Protein tyrosine phosphatase 1B: a potential leptin resistance factor of obesity.

Indirect evidence implicates leptin resistance in the pathogenesis of the lipotoxicity that complicates obesity and results in the metabolic syndrome. In this issue of Developmental Cell, two groups identify protein tyrosine phosphatase 1B (PTP1B) as a cause of leptin resistance through dephosphorylation of Jak2.

Peroxisome proliferator-activated receptor alpha-dependent induction of cell surface antigen Ly-6D gene in the mouse liver.

Spontaneous peroxisome proliferation-related pleiotropic responses occurring in the liver of mice lacking peroxisomal fatty acyl-CoA oxidase (AOX-/-) are attributed to sustained activation of peroxisome proliferator-activated receptor alpha (PPARalpha) by its putative natural ligands that require AOX for their metabolism. In this study, using a gene expression screen, we show that Ly-6 (lymphocyte antigen 6 complex, locus D; mouse ThB), which belongs to a distinctive family of low molecular weight phosphatidyl inositol anchored cell surface glycoproteins, is upregulated in mouse liver with peroxisome proliferation. Increases in Ly-6D mRNA levels are observed in AOX-/- mouse liver with spontaneous peroxisome proliferation and also in the liver of wild-type mice treated with synthetic peroxisome proliferators. Peroxisome proliferators failed to increase hepatic Ly-6D mRNA levels in mice lacking PPARalpha (PPARalpha-/-), suggesting a regulatory role for PPARalpha in the induction of Ly-6D. These observations suggest that changes in certain cell surface proteins also form part of the pleiotropic responses associated with peroxisome proliferation.

Peroxisome proliferator-activated receptor alpha-responsive genes induced in the newborn but not prenatal liver of peroxisomal fatty acyl-CoA oxidase null mice.

Mice deficient in fatty acyl-CoA oxidase (AOX(-/-)), the first enzyme of the peroxisomal beta-oxidation system, develop specific morphological and molecular changes in the liver characterized by microvesicular fatty change, increased mitosis, spontaneous peroxisome proliferation, increased mRNA and protein levels of genes regulated by peroxisome proliferator-activated receptor alpha (PPARalpha), and hepatocellular carcinoma. Based on these findings it is proposed that substrates for AOX function as ligands for PPARalpha. In this study we examined the sequential changes in morphology and gene expression in the liver of wild-type and AOX(-/-) mice at Embryonic Day 17.5, and during postnatal development up to 2 months of age. In AOX(-/-) mice high levels of expression of PPARalpha-responsive genes in the liver commenced on the day of birth and persisted throughout the postnatal period. We found no indication of PPARalpha activation in the livers of AOX(-/-) mice at embryonic age E17.5. In AOX(-/-) mice microvesicular fatty change in liver cells was evident at 7 days. At 2 months of age livers showed extensive steatosis and the presence in the periportal areas of clusters of hepatocytes with abundant granular eosinophilic cytoplasm rich in peroxisomes. These results suggest that the biological ligands for PPARalpha vis a vis substrates for AOX either are not functional in fetal liver or do not cross the placental barrier during the fetal development and that postnatally they are likely derived from milk and diet.

Less extrahepatic induction of fatty acid beta-oxidation enzymes by PPAR alpha.

The peroxisome proliferator-activated receptor alpha (PPAR alpha) is a nuclear receptor that transcriptionally regulates mitochondrial and peroxisomal fatty acid beta-oxidation enzymes in the liver. Ligands include synthetic peroxisome proliferators and some fatty acids. PPARalpha activation leads to predictable pleiotropic responses in liver including peroxisome proliferation, increased fatty acid oxidation, and hepatocellular carcinoma. In the current study, the response to PPAR alpha-activation was compared in the heart, kidney, and liver since the role of PPAR alpha in extrahepatic fatty acid-oxidizing organs has not been fully explored. Basal expression of mitochondrial beta-oxidation enzymes was comparable in the three tissues, but peroxisomal beta-oxidation enzymes were most abundant in the liver and less so in the kidney and especially in the heart. After PPAR alpha activation with ciprofibrate, both mitochondrial and peroxisomal beta-oxidation enzymes were induced, with the strongest response seen in the liver, a moderate response in the kidney, and no significant response in the heart. PPAR alpha mRNA analysis suggested that the differential response may be related to PPAR alpha expression.

