Ribonuclease-Mediated Control of Body Fat

Habacher, Cornelia; Guo, Yanwu; Venz, Richard; Kumari, Pooja; Neagu, Anca; Gaidatzis, Dimos; Harvald, Eva Bang; Færgeman, Nils J.; Gut, H.; Ciosk, Rafal

doi:10.1016/j.devcel.2016.09.018

Cited by 37 publications

(82 citation statements)

References 46 publications

(60 reference statements)

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“…Younce and collaborators showed that MCPIP has a strong differentiation potential and can induce adipogenesis without activity of PPARγ [34]. Similarly, Habacher et al demonstrated that C. elegans, when adapted to stressful conditions caused by decreasing temperature, overexpresses REGE-1, a protein exhibiting close homology to MCPIP1 [35]. This protein controls body fat by targeting the 3′ UTR of an mRNA encoding a fat-loss-promoting transcription factor, ETS-4.…”

Section: Discussionmentioning

confidence: 97%

Integrative genomics reveal a role for MCPIP1 in adipogenesis and adipocyte metabolism

Losko

Dolicka

Pydyn

et al. 2019

Cell. Mol. Life Sci.

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Obesity is considered a serious chronic disease, associated with an increased risk of developing cardiovascular diseases, non-alcoholic fatty liver disease and type 2 diabetes. Monocyte chemoattractant protein-1-induced protein-1 (MCPIP1) is an RNase decreasing stability of transcripts coding for inflammation-related proteins. In addition, MCPIP1 plays an important role in the regulation of adipogenesis in vitro by reducing the expression of key transcription factors, including C/EBPβ. To elucidate the role of MCPIP1 in adipocyte biology, we performed RNA-Seq and proteome analysis in 3T3-L1 adipocytes overexpressing wild-type ( WT MCPIP1) and the mutant form of MCPIP1 protein ( D141N MCPIP1). Our RNA-Seq analysis followed by confirmatory Q-RT-PCR revealed that elevated MCPIP1 levels in 3T3-L1 adipocytes upregulated transcripts encoding proteins involved in signal transmission and cellular remodeling and downregulated transcripts of factors involved in metabolism. These data are consistent with our proteomic analysis, which showed that MCPIP1 expressing adipocytes exhibit upregulation of proteins involved in cellular organization and movement and decreased levels of proteins involved in lipid and carbohydrate metabolism. Moreover, MCPIP1 adipocytes are characterized by decreased level of insulin receptor, reduced insulin-induced Akt phosphorylation, as well as depleted Glut4 level and impaired glucose uptake. Overexpression of Glut4 in 3T3-L1 cells expressed WT MCPIP1 rescued adipogenesis. Interestingly, we found decreased level of MCPIP1 along with an increase in body mass index in subcutaneous adipose tissue. The presented data show a novel role of MCPIP1 in modulating insulin sensitivity in adipocytes. Overall, our findings demonstrate that MCPIP1 is an important regulator of adipogenesis and adipocyte metabolism.Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Section: Discussionmentioning

confidence: 97%

Integrative genomics reveal a role for MCPIP1 in adipogenesis and adipocyte metabolism

Losko

Dolicka

Pydyn

et al. 2019

Cell. Mol. Life Sci.

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“…As outlined above, pale phenotypes are often associated with lipid storage defects in worms 25,27 . Nile Red staining indeed showed a reduction in lipid content in ptc-3(RNAi) animals ( Fig.…”

