GDF15 Is an Inflammation-Induced Central Mediator of Tissue Tolerance

Luan, Harding H.; Wang, Andrew; Hilliard, Brandon; Carvalho, F.; Rosen, Connor; Ahasic, Amy M.; Herzog, Erica L.; Kang, Insoo; Pisani, Margaret A.; Yu, Shuang; Zhang, Cuiling; Ring, Aaron M.; Young, Lawrence H.; Medzhitov, Ruslan

doi:10.1016/j.cell.2019.07.033

Cited by 371 publications

(406 citation statements)

References 67 publications

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“…As pointed out by Breit et al there is the possibility that GDF15 effects on other cells or tissues could be mediated by a soluble form of GFRAL resulting from an alternative transcript which lacks transmembrane and cytoplasmatic domains. In contrast, it has been demonstrated previously in several studies that GFRAL is not expressed in WAT depots . However, we cannot rule out a possible direct GDF15‐dependent muscle–adipose tissue crosstalk, independent of a GFRAL receptor signaling.…”

Section: Discussioncontrasting

confidence: 77%

Muscle‐derived GDF15 drives diurnal anorexia and systemic metabolic remodeling during mitochondrial stress

et al. 2020

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Mitochondrial dysfunction promotes metabolic stress responses in a cell‐autonomous as well as organismal manner. The wasting hormone growth differentiation factor 15 (GDF15) is recognized as a biomarker of mitochondrial disorders, but its pathophysiological function remains elusive. To test the hypothesis that GDF15 is fundamental to the metabolic stress response during mitochondrial dysfunction, we investigated transgenic mice (Ucp1‐TG) with compromised muscle‐specific mitochondrial OXPHOS capacity via respiratory uncoupling. Ucp1‐TG mice show a skeletal muscle‐specific induction and diurnal variation of GDF15 as a myokine. Remarkably, genetic loss of GDF15 in Ucp1‐TG mice does not affect muscle wasting or transcriptional cell‐autonomous stress response but promotes a progressive increase in body fat mass. Furthermore, muscle mitochondrial stress‐induced systemic metabolic flexibility, insulin sensitivity, and white adipose tissue browning are fully abolished in the absence of GDF15. Mechanistically, we uncovered a GDF15‐dependent daytime‐restricted anorexia, whereas GDF15 is unable to suppress food intake at night. Altogether, our evidence suggests a novel diurnal action and key pathophysiological role of mitochondrial stress‐induced GDF15 in the regulation of systemic energy metabolism.

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Section: Discussioncontrasting

confidence: 77%

Muscle‐derived GDF15 drives diurnal anorexia and systemic metabolic remodeling during mitochondrial stress

et al. 2020

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“…The availability of fatty acids and triglycerides appears essential to support metabolic demands of parenchymal tissues and promote tolerance during the disease state. For instance, plasma triglycerides are essential to exit from the initial hypometabolic-hypodermic state in septic LPS-injected mice [13] and safeguarding the lower limit of plasma triglycerides is also essential to maintain body temperature, cardiac, and renal function [20]. These findings highlight the importance of integrating immune and parenchymal tissues metabolic demands during the disease state to promote disease tolerance.…”

Section: Metabolic Substrates Utilization and Disease Tolerancementioning

confidence: 99%

“…The lower plasma levels of energetic substrates need to be regulated by the liver both under homeostatic conditions and during sepsis, and the timely control of metabolic substrates utilization appears a major goal of tolerance mechanisms. Both hepatic gluconeogenesis [21] and triglycerides production [20] are essential to promote disease tolerance in mouse models of LPS‐induced sepsis. Mechanistically, the wiring of the circuits that control these processes in the disease state is different from that of the homeostatic basal condition.…”

Section: Introductionmentioning

confidence: 99%

Crossroads between immune responses and physiological regulation: Metabolic control of resistance versus tolerance against disease

Pucillo

Vitale

2020

Eur J Immunol

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If a threat cannot be avoided, the organism has two defense options: it can try to eliminate the threatening agent or boost physiological mechanisms to tolerate the challenge and its consequences. Both strategies can be (and usually are) used at the same time. Fighting an infection, for instance, requires mounting immune responses to control pathogen burden as well as physiologic adaptations to tolerate stress and damage. Thus, the two strategies are connected and interdependent. We are starting to understand how the regulation of host metabolic physiology during disease impacts both the ability to resist pathogens’ burden and tolerate parenchymal tissue functional damage. Here, we review a number of recent publications that have begun to shed light on the physiological and immunological mechanisms that coordinate host defense and metabolic processes. In particular, we will cover the areas of energetic control, substrates utilization, and the regulatory signals that promote infectious disease tolerance.

