transforming-growth-factor-beta and Starvation

During hunger or malnutrition, animals prioritize alimentation of the brain over other organs to ensure its function and, thus, their survival. This protection, also-called brain sparing, is described from

Topics: Animals; Biological Transport; Blood-Brain Barrier; Carbohydrate Metabolism; Drosophila; Gene Expression Regulation; Glucose; Membrane Transport Proteins; Neuroglia; rab GTP-Binding Proteins; Signal Transduction; Starvation; Transcription, Genetic; Transforming Growth Factor beta; Trehalose; Up-Regulation

Animals rely on complex signaling network to mobilize its energy stores during starvation. We have previously shown that the sugar-responsive TGFβ/Activin pathway, activated through the TGFβ ligand Dawdle, plays a central role in shaping the post-prandial digestive competence in the Drosophila midgut. Nevertheless, little is known about the TGFβ/Activin signaling in sugar metabolism beyond the midgut. Here, we address the importance of Dawdle (Daw) after carbohydrate ingestion. We found that Daw expression is coupled to dietary glucose through the evolutionarily conserved Mio-Mlx transcriptional complex. In addition, Daw activates the TGFβ/Activin signaling in neuronal populations to regulate triglyceride and glycogen catabolism and energy homeostasis. Loss of those neurons depleted metabolic reserves and rendered flies susceptible to starvation.

Topics: Activins; Animals; Drosophila; Glycogen; Neurons; Signal Transduction; Starvation; Transforming Growth Factor beta; Triglycerides

Nutrient availability has profound influence on development. In the nematode C. elegans, nutrient availability governs post-embryonic development. L1-stage larvae remain in a state of developmental arrest after hatching until they feed. This "L1 arrest" (or "L1 diapause") is associated with increased stress resistance, supporting starvation survival. Loss of the transcription factor daf-16/FOXO, an effector of insulin/IGF signaling, results in arrest-defective and starvation-sensitive phenotypes. We show that daf-16/FOXO regulates L1 arrest cell-nonautonomously, suggesting that insulin/IGF signaling regulates at least one additional signaling pathway. We used mRNA-seq to identify candidate signaling molecules affected by daf-16/FOXO during L1 arrest. dbl-1/TGF-β, a ligand for the Sma/Mab pathway, daf-12/NHR and daf-36/oxygenase, an upstream component of the daf-12 steroid hormone signaling pathway, were up-regulated during L1 arrest in a daf-16/FOXO mutant. Using genetic epistasis analysis, we show that dbl-1/TGF-β and daf-12/NHR steroid hormone signaling pathways are required for the daf-16/FOXO arrest-defective phenotype, suggesting that daf-16/FOXO represses dbl-1/TGF-β, daf-12/NHR and daf-36/oxygenase. The dbl-1/TGF-β and daf-12/NHR pathways have not previously been shown to affect L1 development, but we found that disruption of these pathways delayed L1 development in fed larvae, consistent with these pathways promoting development in starved daf-16/FOXO mutants. Though the dbl-1/TGF-β and daf-12/NHR pathways are epistatic to daf-16/FOXO for the arrest-defective phenotype, disruption of these pathways does not suppress starvation sensitivity of daf-16/FOXO mutants. This observation uncouples starvation survival from developmental arrest, indicating that DAF-16/FOXO targets distinct effectors for each phenotype and revealing that inappropriate development during starvation does not cause the early demise of daf-16/FOXO mutants. Overall, this study shows that daf-16/FOXO promotes developmental arrest cell-nonautonomously by repressing pathways that promote larval development.

