RESUMO
The transition from the fed to the fasted state necessitates a shift from carbohydrate to fat metabolism that is thought to be mostly orchestrated by reductions in plasma insulin concentrations. Here, we show in awake rats that insulinopenia per se does not cause this transition but that both hypoleptinemia and insulinopenia are necessary. Furthermore, we show that hypoleptinemia mediates a glucose-fatty acid cycle through activation of the hypothalamic-pituitary-adrenal axis, resulting in increased white adipose tissue (WAT) lipolysis rates and increased hepatic acetyl-coenzyme A (CoA) content, which are essential to maintain gluconeogenesis during starvation. We also show that in prolonged starvation, substrate limitation due to reduced rates of glucose-alanine cycling lowers rates of hepatic mitochondrial anaplerosis, oxidation, and gluconeogenesis. Taken together, these data identify a leptin-mediated glucose-fatty acid cycle that integrates responses of the muscle, WAT, and liver to promote a shift from carbohydrate to fat oxidation and maintain glucose homeostasis during starvation.
Assuntos
Glicemia/metabolismo , Ácidos Graxos/metabolismo , Gluconeogênese , Homeostase , Leptina/metabolismo , Inanição/metabolismo , Tecido Adiposo Branco/metabolismo , Alanina/metabolismo , Animais , Insulina/sangue , Leptina/sangue , Lipólise , Fígado/metabolismo , Masculino , Mitocôndrias/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
Mechanistic target of rapamycin complex 1 (mTORC1) integrates diverse environmental signals to control cellular growth and organismal homeostasis. In response to nutrients, Rag GTPases recruit mTORC1 to the lysosome to be activated, but how Rags are regulated remains incompletely understood. Here, we show that Sestrins bind to the heterodimeric RagA/B-RagC/D GTPases, and function as guanine nucleotide dissociation inhibitors (GDIs) for RagA/B. Sestrin overexpression inhibits amino-acid-induced Rag guanine nucleotide exchange and mTORC1 translocation to the lysosome. Mutation of the conserved GDI motif creates a dominant-negative form of Sestrin that renders mTORC1 activation insensitive to amino acid deprivation, whereas a cell-permeable peptide containing the GDI motif inhibits mTORC1 signaling. Mice deficient in all Sestrins exhibit reduced postnatal survival associated with defective mTORC1 inactivation in multiple organs during neonatal fasting. These findings reveal a nonredundant mechanism by which the Sestrin family of GDIs regulates the nutrient-sensing Rag GTPases to control mTORC1 signaling.
Assuntos
Proteínas de Ciclo Celular/metabolismo , Proteínas de Choque Térmico/metabolismo , Complexos Multiproteicos/metabolismo , Proteínas Nucleares/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Sequência de Aminoácidos , Aminoácidos/metabolismo , Animais , Animais Recém-Nascidos , Proteínas de Ciclo Celular/genética , Embrião de Mamíferos/citologia , Feminino , Fibroblastos/metabolismo , Técnicas de Introdução de Genes , Proteínas de Choque Térmico/genética , Alvo Mecanístico do Complexo 1 de Rapamicina , Camundongos , Camundongos Knockout , Dados de Sequência Molecular , Proteínas Monoméricas de Ligação ao GTP/genética , Proteínas Monoméricas de Ligação ao GTP/metabolismo , Proteínas Nucleares/genética , Peroxidases , Gravidez , Alinhamento de Sequência , Inanição/metabolismo , Proteína 2 do Complexo Esclerose Tuberosa , Proteínas Supressoras de Tumor/metabolismoRESUMO
Amino acid starvation is sensed by Escherichia coli RelA and Bacillus subtilis Rel through monitoring the aminoacylation status of ribosomal A-site tRNA. These enzymes are positively regulated by their product-the alarmone nucleotide (p)ppGpp-through an unknown mechanism. The (p)ppGpp-synthetic activity of Rel/RelA is controlled via auto-inhibition by the hydrolase/pseudo-hydrolase (HD/pseudo-HD) domain within the enzymatic N-terminal domain region (NTD). We localize the allosteric pppGpp site to the interface between the SYNTH and pseudo-HD/HD domains, with the alarmone stimulating Rel/RelA by exploiting intra-NTD autoinhibition dynamics. We show that without stimulation by pppGpp, starved ribosomes cannot efficiently activate Rel/RelA. Compromised activation by pppGpp ablates Rel/RelA function in vivo, suggesting that regulation by the second messenger (p)ppGpp is necessary for mounting an acute starvation response via coordinated enzymatic activity of individual Rel/RelA molecules. Control by (p)ppGpp is lacking in the E. coli (p)ppGpp synthetase SpoT, thus explaining its weak synthetase activity.
