Dysfunctional white adipose tissue (WAT) plays a central role in the etiology of metabolic disorders including diabetes and metabolic syndromes. However, not all obese adipose tissue is necessarily associated with pathological changes. Individuals seem to have a functional set limit beyond which WAT fails to function properly. Identification of such mechanisms or factors that control the set point is of great interest. Given the importance of a homeostatic protein synthesis as a basic cellular function, it is postulated that the healthy adipocyte's functional regulation should also incorporate allostatic adaptions of protein synthesis aiming to maintain larger cellular body and adipokine secretion demands as long as possible, particularly under metabolically challenging conditions. In this proposal it is hypothesized that the capacity of adaptational ribosome biogenesis may determine the maximal limit of adipocyte functional homeostasis. PTRF (Cavin-1) was original cloned as polymerase I and transcription release factor. The preliminary data here show PTRF functionally localizing in the nucleus and playing a critical role on the regulation of ribosomal DNA transcription efficiency. To study the details of molecular mechanisms, 3 aims are proposed:
Aim -1, to define the PTRF, ribosome biogenesis and adipocyte function regulatory pathway;
Aim -2, to understand how this pathway regulates the cellular localization of PTRF;
and Aim -3, to explore the physiological relevance of these observations. By using comprehensive cell culture and mouse models, the studies from this proposal will not only shed light on the molecular mechanistic details of this regulatory pathway but also provide potential therapeutic targets for improving adipocyte homeostasis and quality control in human obesity and diabetes.
The ribosome, as the fundamental cellular machinery for protein synthesis, plays critical roles in almost every cellular function. In this proposal it is hypothesized that the adipocyte's functional regulation should also incorporate the adaptions of protein synthesis by ribosome biogenesis aiming to maintain larger cellular body and adipokine secretion particularly under metabolically challenging conditions, and the capacity of adaptational ribosome biogenesis may determine the maximal limit of adipocyte functional homeostasis. The work from this proposal will help to understand the mechanism of adipocyte quality control and develop new therapeutic strategies to decrease the risk of obese individuals for developing type 2 diabetes or other pathologies.