Topics: Animals; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Embryo, Nonmammalian; Embryonic Development; Forkhead Transcription Factors; Gene Expression Regulation, Developmental; Humans; Insulin; Larva; Neuropeptides; Receptors, Cytoplasmic and Nuclear; RNA, Messenger; Signal Transduction; Somatomedins; Starvation; Transforming Growth Factor beta

Caenorhabditis elegans enter an alternate developmental stage called dauer in unfavorable conditions such as starvation, overcrowding, or high temperature. Several evolutionarily conserved signaling pathways control dauer formation. DAF-7/TGFβ and serotonin, important ligands in these signaling pathways, affect not only dauer formation, but also the expression of one another. The heterotrimeric G proteins GOA-1 (Gα(o)) and EGL-30 (Gα(q)) mediate serotonin signaling as well as serotonin biosynthesis in C. elegans. It is not known whether GOA-1 or EGL-30 also affect dauer formation and/or daf-7 expression, which are both modulated in part by serotonin. The purpose of this study is to better understand the relationship between proteins important for neuronal signaling and developmental plasticity in both C. elegans and humans. Using promoter-GFP transgenic worms, it was determined that both goa-1 and egl-30 regulate daf-7 expression during larval development. In addition, the normal daf-7 response to high temperature or starvation was altered in goa-1 and egl-30 mutants. Despite the effect of goa-1 and egl-30 mutations on daf-7 expression in various environmental conditions, there was no effect of the mutations on dauer formation. This paper provides evidence that while goa-1 and egl-30 are important for normal daf-7 expression, mutations in these genes are not sufficient to disrupt dauer formation.

Topics: Animals; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Cell Shape; Gene Expression Regulation; Genes, Helminth; GTP-Binding Protein alpha Subunits, Gi-Go; GTP-Binding Protein alpha Subunits, Gq-G11; Larva; Mutation; Starvation; Temperature; Transforming Growth Factor beta

When food becomes scarce, animals undergo distinct metabolic, behavioral, and physiological changes that allow them to survive. In this issue, Greer et al. (2008) take advantage of the relatively simple and well-characterized nervous system of C. elegans to elucidate a neural circuit regulating feeding behavior and fat storage.

Topics: Adipose Tissue; Animals; Appetite Regulation; Behavior, Animal; Caenorhabditis elegans; Energy Metabolism; Movement; Nervous System; Starvation; Transforming Growth Factor beta

A major challenge in understanding energy balance is deciphering the neural and molecular circuits that govern behavioral, physiological, and metabolic responses of animals to fluctuating environmental conditions. The neurally expressed TGF-beta ligand DAF-7 functions as a gauge of environmental conditions to modulate energy balance in C. elegans. We show that daf-7 signaling regulates fat metabolism and feeding behavior through a compact neural circuit that allows for integration of multiple inputs and the flexibility for differential regulation of outputs. In daf-7 mutants, perception of depleting food resources causes fat accumulation despite reduced feeding rate. This fat accumulation is mediated, in part, through neural metabotropic glutamate signaling and upregulation of peripheral endogenous biosynthetic pathways that direct energetic resources into fat reservoirs. Thus, neural perception of adverse environmental conditions can promote fat accumulation without a concomitant increase in feeding rate.

Topics: Adaptation, Physiological; Adipose Tissue; Animals; Appetite Regulation; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Energy Metabolism; Environment; Feeding Behavior; Lipid Metabolism; Models, Animal; Mutation; Nervous System; Neural Pathways; Neurons, Afferent; Receptors, Metabotropic Glutamate; Starvation; Transforming Growth Factor beta

Mutations in the insulin/IGF-1 neuroendocrine pathway extend lifespan and affect development, metabolism, and other biological processes in Caenorhabditis elegans and in other species. In addition, they may play a role in learning and memory. Investigation of the insulin/IGF-1 pathway may provide clues for the prevention of age-related declines in cognitive functions. Here, we examined the effects of the life-extending (Age) mutations, such as the age-1 (phosphatidylinositol 3-OH kinase) and daf-2 (insulin/IGF-1 receptor) mutations, on associative learning behavior called isothermal tracking. This thermotaxis learning behavior associates paired stimuli, temperature, and food. The age-1 mutation delayed the age-related decline of isothermal tracking, resulting in a 210% extension of the period that ensures it. The effect is dramatic compared with the extension of other physiological health spans. In addition, young adults of various Age mutants (age-1, daf-2, clk-1, and eat-2) showed increased consistency of temperature-food association, which may be caused by a common feature of the mutants, such as the secondary effects of life extension (i.e., enhanced maintenance of neural mechanisms). The age-1 and daf-2 mutants but not the other Age mutants showed an increase in temperature-starvation association through a different mechanism. Increased temperature-food association of the daf-2 mutant was dependent on neuronal Ca2+-sensor ncs-1, which modulates isothermal tracking in the AIY interneuron. Interestingly, mutations in the daf-7 TGFbeta gene, which functions in parallel to the insulin/IGF-1 pathway, caused deficits in acquisition of temperature-food and temperature-starvation association. This study highlights roles of the Age mutations in modulation of certain behavioral plasticity.