Assuntos
Regulação Alostérica/genética , Proteínas de Escherichia coli/genética , GTP Pirofosfoquinase/genética , Guanosina Pentafosfato/genética , Pirofosfatases/genética , Aminoácidos/metabolismo , Bacillus subtilis/genética , Bacillus subtilis/metabolismo , Domínio Catalítico/genética , Escherichia coli/genética , Escherichia coli/metabolismo , Hidrolases/genética , Ribossomos/genética , Ribossomos/metabolismo , Inanição/genética , Inanição/metabolismoRESUMO
Social isolation and loneliness have potent effects on public health1-4. Research in social psychology suggests that compromised sleep quality is a key factor that links persistent loneliness to adverse health conditions5,6. Although experimental manipulations have been widely applied to studying the control of sleep and wakefulness in animal models, how normal sleep is perturbed by social isolation is unknown. Here we report that chronic, but not acute, social isolation reduces sleep in Drosophila. We use quantitative behavioural analysis and transcriptome profiling to differentiate between brain states associated with acute and chronic social isolation. Although the flies had uninterrupted access to food, chronic social isolation altered the expression of metabolic genes and induced a brain state that signals starvation. Chronically isolated animals exhibit sleep loss accompanied by overconsumption of food, which resonates with anecdotal findings of loneliness-associated hyperphagia in humans. Chronic social isolation reduces sleep and promotes feeding through neural activities in the peptidergic fan-shaped body columnar neurons of the fly. Artificial activation of these neurons causes misperception of acute social isolation as chronic social isolation and thereby results in sleep loss and increased feeding. These results present a mechanistic link between chronic social isolation, metabolism, and sleep, addressing a long-standing call for animal models focused on loneliness7.
Assuntos
Encéfalo/metabolismo , Drosophila melanogaster/metabolismo , Comportamento Alimentar , Modelos Animais , Sono , Isolamento Social , Inanição/metabolismo , Animais , Encéfalo/citologia , Drosophila melanogaster/citologia , Drosophila melanogaster/genética , Feminino , Fome , Hiperfagia/genética , Solidão , Masculino , Neurônios/metabolismo , Sono/genética , Privação do Sono/genética , Privação do Sono/metabolismo , Inanição/genética , Fatores de Tempo , TranscriptomaRESUMO
Refeeding after a period of starvation is known to suppress autophagy in the liver. Surprising new work by Seok et al (2022) shows that refeeding activates lipophagy in the intestine, which may help fats in our diet to be efficiently processed after a meal.
Assuntos
Metabolismo dos Lipídeos , Inanição , Autofagia/fisiologia , Humanos , Fígado/metabolismo , Inanição/metabolismoRESUMO
Internal physiological states influence behavioral decisions. We have investigated the underlying cellular and molecular mechanisms at the first olfactory synapse for starvation modulation of food-search behavior in Drosophila. We found that a local signal by short neuropeptide F (sNPF) and a global metabolic cue by insulin are integrated at specific odorant receptor neurons (ORNs) to modulate olfactory sensitivity. Results from two-photon calcium imaging show that starvation increases presynaptic activity via intraglomerular sNPF signaling. Expression of sNPF and its receptor (sNPFR1) in Or42b neurons is necessary for starvation-induced food-search behavior. Presynaptic facilitation in Or42b neurons is sufficient to mimic starvation-like behavior in fed flies. Furthermore, starvation elevates the transcription level of sNPFR1 but not that of sNPF, and insulin signaling suppresses sNPFR1 expression. Thus, starvation increases expression of sNPFR1 to change the odor map, resulting in more robust food-search behavior.
