Fatty acid synthesis in the central nervous system is implicated in the control of food intake and energy expenditure. An intermediate in this pathway, malonyl-CoA, mediates these effects. Malonyl-CoA is an established inhibitor of carnitine palmitoyltransferase-1 (CPT1), an outer mitochondrial membrane enzyme that controls entry of fatty acids into mitochondria and, thereby, fatty acid oxidation. CPT1c, a brain-specific enzyme with high sequence similarity to CPT1a (liver) and CPT1b (muscle) was recently discovered. All three CPTs bind malonyl-CoA, and CPT1a and CPT1b catalyze acyl transfer from various fatty acyl-CoAs to carnitine, whereas CPT1c does not. These findings suggest that CPT1c has a unique function or activation mechanism. We produced a targeted mouse knockout (KO) of CPT1c to investigate its role in energy homeostasis. CPT1c KO mice have lower body weight and food intake, which is consistent with a role as an energy-sensing malonyl-CoA target. Paradoxically, CPT1c KO mice fed a high-fat diet are more susceptible to obesity, suggesting that CPT1c is protective against the effects of fat feeding. CPT1c KO mice also exhibit decreased rates of fatty acid oxidation, which may contribute to their increased susceptibility to diet-induced obesity. These findings indicate that CPT1c is necessary for the regulation of energy homeostasis.acetyl-CoA carboxylase ͉ fatty acid synthase ͉ food intake ͉ malonyl-CoA ͉ obesity B ody weight is maintained by regulating food intake and energy expenditure. This balance is monitored by the central nervous system (CNS) in response to cytokine and endocrine signals, including leptin, ghrelin, obestatin, insulin, cholecystokinin, and peptide YY secreted by peripheral tissues. Concomitantly, parallel pathways in the CNS regulate energy balance by monitoring the availability of neuronal energy-rich metabolic substrates. Integration of these signals occurs in the hypothalamus and, ultimately, in higher brain centers where feeding behavior and energy expenditure are adjusted. Two primary indicators of energy surplus, glucose and fatty acids, are also monitored by subsets of hypothalamic neurons that modulate feeding behavior and energy expenditure (1). Fatty acids (2) and de novo fatty acid synthesis from glucose (3) are known to mediate these effects. Indeed, food intake and body weight have been shown to be altered by manipulating the activities of the enzymes involved in fatty acid synthesis, e.g., fatty acid synthase (FAS) (3), malonyl-CoA decarboxylase (4, 5), acetyl-CoA carboxylase (ACC) (6, 7), stearoyl-CoA desaturase (8, 9), and 5Ј-AMP kinase (10, 11).Inhibition of FAS in the CNS, for example, reduces body weight by rapidly provoking a reduction in food intake and an increase in peripheral energy expenditure (3,12). This inhibition can reverse the weight gain caused by diet-induced obesity (13,14) or mutations in leptin (ob͞ob) or its receptor (db͞db) (3, 15), suggesting that it acts independently of STAT3, which is known to be essential for leptin 's action (16, 17). I...
Angiopoietin-related growth factor (AGF), a member of the angiopoietin-like protein (Angptl) family, is secreted predominantly from the liver into the systemic circulation. Here, we show that most (>80%) of the AGF-deficient mice die at about embryonic day 13, whereas the surviving AGF-deficient mice develop marked obesity, lipid accumulation in skeletal muscle and liver, and insulin resistance accompanied by reduced energy expenditure relative to controls. In parallel, mice with targeted activation of AGF show leanness and increased insulin sensitivity resulting from increased energy expenditure. They are also protected from high-fat diet-induced obesity, insulin resistance and nonadipose tissue steatosis. Hepatic overexpression of AGF by adenoviral transduction, which leads to an approximately 2.5-fold increase in serum AGF concentrations, results in a significant (P < 0.01) body weight loss and increases insulin sensitivity in mice fed a high-fat diet. This study establishes AGF as a new hepatocyte-derived circulating factor that counteracts obesity and related insulin resistance.
