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Int J Obes (Lond),
2012]
Caenorhabditis elegans (C. elegans) is a small nematode that conserves 65% of the genes associated with human disease, has a 21-day lifespan, reproductive cycles of 3 days, large brood sizes, lives in an agar dish and does not require committee approvals for experimentation. Research using C. elegans is encouraged and a Caenorhabditis Genetics Center (CGC, Minnesota) is funded by the National Institutes of Health-National Center for Research Resources. Many genetically manipulated strains of C. elegans are available at nominal cost from the CGC. Studies using the C. elegans model have explored insulin signaling, response to dietary glucose, the influence of serotonin on obesity, satiety, feeding and hypoxia-associated illnesses. C. elegans has also been used as a model to evaluate potential obesity therapeutics, explore the mechanisms behind single gene mutations related to obesity and to define the mechanistic details of fat metabolism. Obesity now affects a third of the US population and is becoming a progressively more expensive public health problem. Faster and less expensive methods to reach more effective treatments are clearly needed. We present this review hoping to stimulate interest in using the C. elegans model as a vehicle to advance the understanding and future treatment of obesity.
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Curr Opin Endocrinol Diabetes Obes,
2010]
PURPOSE OF REVIEW: To describe recent advances in our understanding of the evolution of gastrointestinal hormones, with the gastrin/cholecystokinin (CCK) family as a model. RECENT FINDINGS: The release of 11 genomic sequences in the last year has provided a wealth of additional information on peptide hormone sequences. The alternative approach of reverse genetics has identified a separate class of CCK receptor ligands in the nematode Caenorhabditis elegans. SUMMARY: Three classes of ligands, insect sulfakinins, nematode neuropeptide-like proteins and vertebrate gastrins/cholecystokinins, have now been described for the family of CCK receptors. Although all terminate in an amidated phenylalanine, similarity between the three classes is minimal elsewhere in the sequences. The occurrence of separate gastrin and CCK genes in the dogfish Squalus acanthias dates the divergence of gastrin and CCK to at least 528 +/- 56 Myr ago. The presence of a polyglutamate sequence in marsupial gastrins suggests that the ability to bind ferric ions, which is a critical determinant of biological activity for nonamidated gastrins, was acquired at least 173 +/- 12 Myr ago. Comparison of gastrin or CCK sequences between species suggests that, apart from the C-terminal tetrapeptide amide that is required for receptor binding, conservation is largely restricted to the dibasic processing sites and to the C-terminal flanking peptides of gastrin and CCK. The independent conservation of the latter peptide may be either a consequence of a requirement for precise processing, or may indicate a separate function.
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Metab Brain Dis,
2016]
As the burden of Alzheimer's dementia rises, so does our understanding of the cellular and molecular basis of this neurodegenerative disease. Some of the recent advances in the aetiopathogenesis of neurodegeneration include the finding that insulin receptor signalling is key to neurogenesis and synaptogenesis in the brain, especially in areas related to memory formation and storage, including the hippocampus. This suggests an association between impaired insulin receptor signalling and neurodegenerative events. To decipher this association, several animal models are being employed. Such models include transgenic and non-transgenic animals that range from invertebrates (Drosophila melanogaster and Caenorhabditis elegans), to vertebrates (mouse, rats and primates). The current review is an account of such models and how they have contributed to our understanding of the relationship between type 2 diabetes mellitus, ageing and dementia.