Assuntos
Proteínas de Drosophila/metabolismo , Drosophila/fisiologia , Neuropeptídeos/metabolismo , Receptores de Neuropeptídeos/metabolismo , Receptores Odorantes/metabolismo , Transdução de Sinais , Animais , Antenas de Artrópodes/metabolismo , Feminino , Odorantes , Células Receptoras Sensoriais/metabolismo , Inanição/metabolismo , Sinapses/metabolismoRESUMO
Circular RNAs (circRNAs) are abundant and evolutionarily conserved RNAs of largely unknown function. Here, we show that a subset of circRNAs is translated in vivo. By performing ribosome footprinting from fly heads, we demonstrate that a group of circRNAs is associated with translating ribosomes. Many of these ribo-circRNAs use the start codon of the hosting mRNA, are bound by membrane-associated ribosomes, and have evolutionarily conserved termination codons. In addition, we found that a circRNA generated from the muscleblind locus encodes a protein, which we detected in fly head extracts by mass spectrometry. Next, by performing in vivo and in vitro translation assays, we show that UTRs of ribo-circRNAs (cUTRs) allow cap-independent translation. Moreover, we found that starvation and FOXO likely regulate the translation of a circMbl isoform. Altogether, our study provides strong evidence for translation of circRNAs, revealing the existence of an unexplored layer of gene activity.
Assuntos
Proteínas de Drosophila/biossíntese , Drosophila melanogaster/metabolismo , Proteínas Nucleares/biossíntese , Biossíntese de Proteínas , RNA/metabolismo , Ribossomos/metabolismo , Animais , Linhagem Celular , Códon de Iniciação , Códon de Terminação , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Fatores de Transcrição Forkhead/metabolismo , Genótipo , Cabeça , Espectrometria de Massas , Camundongos , Mutação , Proteínas Nucleares/genética , Conformação de Ácido Nucleico , Estado Nutricional , Fenótipo , RNA/química , RNA/genética , Capuzes de RNA/química , Capuzes de RNA/genética , RNA Circular , Ratos , Ribossomos/química , Ribossomos/genética , Inanição/genética , Inanição/metabolismo , Relação Estrutura-Atividade , TransfecçãoRESUMO
During starvation, organisms modify both gene expression and metabolism to adjust to the energy stress. We previously reported that Caenorhabditis elegans lacing AMP-activated protein kinase (AMPK) exhibit transgenerational reproductive defects associated with abnormally elevated trimethylated histone H3 at lysine 4 (H3K4me3) levels in the germ line following recovery from acute starvation. Here, we show that these H3K4me3 marks are significantly increased at promoters, driving aberrant transcription elongation resulting in the accumulation of R-loops in starved AMPK mutants. DNA-RNA immunoprecipitation followed by high-throughput sequencing (DRIP-seq) analysis demonstrated that a significant proportion of the genome was affected by R-loop formation. This was most pronounced in the promoter-transcription start site regions of genes, in which the chromatin was modified by H3K4me3. Like H3K4me3, the R-loops were also found to be heritable, likely contributing to the transgenerational reproductive defects typical of these mutants following starvation. Strikingly, AMPK mutant germ lines show considerably more RAD-51 (the RecA recombinase) foci at sites of R-loop formation, potentially sequestering them from their roles at meiotic breaks or at sites of induced DNA damage. Our study reveals a previously unforeseen role of AMPK in maintaining genome stability following starvation. The downstream effects of R-loops on DNA damage sensitivity and germline stem cell integrity may account for inappropriate epigenetic modification that occurs in numerous human disorders, including various cancers.
Assuntos
Caenorhabditis elegans , Epigênese Genética , Instabilidade Genômica , Estruturas R-Loop , Animais , Humanos , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/fisiologia , Infertilidade/genética , Inanição/metabolismoRESUMO
Wild-type (WT) mice maintain viable levels of blood glucose even when adipose stores are depleted by 6 d of 60% calorie restriction followed by a 23-h fast (hereafter designated as "starved" mice). Survival depends on ghrelin, an octanoylated peptide hormone. Mice that lack ghrelin suffer lethal hypoglycemia when subjected to the same starvation regimen. Ghrelin is known to stimulate secretion of growth hormone (GH), which in turn stimulates secretion of IGF-1 (insulin-like growth factor-1). In the current study, we found that starved ghrelin-deficient mice had a 90% reduction in plasma IGF-1 when compared with starved WT mice. Injection of IGF-1 in starved ghrelin-deficient mice caused a twofold increase in glucose production and raised blood glucose to levels seen in starved WT mice. Increased glucose production was accompanied by increases in plasma glycerol, fatty acids and ketone bodies, and hepatic triglycerides. All of these increases were abolished when the mice were treated with atglistatin, an inhibitor of adipose tissue triglyceride lipase. We conclude that IGF-1 stimulates adipose tissue lipolysis in starved mice and that this lipolysis supplies energy and substrates that restore hepatic gluconeogenesis. This action of IGF-1 in starved mice is in contrast to its known action in inhibiting adipose tissue lipase in fed mice. Surprisingly, the ghrelin-dependent maintenance of plasma IGF-1 in starved mice was not mediated by GH. Direct injection of GH into starved ghrelin-deficient mice failed to increase plasma IGF-1. These data call attention to an unsuspected role of IGF-1 in the adaptation to starvation.
