A novel nuclear receptor/coregulator complex controls <i>C. elegans</i> lipid metabolism, larval development, and aging

Ludewig, Andreas H.; Kober-Eisermann, Corinna; Weitzel, Cindy; Bethke, Axel; Neubert, Kerstin; Gerisch, Birgit; Hutter, Harald; Antebi, Adam

doi:10.1101/gad.312604

Cited by 122 publications

(140 citation statements)

References 60 publications

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“…1A). All LBD fusions were expressed at similar levels; moreover, the LBDs of NHR-3, NHR-14, NHR-31, NHR-35, and NHR-64 homodimerized (data not shown), and the DAF-12-LBD interacted with the corepressor DIN-1S (Ludewig et al 2004), suggesting that these LBDs assume their functional conformations. Taken together, these data imply that association of with MDT-15 is selective and may be biologically significant.…”

Section: Specific Interaction Between Nhr-49 and Mdt-15mentioning

confidence: 94%

A Mediator subunit, MDT-15, integrates regulation of fatty acid metabolism by NHR-49-dependent and -independent pathways inC. elegans

Taubert¹,

Gilst²,

Hansen³

et al. 2006

Genes Dev.

234

312

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Section: Specific Interaction Between Nhr-49 and Mdt-15mentioning

confidence: 94%

A Mediator subunit, MDT-15, integrates regulation of fatty acid metabolism by NHR-49-dependent and -independent pathways inC. elegans

Taubert¹,

Gilst²,

Hansen³

et al. 2006

Genes Dev.

234

312

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“…However, daf-12(0) mutants develop almost normally (9), suggesting that the role for DAF-12 in developmental timing is modulatory rather than essential. We reasoned that the daf-12(rh61) mutation, encoding a DAF-12 protein lacking the ligand-binding domain (11,13), would result in DAF-12 acting as a constitutive repressor of let-7-Fam miRNA expression. Indeed daf-12(rh61) animals exhibit developmental timing defects similar to those of let-7-Fam compound mutants (8,9).…”

Section: Resultsmentioning

confidence: 99%

“…In favorable culture conditions, DA ligand is abundant, and liganded DAF-12 activates transcription. In harsh environments, DA production is dramatically reduced, so most DAF-12 is unliganded and hence free to bind the corepressor DIN-1S (10,11). The DAF-12:DIN-1 repressive complex is required for dauer formation.…”

mentioning

confidence: 99%

“…Direct binding of an endogenous steroid ligand, dafachronic acid (DA), modulates the activity of DAF-12 protein (10). Synthesis of DA ligand is coupled to environmental conditions (5), and DA regulates DAF-12 activity by binding and displacing a corepressor DIN-1S (10,11). In favorable culture conditions, DA ligand is abundant, and liganded DAF-12 activates transcription.…”

mentioning

confidence: 99%

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A feedback circuit involving let-7-family miRNAs and DAF-12 integrates environmental signals and developmental timing in Caenorhabditis elegans

Hammell

Karp

Ambros

2009

Proc. Natl. Acad. Sci. U.S.A.

152

149

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Animal development is remarkably robust; cell fates are specified with spatial and temporal precision despite physiological and environmental contingencies. Favorable conditions cause Caenorhabditis elegans to develop rapidly through four larval stages (L1-L4) to the reproductive adult. In unfavorable conditions, L2 larvae can enter the developmentally quiescent, stress-resistant dauer larva stage, enabling them to survive for prolonged periods before completing development. A specific progression of cell division and differentiation events occurs with fidelity during the larval stages, regardless of whether an animal undergoes continuous or dauer-interrupted development. The temporal patterning of developmental events is controlled by the heterochronic genes, whose products include microRNAs (miRNAs) and regulatory proteins. One of these proteins, the DAF-12 nuclear hormone receptor, modulates the transcription of certain let-7-family miRNAs, and also mediates the choice between the continuous vs. dauer-interrupted life history. Here, we report a complex feedback loop between DAF-12 and the let-7-family miRNAs involving both the repression of DAF-12 by let-7-family miRNAs and the ligandmodulated transcriptional activation and repression of the let-7-Fam miRNAs by DAF-12. We propose that this feedback loop functions to ensure robustness of cell fate decisions and to coordinate cell fate with developmental arrest.gene regulation ͉ microRNA ͉ nuclear hormone receptor T he complexity of animal development requires the coordination of temporal, spatial, and physiological cues. Successful development is necessary to achieve optimal fitness, and natural selection has favored developmental programs that robustly produce a desired outcome in a range of physiological and environmental conditions. Forward genetics has revealed much of the internal programming of several developmental processes in standardized laboratory conditions. A fundamental question emerging from these studies is how these genetic circuits are affected by conditions that are more similar to natural, variable environments. Caenorhabditis elegans has been an excellent system to uncover developmental mechanisms because of its well-defined cell lineage and tractability to genetic analysis. C. elegans development is robust in a wide range of environmental conditions, providing an excellent opportunity to determine how genetic pathways are modulated in these diverse environments (1).There are two distinct life histories a C. elegans larva may follow: a rapid, continuous life history that occurs in favorable environments and an extended, interrupted life history (2) that occurs in response to increased population density, decreasing food supplies, and elevated temperature (Fig. 1) (3). Within the continuous life history, animals progress through four larval stages (L1-L4) to a reproductively competent adult within Ϸ40-50 h after hatching (4). By contrast, unfavorable environments sensed during L1 stage cause larvae to enter the predauer L2d stage, which is ...