We report here the identification of an angiopoietin-related growth factor (AGF). To examine the biological function of AGF in vivo, we created transgenic mice expressing AGF in epidermal keratinocytes (K14-AGF). K14-AGF mice exhibited swollen and reddish ears, nose and eyelids. Histological analyses of K14-AGF mice revealed significantly thickened epidermis and a marked increase in proliferating epidermal cells as well as vascular cells in the skin compared with nontransgenic controls. In addition, we found rapid wound closure in the healing process and an unusual closure of holes punched in the ears of K14-AGF mice. Furthermore, we observed that AGF is expressed in platelets and mast cells, and detected at wounded skin, whereas there was no expression of AGF detected in normal skin tissues, suggesting that AGF derived from these infiltrated cells affects epidermal proliferation and thereby plays a role in the wound healing process. These findings demonstrate that biological functions of AGF in epidermal keratinocytes could lead to novel therapeutic strategies for wound care and epidermal regenerative medicine. S kin tissues, especially epidermis, are a barrier against the environment, which becomes accessible in wounds and various infections. An important goal in wound management is to achieve rapid wound closure. Analysis of gene activation in skin tissues shows that transforming growth factor-␣ (TGF-␣) (1) produced by keratinocytes and keratinocyte growth factor (KGF) (2, 3) made by dermal fibroblasts are both powerful growth factors for epidermal keratinocytes, indicating an important role for the interaction between dermis-epidermis in skin development. Although these two growth factors play critical roles in wound healing, gene inactivation studies show that these factors are not essential for epidermal growth or regeneration and suggest that regulation of epidermal growth is more complex than has been previously appreciated (4, 5).Angiopoietin-1 (Ang-1) (6) is a ligand for the receptor tyrosine kinase TIE2 (7,8), which contributes to signaling in angiogenesis (9). Ang-1 is characterized structurally by two domains, a coiled-coil domain and a fibrinogen-like domain (10). Recently, members of the angiopoietins (Angs) family have been identified by a domain homology-based molecular cloning strategy. One of these proteins, angiopoietin-related protein 2 (ARP2), was also reported as an angiogenic factor (11). Several recent reports demonstrate that angiopoietin-related proteins (ARPs) show pleiotropic effects not only on vascular cells but on cells of other lineages. For example, it has been shown that ANGPTL3 (12, 13) and FIAF͞PGAR͞ARP4 (14) may play central roles in lipid͞adipocyte metabolism as well as in angiogenesis. Here we identify, by screening EST databases, a previously undescribed angiopoietin-related growth factor (AGF), which is abundantly expressed in hepatocytes. To determine whether AGF promotes in vivo angiogenesis as does Ang-1, we created transgenic (TG) mice overexpressing mouse AGF in epi...
The G protein-coupled receptor (GPCR) family is highly diversified and involved in many forms of information processing. SREB2 (GPR85) is the most conserved GPCR throughout vertebrate evolution and is expressed abundantly in brain structures exhibiting high levels of plasticity, e.g., the hippocampal dentate gyrus. Here, we show that SREB2 is involved in determining brain size, modulating diverse behaviors, and potentially in vulnerability to schizophrenia. Mild overexpression of SREB2 caused significant brain weight reduction and ventricular enlargement in transgenic (Tg) mice as well as behavioral abnormalities mirroring psychiatric disorders, e.g., decreased social interaction, abnormal sensorimotor gating, and impaired memory. SREB2 KO mice showed a reciprocal phenotype, a significant increase in brain weight accompanying a trend toward enhanced memory without apparent other behavioral abnormalities. In both Tg and KO mice, no gross malformation of brain structures was observed. Because of phenotypic overlap between SREB2 Tg mice and schizophrenia, we sought a possible link between the two. Minor alleles of two SREB2 SNPs, located in intron 2 and in the 3 UTR, were overtransmitted to schizophrenia patients in a family-based sample and showed an allele load association with reduced hippocampal gray matter volume in patients. Our data implicate SREB2 as a potential risk factor for psychiatric disorders and its pathway as a target for psychiatric therapy.gene manipulation ͉ memory ͉ SNPs T he SREB (superconserved receptor expressed in brain) family of SREB1 (GPR27), SREB2 (GPR85), and SREB3 (GPR173) is a unique subfamily of G protein-coupled receptor (GPCR) selectively expressed in neurons (1-5). Intriguing features of the SREB family include its high degree of sequence conservation throughout vertebrate evolution and its abundant expression in brain structures showing high levels of plasticity, for example the hippocampal dentate gyrus. Among these three members, SREB2 is the most conserved-the primary amino acid sequence is 100% identical among humans, rats, and mice. SREB1 and SREB3 are also highly conserved in mammals. Despite the extraordinary conservation rate in vertebrates, SREB orthologues are not encoded in the genome sequence of Caenorhabditis elegans or Drosophila melanogaster (3).The history of drug discovery has proven that GPCRs are excellent therapeutic targets (6, 7). Although efforts have been made to identify endogenous ligand(s) for SREB, they have been unsuccessful (3). Recent progress in understanding of GPCR physiology has, however, enabled screening of drug candidates for promising GPCRs without knowledge of their endogenous ligands, e.g., screening compounds by using constitutively active mutants (8) or ligand-induced conformational change (9). Thus, if their physiological function is clarified, and their link to the pathophysiology of diseases is demonstrated, then newly discovered GPCRs, even orphan GPCRs like SREB2, become promising drug targets. The distinct features of SREB2, namel...