Assuntos
Glicemia , Fator de Crescimento Insulin-Like I , Inanição , Adaptação Fisiológica , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/enzimologia , Tecido Adiposo/metabolismo , Animais , Glicemia/metabolismo , Ácidos Graxos/sangue , Grelina/metabolismo , Gluconeogênese , Glicerol/sangue , Hormônio do Crescimento/metabolismo , Fator de Crescimento Insulin-Like I/análise , Fator de Crescimento Insulin-Like I/metabolismo , Corpos Cetônicos/sangue , Lipase/antagonistas & inibidores , Lipase/metabolismo , Lipólise , Fígado/metabolismo , Camundongos , Compostos de Fenilureia/farmacologia , Inanição/sangue , Inanição/metabolismo , Triglicerídeos/metabolismoRESUMO
BACKGROUND AND AIMS: Hepatocytes were the first cell type for which oscillations of cytoplasmic calcium levels in response to hormones were described. Since then, investigation of calcium dynamics in liver explants and culture has greatly increased our understanding of calcium signaling. A bottleneck, however, exists in observing calcium dynamics in a noninvasive manner because of the optical inaccessibility of the mammalian liver. Here, we aimed to take advantage of the transparency of the zebrafish larvae to image hepatocyte calcium dynamics in vivo at cellular resolution. APPROACH AND RESULTS: We developed a transgenic model expressing a calcium sensor, GCaMP6s, specifically in zebrafish hepatocytes. Using this, we provide a quantitative assessment of intracellular calcium dynamics during multiple contexts, including growth, feeding, ethanol-induced stress, and cell ablation. Specifically, we show that synchronized calcium oscillations are present in vivo , which are lost upon starvation. Starvation induces lipid accumulation in the liver. Feeding recommences calcium waves in the liver, but in a spatially restricted manner, as well as resolves starvation-induced hepatic steatosis. By using a genetically encoded scavenger for calcium, we show that dampening of calcium signaling accelerates the accumulation of starvation-related lipid droplets in the liver. Furthermore, ethanol treatment, as well as cell ablation, induces calcium flux, but with different dynamics. The former causes asynchronous calcium oscillations, whereas the latter leads to a single calcium spike. CONCLUSIONS: We demonstrate the presence of oscillations, waves, and spikes in vivo . Calcium waves are present in response to nutrition and negatively regulate starvation-induced accumulation of lipid droplets.
Assuntos
Inanição , Peixe-Zebra , Animais , Peixe-Zebra/metabolismo , Cálcio/metabolismo , Hepatócitos/metabolismo , Fígado/metabolismo , Etanol/farmacologia , Sinalização do Cálcio , Inanição/metabolismo , Mamíferos/metabolismoRESUMO
INTRODUCTION: Neuropeptides regulate vital physiological processes in multicellular organisms, including growth, reproduction, metamorphosis, and feeding. Recent transcriptome analyses have revealed neuropeptide genes with potential roles in vertebrate and invertebrate growth and reproduction. Among these genes, haliotid growth-associated peptide (HGAP) was identified as a novel gene in abalone. METHODS: This study focused on HGAP in Pacific abalone (Haliotis discus hannai), where the complete cDNA sequence named Hdh-HGAP was identified and characterized. Samples from different experiments, such as metamorphosis, juvenile abalone growth, gonad development stages, muscle remodeling, and starvation, were collected for mRNA expression analysis. RESULTS: The sequence spans 552 bp, encoding 96 amino acids with a molecular weight of 10.96 kDa. Expression analysis revealed that Hdh-HGAP exhibited higher levels in muscle tissue. Notably, during metamorphosis, Hdh-HGAP exhibited greater expression in the trochophore, veliger, and juvenile stages than in the cell division stages. Regarding growth patterns, Hdh-HGAP was highly expressed during rapid growth compared to stunted, minimal, and normal growth. In gonadal development, Hdh-HGAP mRNA reached its highest expression level during the ripening stage, indicating a potential role in gonadal cell proliferation and maturation. The in vivo effects of GnRH on gonad development and the expression of the Hdh-HGAP neuropeptide indicate its involvement in regulating reproduction in Pacific abalone. While tissue remodeling is primarily governed by immune genes, Hdh-HGAP was also upregulated during muscle tissue remodeling. Conversely, Hdh-HGAP was downregulated during prolonged starvation. CONCLUSION: This study marks the first comprehensive exploration of the Hdh-HGAP neuropeptide gene in Pacific abalone, shedding light on its involvement in growth, reproduction, metamorphosis, tissue remodeling, and response to starvation, although regulatory mechanisms are mostly unknown.