Topics: Aging; Animal Feed; Animals; Association Learning; Behavior, Animal; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Calcium; Calcium-Binding Proteins; Chemoreceptor Cells; Insulin; Insulin-Like Growth Factor I; Interneurons; Locomotion; Longevity; Motor Activity; Mutation; Neuronal Calcium-Sensor Proteins; Neuropeptides; Phosphatidylinositol 3-Kinases; Receptor, Insulin; Signal Transduction; Starvation; Temperature; Transforming Growth Factor beta

Transforming growth factor beta (TGFbeta) and hepatocyte growth factor (HGF) promote glioma progression. Using U87human astrocytoma cells, which express TGFbeta receptors (TbetaRs), we show (1) mRNA expression of Smads (2, 3, 4), bone morphogenetic protein (BMP)- and activin-A receptors; (2) TGFbeta1 inhibits and HGF induces proliferation; (3) TGFbeta1 and activin-A equipotently inhibit HGF secretion more than BMP-2, but none alters c-Met expression. Because interfering with TbetaR signaling might nullify the beneficial inhibition of HGF secretion, activin-A should instead be considered for combination glioma therapy.

Topics: Activin Receptors; Activins; Analysis of Variance; Astrocytoma; Blotting, Northern; Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins; Bromodeoxyuridine; Cell Division; Cell Line, Tumor; Culture Media, Conditioned; DNA-Binding Proteins; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Gene Expression Regulation; Hepatocyte Growth Factor; Humans; Inhibin-beta Subunits; Ligands; Receptors, Transforming Growth Factor beta; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Smad Proteins; Starvation; Trans-Activators; Transforming Growth Factor beta; Transforming Growth Factor beta1

To learn more about tissue remodelling in fibrotic livers of tetracycline-controlled TGF-beta1 transgenic mice (TGF-beta1-on-mice) and during regeneration after removal of the fibrotic stimulus (off-mice), we investigated the expression of glutamine synthetase (GS), an exclusive pericentrally expressed enzyme.. GS was localised immunohistochemically and quantified by real-time RT-PCR and enzymatic activity measurement. Apoptosis in livers of TGF-beta1-on-mice was demonstrated by in situ apoptosis detection kit (TUNEL reaction).. Livers of TGF-beta1-on-mice harbour a reduced number of GS-positive hepatocytes and expression of GS is downregulated, while multiple starved mice serving as controls for malnutrition during TGF-beta1 exposure surprisingly showed an impressive amplification of GS-positive hepatocytes. Apoptotic events were frequent around central veins in livers of TGF-beta1-on-mice, while in multiple induced mice apoptosis was dominant around all vessels and weak in midzonal areas. During regeneration from fibrosis, control levels were regained within 21 days. Beta-catenin was dislocated from plasma membrane to cytoplasm exclusively in pericentral hepatocytes during a short time slot after a unique expression of TGF-beta1.. Reduction of GS in TGF-beta1-on-mice results from apoptosis of GS-positive hepatocytes rather than downregulation of GS expression. Beta-catenin seems involved in the recovery of GS-positive hepatocytes.

Topics: Animals; Anti-Bacterial Agents; Apoptosis; beta Catenin; Cell Division; Cytoskeletal Proteins; Gene Expression; Glutamate-Ammonia Ligase; Liver; Liver Cirrhosis; Liver Regeneration; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Transgenic; RNA, Messenger; Starvation; Tetracycline; Trans-Activators; Transforming Growth Factor beta; Transforming Growth Factor beta1

Topics: Animals; Caenorhabditis elegans Proteins; Cholesterol; Hormones; Insulin; Mutation; Nematoda; Receptors, Cytoplasmic and Nuclear; Signal Transduction; Starvation; Survival; Transforming Growth Factor beta