To read the article visit the link below.
To read the article visit the link below.
Published in the journal “Diabetologia”
Obesity is a global epidemic resulting from increased energy intake, which alters energy homeostasis and results in an imbalance in fat storage and breakdown. G0/G1 switch gene 2 (G0s2) has been recently characterised in vitro as an inhibitor of adipose triglyceride lipase (ATGL), the rate limiting step in fat catabolism. In the current study we aim to functionally characterise G0s2 within the physiological context of a mouse model. We generated a mouse model in which G0s2 was deleted. The homozygous G0s2 knockout (G0s2−/−) mice were studied over a period of 22 weeks. Metabolic variables were measured including body weight and body composition, food intake, glucose and insulin tolerance tests, energy metabolism and thermogenesis.
We report that G0s2 inhibits ATGL and regulates lipolysis and energy metabolism in vivo. G0s2−/− mice are lean, resistant to weight gain induced by a high-fat diet and are glucose tolerant and insulin sensitive. The white adipose tissue of G0s2−/− mice has enhanced lipase activity and adipocytes showed enhanced stimulated lipolysis. Energy metabolism in the G0s2−/− mice is shifted towards enhanced lipid metabolism and increased thermogenesis. G0s2−/− mice showed enhanced cold tolerance and increased expression of thermoregulatory and oxidation genes within white adipose tissue, suggesting enhanced ‘browning’ of the white adipose tissue. Our data show that G0s2 is a physiological regulator of adiposity and energy metabolism and is a potential target in the treatment of obesity and insulin resistance.
The Honourable Ed Holder, Minister of State (Science and Technology), announced the results of the 2013-2014 Vanier Canada Graduate Scholarships today at the University of Toronto. We are proud that Amro Mohammad from the Teodoro lab is a recipient of this prestigious award.
From the Vanier Website:
“The Vanier Canada Graduate Scholarships (Vanier CGS) program helps Canada’s universities attract sought-after doctoral students from across Canada and around the world. These promising scholars help to create a dynamic and innovative environment within our university campuses. Many will stay to pursue academic and professional careers in Canada, helping to foster innovation and creating future leaders.”
Tom Kucharski from the Teodoro Lab presented a talk at the recent cell cycle meeting at Cold Spring Harbor Laboratory entitled: “53BP1 is a novel anaphase promoting complex/cyclosome mitotic substrate and regulator”.
Cells respond to DNA damage through highly conserved mechanisms that result in the rapid recruitment of repair factors to sites known as ionizing radiation induced foci (IRIFs). Among such factors is the repair protein53BP1, which is a tumour suppressor known for its role in promoting DNA repair through the Non-homologous End Joining pathway (NHEJ). The Anaphase Promoting Complex/Cyclosome is an E3 Ubiquitin Ligase whose activity is essential for proper mitotic progression. APC/C activity is therefore tightly regulated by a combination of post-translational modifications, co-activator proteins, and inhibitory proteins such as EMI and RASSF1A. Here we show that 53BP1 is itself a target of the APC/C during mitosis and that this regulation is important in the control of mitotic progression. 53BP1 contains three highly conserved KEN boxes that are required for its APC/C and proteasome dependent degradation during prometaphase, which occurs both during unperturbed mitosis and also under an active Spindle Assembly Checkpoint. Accordingly, 53BP1 is heavily ubiquitinated during mitosis through K11 linked Ubiquitin chains, a recently discovered hallmark of APC/C substrates. We also show that 53BP1 is constitutively bound to the APC/C co-activator cdc20 and crucially, inhibits its activity. However, binding of 53BP1 to cdc20 in interphase cells does not require the KEN boxes, but instead requires the tandem BRCT repeats of 53BP1. Silencing of 53BP1 expression results in a decrease in the levels of most APC/C substrates, which does not disturb cell proliferation under normal conditions, but is lethal when the cells are faced with the spindle poisons Nocodazole or Taxol. We therefore propose that 53BP1 may be a novel APC/C inhibitor. Consistent with this hypothesis, the half-lives of APC/C substrates are shortened in the absence of 53BP1, and the substrates are more extensively ubiquitinated. The degradation of 53BP1 in early mitosis, therefore appears to allow proper temporal activation of the APC/C and prevent premature mitotic entry, and thus likely contributes to the tumour suppressor status of 53BP1.
Joe Teodoro recently presented a talk at BIotransfer 2014 in Toronto. The presentation was following up the use of a PTEN regulated factor identified in the lab as a potential prostate cancer biomarker. Biotransfer brings together industry and academia to promote the commercialization of scientific discoveries. A video of the talk is available at the following link.