Assuntos
Gastrópodes , Metamorfose Biológica , Neuropeptídeos , Reprodução , Animais , Gastrópodes/crescimento & desenvolvimento , Gastrópodes/genética , Gastrópodes/metabolismo , Metamorfose Biológica/fisiologia , Reprodução/fisiologia , Neuropeptídeos/metabolismo , Neuropeptídeos/genética , Inanição/metabolismo , Regulação da Expressão Gênica no DesenvolvimentoRESUMO
Neurons in the arcuate nucleus that produce AgRP, NPY, and GABA (AgRP neurons) promote feeding. Ablation of AgRP neurons in adult mice results in Fos activation in postsynaptic neurons and starvation. Loss of GABA is implicated in starvation because chronic subcutaneous delivery of bretazenil (a GABA(A) receptor partial agonist) suppresses Fos activation and maintains feeding during ablation of AgRP neurons. Moreover, under these conditions, direct delivery of bretazenil into the parabrachial nucleus (PBN), a direct target of AgRP neurons that also relays gustatory and visceral sensory information, is sufficient to maintain feeding. Conversely, inactivation of GABA biosynthesis in the ARC or blockade of GABA(A) receptors in the PBN of mice promote anorexia. We suggest that activation of the PBN by AgRP neuron ablation or gastrointestinal malaise inhibits feeding. Chronic delivery of bretazenil during loss of AgRP neurons provides time to establish compensatory mechanisms that eventually allow mice to eat.
Assuntos
Anorexia/fisiopatologia , Neurônios/metabolismo , Rombencéfalo/metabolismo , Transdução de Sinais , Inanição/metabolismo , Ácido gama-Aminobutírico/metabolismo , Animais , Astrócitos/metabolismo , Agonistas de Receptores de GABA-A , Glutamato Descarboxilase , Camundongos , Proteínas Proto-Oncogênicas c-fos/metabolismoRESUMO
Here we report the identification and verification of a ß-hydroxybutyrate-derived protein modification, lysine ß-hydroxybutyrylation (Kbhb), as a new type of histone mark. Histone Kbhb marks are dramatically induced in response to elevated ß-hydroxybutyrate levels in cultured cells and in livers from mice subjected to prolonged fasting or streptozotocin-induced diabetic ketoacidosis. In total, we identified 44 histone Kbhb sites, a figure comparable to the known number of histone acetylation sites. By ChIP-seq and RNA-seq analysis, we demonstrate that histone Kbhb is a mark enriched in active gene promoters and that the increased H3K9bhb levels that occur during starvation are associated with genes upregulated in starvation-responsive metabolic pathways. Histone ß-hydroxybutyrylation thus represents a new epigenetic regulatory mark that couples metabolism to gene expression, offering a new avenue to study chromatin regulation and diverse functions of ß-hydroxybutyrate in the context of important human pathophysiological states, including diabetes, epilepsy, and neoplasia.
