Here we report the isolation of a cDNA encoding a new p53‐associating protein. This new protein has been called MDMX on the basis of its structural similarity to MDM2, which is especially notable in the p53‐binding domain. In addition, the putative metal binding domains in the C‐terminal part of MDM2 are completely conserved in MDMX. The middle part of the MDMX and MDM2 proteins shows a low degree of conservation. We can show by co‐immunoprecipitation that the MDMX protein interacts specifically with p53 in vivo. This interaction probably occurs with the N‐terminal part of p53, because the activity of the transcription activation domain of p53 was inhibited by co‐transfection of MDMX. Northern blotting showed that MDMX, like MDM2, is expressed in all tissues tested, and that several mRNAs for MDMX can be detected. Interestingly, the level of MDMX mRNA is unchanged after UV irradiation, in contrast to MDM2 transcription. This observation suggests that MDMX may be a differently regulated modifier of p53 activity in comparison with MDM2. Our study indicates that at least one additional member of the MDM protein family exists which can modulate p53 function.

Summary Obesity is associated with chronic low-grade inflammation that negatively impacts insulin sensitivity. Here we show that high fat diet can increase NFκB activation in mice, which leads to a sustained elevation in level of IκB kinase ε (IKKε) in liver, adipocytes and adipose tissue macrophages. IKKε knockout mice are protected from high fat diet-induced obesity, chronic inflammation in liver and fat, hepatic steatosis and whole-body insulin resistance. These mice show increased energy expenditure and thermogenesis via enhanced expression of the uncoupling protein UCP-1. They maintain insulin sensitivity in liver and fat, without activation of the proinflammatory JNK pathway. Gene expression analyses indicate that IKKε knockout reduces expression of inflammatory cytokines, and changes expression of certain regulatory proteins and enzymes involved in glucose and lipid metabolism. Thus, IKKε may represent an attractive new therapeutic target for obesity, insulin resistance, diabetes and other complications associated with these disorders.

OBJECTIVELipocalin (LCN) 2 belongs to the lipocalin subfamily of low–molecular mass–secreted proteins that bind small hydrophobic molecules. LCN2 has been recently characterized as an adipose-derived cytokine, and its expression is upregulated in adipose tissue in genetically obese rodents. The objective of this study was to investigate the role of LCN2 in diet-induced insulin resistance and metabolic homeostasis in vivo.RESEARCH DESIGN AND METHODSSystemic insulin sensitivity, adaptive thermogenesis, and serum metabolic and lipid profile were assessed in LCN2-deficient mice fed a high-fat diet (HFD) or regular chow diet.RESULTSThe molecular disruption of LCN2 in mice resulted in significantly potentiated diet-induced obesity, dyslipidemia, fatty liver disease, and insulin resistance. LCN2−/− mice exhibit impaired adaptive thermogenesis and cold intolerance. Gene expression patterns in white and brown adipose tissue, liver, and muscle indicate that LCN2−/− mice have increased hepatic gluconeogenesis, decreased mitochondrial oxidative capacity, impaired lipid metabolism, and increased inflammatory state under the HFD condition.CONCLUSIONSLCN2 has a novel role in adaptive thermoregulation and diet-induced insulin resistance.

We recently reported the identification of a mouse cDNA encoding a new p53-associating protein that w e called Mdmx because of its structural sim ilarity to Mdm2, a well-known p53"binding protein.