Obesity is a worldwide epidemic, with the number of overweight and obese individuals climbing from just over 500 million in 2008 to 1.9 billion in 2014. Type 2 diabetes (T2D), cardiovascular disease and non-alcoholic fatty liver disease have long been associated with the obese state, whereas cancer is quickly emerging as another pathological consequence of this disease. Globally, at least 2.8 million people die each year from being overweight or obese. It is estimated that by 2020 being overweight or obese will surpass the health burden of tobacco consumption. Increase in the body mass index (BMI) in overweight (BMI>25 kg/m2) and obese (BMI>30 kg/m2) individuals is a result of adipose tissue (AT) expansion, which can lead to fat comprising >50% of the body weight in the morbidly obese. Extensive research over the last several years has painted a very complex picture of AT biology. One clear link between AT expansion and etiology of diseases like T2D and cancer is the development of insulin resistance (IR) and hyperinsulinemia. This review focuses on defining the link between obesity, IR and cancer.

While the determination of postmortem interval (PMI) is a crucial and fundamental step in any death investigation, the development of appropriate biochemical methods for PMI estimation is still in its infancy. This study focused on the temperature-dependent postmortem degradation of calcineurin A (CnA), calmodulin-dependent kinase II (CaMKII), myristoylated alanine-rich C-kinase substrate (MARCKs), and protein phosphatase 2A (PP2A) in mice. The results show that MARCKS, CaMKII, and the use of lung tissue do not appear to warrant further study for the determination of PMI in humans. In skeletal muscle, CnA underwent a rapid temperature-dependent cleavage (60 --> 57 kDa) over the first 48 h of postmortem interval. At 21 degrees C, this transformation was completed within 24 h. In contrast, PP2A increased within the first 24 h after which it degraded at 21 degrees C but remained stable for up to 96 h at 5 degrees C and 10 degrees C. The 60 --> 57 kDa postmortem conversion of CnA was inhibited by addition of protease inhibitors and MDL-28170 indicating a calpain pathway mediates this breakdown. Proteasome inhibition (MG-132) and calmodulin antagonism (calmidazolium) also inhibited this conversion suggesting that other protein degradation pathways also are in play. In contrast, all of the protease inhibitors and calmidazolium but not ethylene glycol tetraacetic acid led to increased levels of PP2A. The data are discussed in terms of developing a useable field-based biochemical assay for postmortem interval determination in humans and understanding the protein degradation pathways that are initiated upon death.

Nucleomorphin (NumA1) is a nucleolar/nucleoplasmic protein linked to cell cycle in Dictyostelium. It interacts with puromycin-sensitive aminopeptidase A (PsaA) which in other organisms is a Zn(2+)-metallopeptidase thought to be involved in cell cycle progression and is involved in several human diseases. Here, we have shown that Dictyostelium PsaA contains domains characteristic of the M1 family of Zn(2+)-metallopeptidases: a GAMEN motif and a Zn(2+)-binding domain. PsaA colocalized with NumA1 in the nucleoplasm in vegetative cells and was also present to a lesser extent in the cytoplasm. The same localization pattern was observed in cells from slugs, however, in fruiting bodies PsaA was only detected in spore nuclei. During mitosis PsaA redistributed mainly throughout the cytoplasm. It possesses a functional nuclear localization signal ((680)RKRF(683)) necessary for nuclear entry. To our knowledge, this is the first nuclear localization signal identified in a Psa from any organism. Treatment with Ca(2+) chelators or calmodulin antagonists indicated that neither Ca(2+) nor calmodulin is involved in PsaA localization. These results are interpreted in terms of the inter-relationship between NumA1 and PsaA in cell function in Dictyostelium.

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