Assuntos
Cetoacidose Diabética/metabolismo , Metabolismo Energético , Regulação da Expressão Gênica , Histonas/metabolismo , Hidroxibutiratos/metabolismo , Fígado/metabolismo , Processamento de Proteína Pós-Traducional , Inanição/metabolismo , Animais , Sítios de Ligação , Montagem e Desmontagem da Cromatina , Cetoacidose Diabética/induzido quimicamente , Cetoacidose Diabética/genética , Modelos Animais de Doenças , Epigênese Genética , Ácidos Graxos/metabolismo , Glucose/metabolismo , Células HEK293 , Histonas/genética , Humanos , Lisina , Camundongos Endogâmicos C57BL , Regiões Promotoras Genéticas , Inanição/genética , EstreptozocinaRESUMO
Feeding is essential for animal survival and reproduction and is regulated by both internal states and external stimuli. However, little is known about how internal states influence the perception of external sensory cues that regulate feeding behavior. Here, we investigated the neuronal and molecular mechanisms behind nutritional state-mediated regulation of gustatory perception in control of feeding behavior in the brown planthopper and Drosophila. We found that feeding increases the expression of the cholecystokinin-like peptide, sulfakinin (SK), and the activity of a set of SK-expressing neurons. Starvation elevates the transcription of the sugar receptor Gr64f and SK negatively regulates the expression of Gr64f in both insects. Interestingly, we found that one of the two known SK receptors, CCKLR-17D3, is expressed by some of Gr64f-expressing neurons in the proboscis and proleg tarsi. Thus, we have identified SK as a neuropeptide signal in a neuronal circuitry that responds to food intake, and regulates feeding behavior by diminishing gustatory receptor gene expression and activity of sweet sensing GRNs. Our findings demonstrate one nutritional state-dependent pathway that modulates sweet perception and thereby feeding behavior, but our experiments cannot exclude further parallel pathways. Importantly, we show that the underlying mechanisms are conserved in the two distantly related insect species.
Assuntos
Comportamento Alimentar/fisiologia , Percepção Gustatória/genética , Animais , Encéfalo/metabolismo , Metabolismo dos Carboidratos/fisiologia , Carboidratos/fisiologia , Colecistocinina/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/fisiologia , Comportamento Alimentar/psicologia , Expressão Gênica/genética , Regulação da Expressão Gênica/genética , Hemípteros/genética , Hemípteros/fisiologia , Neurônios/metabolismo , Neuropeptídeos/metabolismo , Receptores de Superfície Celular/genética , Inanição/metabolismo , Açúcares/metabolismo , Paladar/fisiologia , Percepção Gustatória/fisiologiaRESUMO
The liver is a crucial center in the regulation of energy homeostasis under starvation. Although downregulation of mammalian target of rapamycin complex 1 (mTORC1) has been reported to play pivotal roles in the starvation responses, the underpinning mechanisms in particular upstream factors that downregulate mTORC1 remain largely unknown. To identify genetic variants that cause liver energy disorders during starvation, we conduct a zebrafish forward genetic screen. We identify a liver hulk (lvh) mutant with normal liver under feeding, but exhibiting liver hypertrophy under fasting. The hepatomegaly in lvh is caused by enlarged hepatocyte size and leads to liver dysfunction as well as limited tolerance to starvation. Positional cloning reveals that lvh phenotypes are caused by mutation in the ftcd gene, which encodes the formimidoyltransferase cyclodeaminase (FTCD). Further studies show that in response to starvation, the phosphorylated ribosomal S6 protein (p-RS6), a downstream effector of mTORC1, becomes downregulated in the wild-type liver, but remains at high level in lvh. Inhibition of mTORC1 by rapamycin rescues the hepatomegaly and liver dysfunction of lvh. Thus, we characterize the roles of FTCD in starvation response, which acts as an important upstream factor to downregulate mTORC1, thus preventing liver hypertrophy and dysfunction.
Assuntos
Amônia-Liases/genética , Glutamato Formimidoiltransferase/genética , Hepatomegalia/genética , Fígado/metabolismo , Enzimas Multifuncionais/genética , Proteína S6 Ribossômica/genética , Animais , Modelos Animais de Doenças , Hepatócitos/metabolismo , Hepatócitos/patologia , Hepatomegalia/metabolismo , Hepatomegalia/patologia , Humanos , Fígado/patologia , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Complexos Multiproteicos/genética , Mutação/genética , Fosforilação , Transdução de Sinais/genética , Inanição/genética , Inanição/metabolismo , Inanição/patologia , Peixe-Zebra/genéticaRESUMO
A single insulin receptor (InR) gene has been identified and extensively studied in model species ranging from nematodes to mice. However, most insects possess additional copies of InR, yet the functional significance, if any, of alternate InRs is unknown. Here, we used the wing-dimorphic brown planthopper (BPH) as a model system to query the role of a second InR copy in insects. NlInR2 resembled the BPH InR homologue (NlInR1) in terms of nymph development and reproduction, but revealed distinct regulatory roles in fuel metabolism, lifespan, and starvation tolerance. Unlike a lethal phenotype derived from NlInR1 null, homozygous NlInR2 null mutants were viable and accelerated DNA replication and cell proliferation in wing cells, thus redirecting short-winged-destined BPHs to develop into long-winged morphs. Additionally, the proper expression of NlInR2 was needed to maintain symmetric vein patterning in wings. Our findings provide the first direct evidence for the regulatory complexity of the two InR paralogues in insects, implying the functionally independent evolution of multiple InRs in invertebrates.