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“…A number of components downstream of DAF-16 have been shown to influence metabolism and life span. These include the DAF-12 nuclear hormone receptor [34] and its coregulator DIN-1 [35], and the DAF-15 regulator of TOR (homologue of mammalian Raptor) [36]. These factors conceivably represent points of convergence of signaling by glucose/insulin, lipophilic factors and amino acid limitation-sensing factors.…”

Section: Spanmentioning

confidence: 99%

Metabolic Reprogramming in Dietary Restriction

Anderson

Weindruch²

2006

Interdisciplinary Topics in Gerontology

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It is widely accepted that energy intake restriction without essential nutrient deficiency delays the onset of aging and extends life span. The mechanism underlying this phenomenon is still unknown though a number of different, nonmutually exclusive explanations have been proposed. In each of these, different facets of physiology play the more significant role in the mechanism of aging retardation. Some examples include the altered lipid composition model, the immune response model and models describing changes in endocrine function. In this paper we propose the hypothesis that metabolic reprogramming is the key event in the mechanism of dietary restriction, and the physiological effects at the cellular, tissue and organismal level may be understood in terms of this initial event.Dietary restriction (DR) is the most successful intervention tested to date in mammals which greatly extends maximum life span and keeps animals 'younger longer' [1][2][3]. Consequently, any hypothesis about the etiology of aging must reconcile the effects of DR on aging. With increased knowledge of the mechanism of DR, we stand to gain a considerable insight into the process of aging.We propose that a change in the regulation of energy metabolism in response to DR is the primary step in the retardation of aging ( fig. 1). First we describe the evidence in support of metabolic reprogramming, a switch to an altered metabolic state, by DR in mice. Next we consider evidence for metabolic shifts in other model organisms where life span is extended by DR or by genetic manipulation. Then we focus on changes in mitochondrial energy metabolism with age and DR in mammals. Next we will explore the effects of altered mitochondrial function in the context of reactive oxygen species (ROS) generation and oxidative stress. Finally we describe the metabolic and morphological changes in white adipose tissue that we believe are a result of altered mitochondrial function. We propose that the activation of adipose tissue through metabolic reprogramming is critical to the mechanism of DR and that it leads to the changes in the animal physiology that are described in the models indicated above. Metabolic Reprogramming in Tissues from Dietary-Restricted AnimalsThe inverse linear relationship between calorie intake and life span in mice [4] suggests that genes central to energy metabolism may be critical in the underlying mechanism of DR in

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A novel nuclear receptor/coregulator complex controls C. elegans lipid metabolism, larval development, and aging

Cited by 122 publications

References 60 publications

A Mediator subunit, MDT-15, integrates regulation of fatty acid metabolism by NHR-49-dependent and -independent pathways inC. elegans

A Mediator subunit, MDT-15, integrates regulation of fatty acid metabolism by NHR-49-dependent and -independent pathways inC. elegans

A feedback circuit involving let-7-family miRNAs and DAF-12 integrates environmental signals and developmental timing in Caenorhabditis elegans

Metabolic Reprogramming in Dietary Restriction

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