Section: Ptc-3 Has Cell Autonomous and Non-autonomous Functions And Imentioning

confidence: 99%

Patched regulates lipid homeostasis by controlling cellular cholesterol levels

Castillo

Hannich

Kaech

et al. 2019

Preprint

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words)Hedgehog (Hh) signaling is essential during development and in organ physiology. In the canonical pathway, Hh binding to Patched (PTCH) relieves the inhibition of Smoothened (SMO). Yet, PTCH may also perform SMO-independent functions. While the PTCH homolog PTC-3 is essential in C. elegans, worms lack SMO, providing an excellent model to probe non-canonical PTCH function. Here, we show that PTC-3 is a cholesterol transporter. ptc-3(RNAi) leads to accumulation of intracellular cholesterol and defects in ER structure and lipid droplet formation. These phenotypes were accompanied by a reduction in acyl chain (FA) length and desaturation. ptc-3(RNAi)induced lethality, fat storage and ER morphology defects were rescued by reducing dietary cholesterol. We provide evidence that cholesterol accumulation modulates the function of nuclear hormone receptors such as of the PPARa homolog NHR-49 and NHR-181, and affects FA composition. Our data uncover a novel role for PTCH in organelle structure maintenance and fat metabolism.No clear SMO homolog is encoded in the genome. In addition, some of the other downstream targets of the canonical Hh signaling pathway are also missing. In fact, it was proposed that SMO and those components were specifically lost during evolution in nematodes 15,21-23 . For example, SUFU is not conserved and the homolog of the transcription factor Gli, TRA-1, is involved in sex determination and gonad development in males and hermaphrodites 24 . Therefore, C. elegans provides an excellent model to study non-canonical, SMO-independent Hh signaling pathways, in particular in somatic tissues. To dissect SMO-independent PTCH functions, we concentrated on PTC-3, which is expressed in somatic tissues, in particular in the hypodermis, glia and gut 20 . We found that reduction of PTC-3 levels causes the accumulation of intracellular cholesterol and reduction in poly unsaturated fatty acids (PUFAs). Moreover, the endoplasmic reticulum lost most of its reticulate tubular form and developed elaborate sheet structures in the intestine. This effect in turn strongly impaired lipid droplet biogenesis, resulting in the inability of the animal to store fat.Reduction of dietary cholesterol rescued fat storage defects, the ER morphology defects, and improved development and survival in ptc-3(RNAi) animals. Cholesterol levels influence nuclear hormone receptor activity such as of the PPARa homolog NHR-49, which is involved in the regulation of FA synthesis. Thus, our data demonstrate that PTCH also controls intracellular cholesterol levels in C. elegans.Moreover, we show that PTCH thereby impinges on FA metabolism, organellar structure and fat storage capacity.

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“…transformed. We specifically chose to not use reads overlapping intronic sequences for this analysis as they can reflect changes in mRNA transcription (Habacher et al, 2016) and thus would potentially complicate the interpretation of those results in the light of alternative splicing.…”

Section: Processing Of the Rna-seq And Chip-seq Datamentioning

confidence: 99%

LSM2-8 and XRN-2 contribute to the silencing of H3K27me3-marked genes through targeted RNA decay

Mattout

Gaidatzis

Padeken

et al. 2019

Preprint

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SummaryIn fission yeast and plants, RNA-processing pathways contribute to constitutive and facultative heterochromatin silencing, complementing well-characterized pathways of transcriptional repression. However, it was unclear whether this additional level of regulation occurs in metazoans. Here we describe a pathway of silencing in C. elegans somatic cells, in which the highly conserved, RNA binding complex LSM2-8 selectively silences heterochromatic reporters and endogenous genes bearing the Polycomb mark H3K27me3. Importantly, the LSM2-8 complex works cooperatively with XRN-2, a 5’-3’ exoribonuclease, and disruption of the pathway leads to mRNA stabilization. This selective LSM2-8-mediated RNA degradation does not target nor depend on H3K9me2/me3, unlike previously described pathways of heterochromatic RNA degradation. Intriguingly, the loss of LSM2-8 coincides with a localized drop in H3K27me3 levels on lsm-8-sensitive loci only. Together this defines a mechanism of RNA degradation that selectively targets a subset of H3K27me3-marked genes, revealing an unrecognized layer of regulation for facultative heterochromatin in animals.

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Ribonuclease-Mediated Control of Body Fat

Cited by 37 publications

References 46 publications

Integrative genomics reveal a role for MCPIP1 in adipogenesis and adipocyte metabolism

Integrative genomics reveal a role for MCPIP1 in adipogenesis and adipocyte metabolism

Patched regulates lipid homeostasis by controlling cellular cholesterol levels

LSM2-8 and XRN-2 contribute to the silencing of H3K27me3-marked genes through targeted RNA decay

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