Assuntos
Evolução Molecular , Regulação da Expressão Gênica no Desenvolvimento , Hemípteros/genética , Proteínas de Insetos/genética , Receptor de Insulina/genética , Asas de Animais/metabolismo , Adaptação Fisiológica/genética , Animais , Sequência de Bases , Sistemas CRISPR-Cas , Metabolismo Energético/genética , Dosagem de Genes , Edição de Genes/métodos , Hemípteros/anatomia & histologia , Hemípteros/crescimento & desenvolvimento , Hemípteros/metabolismo , Proteínas de Insetos/metabolismo , Longevidade/genética , Ninfa/genética , Ninfa/crescimento & desenvolvimento , Ninfa/metabolismo , Fenótipo , Receptor de Insulina/metabolismo , Transdução de Sinais , Inanição/genética , Inanição/metabolismo , Asas de Animais/anatomia & histologia , Asas de Animais/crescimento & desenvolvimentoRESUMO
Clarias gariepinus is an important freshwater fish with high economic value and breeding potential in China. It is a fast-growing and adaptable catfish, but the main problems facing the current market are its low price and poor taste, although starvation is a good solution to these problems. In this study, the effects of starvation on the physiology, biochemistry, and muscle quality of C. gariepinus were investigated. The results showed that compared with the control group, the weight gain rate and specific growth rate of the starvation group were significantly different. Body weight, visceral weight, condition factor, viscerosomatic index, hepatosomatic index, and viscera fat index all decreased, while visceral weight and hepatosomatic index decreased significantly after starvation for 30 days. The hardness and crude protein of muscle increased significantly and crude lipid decreased significantly. Taste-enhancing amino acids increased slightly, and fatty acids increased significantly. Compared with the control group, starvation led to changes in antioxidant defense parameters. The level of malondialdehyde (MDA) in liver increased significantly; the activities of superoxide dismutase (SOD) increased in serum after 30 days; the activities of glutathione peroxidase (GSH-Px) increased considerably in the serum and liver after 15 days; the activities of alanine aminotransferase (ALT) increased considerably in the serum and liver after 30 days. The in-depth study of changes in physiological, biochemical, and nutritional components of fish under starvation is helpful to understand the ecological strategy of fish to adapt to starvation and of great guiding significance for fishery resource management and aquaculture production.
Assuntos
Antioxidantes , Peixes-Gato , Animais , Peixes-Gato/fisiologia , Peixes-Gato/metabolismo , Peixes-Gato/crescimento & desenvolvimento , Antioxidantes/metabolismo , Fígado/metabolismo , Superóxido Dismutase/metabolismo , Malondialdeído/metabolismo , Malondialdeído/sangue , Inanição/metabolismo , Glutationa Peroxidase/metabolismoRESUMO
The present study aims to investigate nutritional programming through early starvation in the European seabass (Dicentrarchus labrax). European seabass larvae were fasted at three different developmental periods for three durations from 60 to 65 dph (F1), 81 to 87 dph (F2), and 123 to 133 dph (F3). Immediate effects were investigated by studying gene expression of npy (neuropeptide Y) and avt (Arginine vasotocin) in the head, while potential long-term effects (i.e., programming) were evaluated on intermediary metabolism later in life (in juveniles). Our findings indicate a direct effect regarding gene expression in the head only for F1, with higher avt mRNA level in fasted larved compared to controls. The early starvation periods had no long-term effect on growth performance (body weight and body length). Regarding intermediary metabolism, we analyzed related key plasma metabolites which reflect the intermediary metabolism: no differences for glucose, triglycerides, and free fatty acids in the plasma were observed in juveniles irrespective of the three early starvation stimuli. As programming is mainly linked to molecular mechanisms, we then studied hepatic mRNA levels for 23 key actors of glucose, lipid, amino acid, and energy metabolism. For many of the metabolic genes, there was no impact of early starvation in juveniles, except for three genes involved in glucose metabolism (glut2-glucose transporter and pk-pyruvate kinase) and lipid metabolism (acly-ATP citrate lyase) which were higher in F2 compared to control. Together, these results highlight that starvation between 81 to 87 dph may have more long-term impact, suggesting the existence of a developmental window for programming by starvation. In conclusion, European seabass appeared to be resilient to early starvation during larvae stages without drastic impacts on intermediary metabolism later in life.
