Ribosomal RNA transcription mediated by RNA polymerase I represents the rate-limiting step in ribosome biogenesis. In eukaryotic cells, nutrients and growth factors regulate ribosomal RNA transcription through various key factors coupled to cell growth. We show here in mature adipocytes, ribosomal transcription can be acutely regulated in response to metabolic challenges. This acute response is mediated by PTRF (polymerase I transcription and release factor, also known as cavin-1), which has previously been shown to play a critical role in caveolae formation. The caveolae–independent rDNA transcriptional role of PTRF not only explains the lipodystrophy phenotype observed in PTRF deficient mice and humans, but also highlights its crucial physiological role in maintaining adipocyte allostasis. Multiple post-translational modifications of PTRF provide mechanistic bases for its regulation. The role of PTRF in ribosomal transcriptional efficiency is likely relevant to many additional physiological situations of cell growth and organismal metabolism.
Obesity can cause several other health conditions to develop. Type 2 diabetes is one such condition, which arises in part because fat cells become unable to store excess fats. This makes certain tissues in the body less sensitive to the hormone insulin, and so the individual is less able to adapt to changing nutrient levels. Without treatment or a change in lifestyle, this insulin resistance may develop into diabetes. However, “healthy obese” individuals also exist, who can accommodate an overabundance of fat without developing insulin resistance and diabetes.
Some forms of rare genetic disorders called lipodystrophies, which result in an almost complete lack of body fat, can also lead to type 2 diabetes. This raises the question of whether lipodystrophy and obesity share some common mechanisms that cause fat cells to trigger insulin resistance. One possible player in such mechanisms is a protein called PTRF. In rare cases, individuals with lipodystrophy lack this protein, and mice that have been engineered to lack PTRF also largely lack body fat and develop insulin resistance.
Fat cells can respond rapidly to changes in nutrients during feeding or fasting, and to do so, they must produce new proteins. Structures called ribosomes, which are made up of proteins and ribosomal RNA, build proteins; thus when the cell needs to make new proteins, it also has to produce more ribosomes. PTRF is thought to play a role in ribosome production, but it is not clear how it does so.
Liu and Pilch analyzed normal mice as well as those that lacked the PTRF protein. This revealed that in response to cycles of fasting and feeding, PTRF increases the production of ribosomal RNA in fat cells, enabling the cells to produce more proteins. By contrast, the fat cells of mice that lack PTRF have much lower levels of ribosomal RNA and proteins.
Liu and Pilch then examined mouse fat cells that were grown in the laboratory. Exposing these cells to insulin caused phosphate groups to be attached to the PTRF proteins inside the cells. This modification caused PTRF to move into the cell’s nucleus, where it increased the production of ribosomal RNA.
Overall, the results show that fat cells that lack PTRF are unable to produce the proteins that they need to deal with changing nutrient levels, leading to an increased likelihood of diabetes. The next steps are to investigate the mechanism by which PTRF is modified, and to see whether the mechanisms uncovered in this study also apply to humans.