., and Schafmeier, T.