Assuntos
Bass , Larva , Fígado , Inanição , Animais , Bass/crescimento & desenvolvimento , Bass/metabolismo , Bass/genética , Fígado/metabolismo , Larva/crescimento & desenvolvimento , Larva/metabolismo , Inanição/metabolismo , Neuropeptídeo Y/metabolismo , Neuropeptídeo Y/genética , Vasotocina/metabolismo , Proteínas de Peixes/genética , Proteínas de Peixes/metabolismoRESUMO
There is a debate on whether lipid-mediated insulin resistance derives from an increased or decreased capacity of muscle to oxidize fats. Here, we examine the involvement of muscle fiber composition in the metabolic responses to a 3-day fast (starvation, which results in increases in plasma lipids and insulin resistance) in two groups of healthy young subjects: 1), area occupied by type I fibers = 61.0 ± 11.8%; 2), type I area = 36.0 ± 4.9% (P < 0.001). Muscle biopsies and intravenous glucose tolerance tests were performed after an overnight fast and after starvation. Biopsies were analyzed for muscle fiber composition and mitochondrial respiration. Indices of glucose tolerance and insulin sensitivity were determined. Glucose tolerance was similar in both groups after an overnight fast and deteriorated to a similar degree in both groups after starvation. In contrast, whole body insulin sensitivity decreased markedly after starvation in group 1 (P < 0.01), whereas the decrease in group 2 was substantially smaller (P = 0.06). Nonesterified fatty acids and ß-hydroxybutyrate levels in plasma after an overnight fast were similar between groups and increased markedly and comparably in both groups after starvation, demonstrating similar degrees of lipid load. The capacity of permeabilized muscle fibers to oxidize lipids was significantly higher in group 1 versus 2, whereas there was no significant difference in pyruvate oxidation between groups. The data demonstrate that loss of whole body insulin sensitivity after short-term starvation is a function of muscle fiber composition and is associated with an elevated rather than a diminished capacity of muscle to oxidize lipids.NEW & NOTEWORTHY Whether lipid-mediated insulin resistance occurs as a result of an increased or decreased capacity of skeletal muscle to oxidize lipids has been debated. We show that a 3-day fast results in increases in circulating lipids and insulin resistance in subjects expressing a high or low proportion of type I muscle fibers. High expression of type I is associated with a higher capacity to oxidize lipids and a greater loss of insulin sensitivity after starvation.
Assuntos
Resistência à Insulina , Inanição , Humanos , Ácidos Graxos não Esterificados/metabolismo , Glucose/metabolismo , Insulina/metabolismo , Resistência à Insulina/fisiologia , Músculo Esquelético/metabolismo , Inanição/metabolismo , Lipídeos , Metabolismo dos Lipídeos , OxirreduçãoRESUMO
Animals increase their locomotion activity and reduce sleep duration under starved conditions. This suggests that sleep and metabolic status are closely interconnected. The nutrient and hunger sensors in the Drosophila brain, including diuretic hormone 44 (DH44)-, CN-, and cupcake-expressing neurons, detect circulating glucose levels in the internal milieu, regulate the insulin and glucagon secretion and promote food consumption. Food deprivation is known to reduce sleep duration, but a potential role mediated by the nutrient and hunger sensors in regulating sleep and locomotion activity remains unclear. Here, we show that DH44 neurons are involved in regulating starvation-induced sleep suppression, but CN neurons or cupcake neurons may not be involved in regulating starvation-induced sleep suppression or baseline sleep patterns. Inactivation of DH44 neurons resulted in normal daily sleep durations and patterns under fed conditions, whereas it ablated sleep reduction under starved conditions. Inactivation of CN neurons or cupcake neurons, which were proposed to be nutrient and hunger sensors in the fly brain, did not affect sleep patterns under both fed and starved conditions. We propose that the glucose-sensing DH44 neurons play an important role in mediating starvation-induced sleep reduction.