Defect in peroxisome proliferator-activated receptor alpha-inducible fatty acid oxidation determines the severity of hepatic steatosis in response to fasting.

Fasting causes lipolysis in adipose tissue leading to the release of large quantities of free fatty acids into circulation that reach the liver where they are metabolized to generate ketone bodies to serve as fuels for other tissues. Since fatty acid-metabolizing enzymes in the liver are transcriptionally regulated by peroxisome proliferator-activated receptor alpha (PPARalpha), we investigated the role of PPARalpha in the induction of these enzymes in response to fasting and their relationship to the development of hepatic steatosis in mice deficient in PPARalpha (PPARalpha(-/-)), peroxisomal fatty acyl-CoA oxidase (AOX(-/-)), and in both PPARalpha and AOX (double knock-out (DKO)). Fasting for 48-72 h caused profound impairment of fatty acid oxidation in both PPARalpha(-/-) and DKO mice, and DKO mice revealed a greater degree of hepatic steatosis when compared with PPARalpha(-/-) mice. The absence of PPARalpha in both PPARalpha(-/-) and DKO mice impairs the induction of mitochondrial beta-oxidation in liver following fasting which contributes to hypoketonemia and hepatic steatosis. Pronounced steatosis in DKO mouse livers is due to the added deficiency of peroxisomal beta-oxidation system in these animals due to the absence of AOX. In mice deficient in AOX alone, the sustained hyperactivation of PPARalpha and up-regulation of mitochondrial beta-oxidation and microsomal omega-oxidation systems as well as the regenerative nature of a majority of hepatocytes containing numerous spontaneously proliferated peroxisomes, which appear refractory to store triglycerides, blunt the steatotic response to fasting. Starvation for 72 h caused a decrease in PPARalpha hepatic mRNA levels in wild type mice, with no perceptible compensatory increases in PPARgamma and PPARdelta mRNA levels. PPARgamma and PPARdelta hepatic mRNA levels were lower in fed PPARalpha(-/-) and DKO mice when compared with wild type mice, and fasting caused a slight increase only in PPARgamma levels and a decrease in PPARdelta levels. Fasting did not change the PPAR isoform levels in AOX(-/-) mouse liver. These observations point to the critical importance of PPARalpha in the transcriptional regulatory responses to fasting and in determining the severity of hepatic steatosis.

Identification of 5-S-cysteinyldopa by high performance liquid chromatography in biopsies from patients with dysplastic melanocytic nevi.

The appearance of 5-[(L)-S-cysteinyl]dopa, a major product in pheomelanogenesis was examined in affected and nonaffected skins from 20 patients with clinical signs of dysplastic melanocytic nevi. Analysis by high performance liquid chromatography and electrochemical detection showed that 20 of the 35 lesions had a pathological formation of 5-[(L)-S-cysteinyl]dopa (0.04-28.86 ng/micrograms acid soluble protein). 5-[(L)-S-cysteinyl]dopa was not detected in any of the normal uninvolved skin samples analyzed.

Composition and structure of the martian atmosphere: preliminary results from viking 1.

Results from the aeroshell-mounted neutral mass spectrometer on Viking I indicate that the upper atmosphere of Mars is composed mainly of CO(2) with trace quantities of N(2), Ar, O, O(2), and CO. The mixing ratios by volume relative to CO(2) for N(2), Ar, and O(2) are about 0.06, 0.015, and 0.003, respectively, at an altitude near 135 kilometers. Molecular oxygen (O(2)(+)) is a major component of the ionosphere according to results from the retarding potential analyzer. The atmosphere between 140 and 200 kilometers has an average temperature of about 180 degrees +/- 20 degrees K. Atmospheric pressure at the landing site for Viking 1 was 7.3 millibars at an air temperature of 241 degrees K. The descent data are consistent with the view that CO(2) should be the major constituent of the lower martian atmosphere.