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“…One such putative region is approximately 11kb upstream of GDF15, which is well-characterized p53 target gene (2,51). GDF15 has also recently been identified as a key modulator of the inflammatory and metabolic responses (52,53). This region is enriched with the histone modifications H3K27ac and H3K4me2 and depleted for H3K4me3, a pattern strongly associated with transcriptional CREs.…”

Section: P53-dependent Transcription Of Gdf15 Requires Regulatory Facmentioning

confidence: 99%

“…6C). We therefore focused on ATF3 because of its previous association as a positive regulator of p53 activity and its well-known role as a modulator of the inflammatory response (26,(56)(57)(58), of which GDF15 is a central regulator (53). Using a luciferase reporter approach, we assessed the activity of the GDF15 E1 enhancer in wild-type, p53-deficient, or ATF3-deficient HCT116 cells.…”

Section: P53-dependent Transcription Of Gdf15 Requires Regulatory Facmentioning

confidence: 99%

Locally acting transcription factors are required for p53-dependent cis-regulatory element activity

Catizone

Uzunbas

Celadova

et al. 2019

Preprint

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The master tumor suppressor p53 controls transcription of a wide-ranging gene network involved in apoptosis, cell cycle arrest, DNA damage repair, and senescence. Recent studies revealed pervasive binding of p53 to cis-regulatory elements (CRE), which are non-coding segments of DNA that spatially and temporally control transcription through the combinatorial binding of local transcription factors (TFs). Although the role of p53 as a strong trans-activator of gene expression is well known, the coregulatory factors and local sequences acting at p53-bound CREs are comparatively understudied. We designed and executed a massively parallel reporter assay (MPRA) to investigate the effect of transcription factor binding motifs and local sequence context on p53-bound CRE activity. Our data indicate that p53-bound CREs are both positively and negatively affected by alterations in local sequence context and changes to co-regulatory TF motifs. We identified a SP1/KLF family motif located in an intronic p53 CRE that is required for the endogenous expression of the p53-dependent gene CCNG1. We also identified ATF3 as a factor that co-regulates the expression of the p53-dependent gene GDF15 through binding with p53 in an upstream CRE. Loss of either p53 or ATF3 severely reduces CRE activity and alters endogenous GDF15 mRNA levels in the cell. Our data suggests that p53 has the flexibility to cooperate with a variety of transcription factors in order to regulate CRE activity. By utilizing different sets of co-factors across CREs, we hypothesize that p53 activity is guarded against loss of any one regulatory partner allowing for dynamic and redundant control of p53mediated transcription.Recent evidence suggests that sequence variation within cis-regulatory elements (CREs) can influence p53 binding, transcriptional activity, and tumor suppressor function (5-7) . The critical nature of the core p53 response element (p53RE) on p53 binding and CRE activity is well understood (8-10), but the influence of local sequence variation and the role of transcription factor motifs outside of the p53RE on p53 activity remains an open and vital question.Cis-regulatory elements, such as promoters and enhancers, govern gene expression through temporal, spatial, and quantitative control of transcription (11,12). While multiple models for CRE function have been proposed, the majority involve cooperative binding and activity of multiple transcription factors and cofactors acting locally to fine-tune gene expression (11)(12)(13). The presence and availability of transcription factors, repressors, and other cofactors vary across cell states such as development, stress, disease, and cell type (14-17). This variability provides a mechanism for differential CRE activity and downstream gene expression. Loss of transcription factor binding within a CRE, through variation in DNA sequence or through changes in trans-factor availability, can strongly influence CRE activity and gene expression (11,12,18), with direct implications in numerous developmental and d...

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GDF15 Is an Inflammation-Induced Central Mediator of Tissue Tolerance

Cited by 371 publications

References 67 publications

Muscle‐derived GDF15 drives diurnal anorexia and systemic metabolic remodeling during mitochondrial stress

Muscle‐derived GDF15 drives diurnal anorexia and systemic metabolic remodeling during mitochondrial stress

Crossroads between immune responses and physiological regulation: Metabolic control of resistance versus tolerance against disease

Locally acting transcription factors are required for p53-dependent cis-regulatory element activity

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