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Adv Exp Med Biol,
2007]
Slit was identified in Drosophila embryo as a gene involved in the patterning of larval cuticle. It was later shown that Slit is synthesized in the fly central nervous system by midline glia cells. Slit homologues have since been found in C. elegans and many vertebrate species, from amphibians, fishes, birds to mammals. A single slit was isolated in invertebrates, whereas there are three slit genes (slit1-slit3) in mammals, that have around 60% homology. All encodes large ECM glycoproteins of about 200 kDa (Fig. 1A), comprising, from their N terminus to their C terminus, a long stretch of four leucine rich repeats (LRR) connected by disulphide bonds, seven to nine EGF repeats, a domain, named ALPS (Agrin, Perlecan, Laminin, Slit) or laminin G-like module (see ref 17), and a cystein knot (Fig. 1A). Alternative spliced transcripts have been reported for Drosophila Slit2, human Slit2 and Slit3, and Slit1. Moreover, two Slit1 isoforms exist in zebrafish as a consequence of gene duplication. Last, in mammals, two Slit2 isoforms can be purified from brain extracts, a long 200 kDa one and a shorter 150 kDa form (Slit2-N) that was shown to result from the proteolytic processing of full-length Slit2. Human Slit and Slit3 and Drosophila Slit are also cleaved by an unknown protease in a large N-terminal fragment and a shorter C-terminal fragment, suggesting conserved mechanisms for Slit cleavage across species. Moreover, Slit fragments have different cell association characteristics in cell culture suggesting that they may also have different extents of diffusion, different binding properties, and, hence, different functional activities in vivo. This conclusion is supported by in vitro data showing that full-length Slit2 functions as an antagonist of Slit2-N in the DRG branching assay, and that Slit2-N, not full-length Slit2, causes collapse of OB growth cones. In addition, Slit1-N and full-length Slit1 can induce branching of cortical neurons (see below), but only full-length Slit1 repels cortical axons. Structure-function analysis in vertebrates and Drosophila demonstrated that the LRRs of Slits are required and sufficient to mediate their repulsive activities in neurons. More recent detailed structure function analysis of the LRR domains of Drosophila Slit, revealed that the active site of Slit (at least regarding its pro-angiogenic activity) is located on the second of the fourth LRR (LRR2), which is highly conserved between Slits. Slit can also dimerize through the LRR4 domain and the cystein knot.However, a Slit1 spliced-variant that lacks the cysteine knot and does not dimerize is still able to repel OB axons.
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Methods Mol Biol,
2002]
Mutations in mitochondrial genes encoded by both mitochondrial DNA (mtDNA) and nuclear DNA (nDNA have been implicated in a wide range of degenerative diseases. MtDNA base substitution and rearrangement mutations can cause myopathy, cardiomyopathy, ophthalmological defects, growth retardation, movement disorders, dementias, and diabetes. nDNA mutations can affect mtDNA replication and transcription, increase mtDNA mutations through defects in the adenine nucleotide translocator isoform 1 (ANT1), or cause Leigh''s syndrome, as a result of defects in oxidative phosphorylation (OXPHOS) structural genes. Mouse models of mtDNA base substitution mutations have been created by introducing the mtDNA 16S rRNA chloramphenicol (CAP)-resistance mutation into the mouse female germline. This resulted in ophthalmological defects in chimeras and perinatal lethality resulting from myopathy and cardiomyopathy in mutant animals. Mouse models of mtDNA rearrangements have resulted in animals with myopathy, cardiomyopathy, and nephropathy. Conditional inactivation of the mouse nDNA mitochondrial transcription factor (Tfam) gene in the heart caused neonatal lethal cardiomyopathy, whereas its inactivation in the pancreatic beta-cells caused diabetes. Mutational inactivation of the mouse Ant1 gene resulted in myopathy, cardiomyopathy, and multiple mtDNA deletions in association with elevated reactive oxygen species (ROS) production. This suggests that multiple mtDNA deletion syndrome can be caused by increased ROS damage. The inactivation of the uncoupler protein genes (Ucp) 1-3 resulted in alterations in delta mu H+ and increased ROS production. Inactivation of the Ucp2 gene, which is expressed in the pancreatic beta-cells, resulted in increased islet ATP, increased serum insulin levels, and suppression of the diabetes of the ob/ob mouse genotype. Transgenic mice with altered beta-cell ATP-sensitive K+ channels (KATP) also developed diabetes. Mutational inactivation of the mitochondrial antioxidant genes for glutathione peroxidase (GPx1) and Mn superoxide dismutase (Sod2) caused reduced energy production and neonatal lethal dilated cardiomyopathy, respectively, the later being ameliorated by treatment with MnSOD mimics. Partial Sod2 deficiency (+/-) resulted in mice with increased mitochondrial damage during aging, and treatment of C. elegans with catalytic antioxidant drugs can extend their life-span. Mice deficient in cytochrome-c died early in embryogenesis, but cells derived from these embryos had a complete deficiency in mitochondrial apoptosis. Mice lacking the proapoptotic Bax and Bak genes were not able to release cytochrome-c from the mitochondrion and were blocked in apoptosis. Mice lacking Apaf1, Cas9, and Cas3 did release mitochondrial cytochrome-c and were blocked in the downstream steps of apoptosis. These animal studies confirm that alterations in mitochondrial energy generation, ROS production, and apoptosis can all contribute to the pathophysiology of mitochondrial disease.