BackgroundAlthough chloride is one of the major electrolytes measured routinely in dairy practice, the amount of attention chloride receives in critically ill patients is limited. There are still a few studies reporting the incidence of derangements of chloride and its association with patients' outcomes. Accordingly, we conducted a retrospective study to assess the prevalence of abnormality of serum chloride level in postoperative patients in the intensive care unit on the early phase of surgery and its association with outcome.MethodsWe conducted a single-center retrospective observational study. All adult patients who underwent elective thoracic or abdominal surgery and required postoperative intensive care for more than 48 h between 2007 and 2011 were included. Chloride levels were measured on each morning of postoperative day 1 and day 2 in the intensive care unit. We defined all-cause hospital death as the primary outcome and compared serum chloride levels on postoperative day 1 and day 2 between hospital survivors and non-survivors. Comparisons among groups were conducted using the chi-square test for equal proportion, Mann-Whitney U tests, or Kruskal-Wallis test.ResultsAmong 98 patients included in this study, hypochloremia (less than 98 mmol/L) during the first 48 h occurred in 14 patients (14.3%). The mortality in hypochloremia patients was 28.6%, which is significantly higher than 6.0% in patients with normal chloride concentration (p = 0.007). Even after being adjusted for severity of illness, the incidence of hypochloremia was independently associated with the risk of hospital death (adjusted odds ratio 5.8 (1.1, 30.2), p = 0.04). Hyperchloremia (more than 112 mmol/L) occurred in one patient (1.0%), who was discharged from the hospital at day 9. There was no significant difference in the total volume of infused fluid (p = 0.30), sum of chloride administration (p = 0.33), and use of furosemide (p = 0.75) from intensive care unit admission to the morning of postoperative day 2 between survivors and non-survivors.ConclusionsHypochloremia observed within 48 h after surgery was not rare and was independently associated with the increased risk of hospital death. Hypochloremia might be a useful indicator of prognosis for patients in the postoperative intensive care unit.
Mutations in the ABCD1 gene that encodes peroxisomal ABCD1 protein cause X-linked adrenoleukodystrophy (X-ALD), a rare neurodegenerative disorder. More than 70% of the patient fibroblasts with this missense mutation display either a lack or reduction of the ABCD1 protein because of posttranslational degradation. In this study, we analyzed the stability of the missense mutant ABCD1 proteins (p.A616T, p.R617H, and p.R660W) in X-ALD fibroblasts and found that the mutant ABCD1 protein p.A616T has the capacity to recover its function by incubating at low temperature. In the case of such a mutation, chemical compounds that stabilize mutant ABCD1 proteins could be therapeutic candidates. Here, we prepared CHO cell lines stably expressing ABCD1 proteins with a missense mutation in fusion with green fluorescent protein (GFP) at the C-terminal. The stability of each mutant ABCD1-GFP in CHO cells was similar to the corresponding mutant ABCD1 protein in X-ALD fibroblasts. Furthermore, it is of interest that the GFP at the C-terminal was degraded together with the mutant ABCD1 protein. These findings prompted us to use CHO cells expressing mutant ABCD1-GFP for a screening of chemical compounds that can stabilize the mutant ABCD1 protein. We established a fluorescence-based assay method for the screening of chemical libraries in an effort to find compounds that stabilize mutant ABCD1 proteins. The work presented here provides a novel approach to finding therapeutic compounds for X-ALD patients with missense mutations.
When there is meticulous attention to the technical details, renal transplantation should incur few urological complications. Early intervention with percutaneous drainage reduces morbidity and the likelihood loss of graft function. Proper and prompt management should not affect the graft and/or the patient's survival.
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