Activin E Controls Energy Homeostasis in Both Brown and White Adipose Tissues as a Hepatokine

Hashimoto, Osamu; Funaba, Masayuki; Sekiyama, Kazunari; Doi, Satoru; Shindo, Daichi; Satoh, Ryohei; Itoi, Hiroshi; Oiwa, Hiroaki; Morita, Masahiro; Suzuki, Chisato; Sugiyama, Makoto; Yamakawa, Noriko; Takada, Hitomi; Matsumura, Shigenobu; Inoue, Kazuo; Oyadomari, Seiichi; Sugino, Hiromu; Kurisaki, Akira

doi:10.1016/j.celrep.2018.10.008

Cited by 61 publications

(55 citation statements)

References 39 publications

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“…Additionally, the SNP associated putative hepatokine Inhbe was positively confirmed in all performed validation experiments. This is in line with previous reports identifying Inhbe as diet-responsive gene in the rodent liver, regulated by HFD feeding, fasting or re-feeding [27–29]. Recently, Sugiyama et al [23] demonstrated that the siRNA-mediated knockdown of Inhbe in obese insulin resistant Lep db mice decreased fat mass and respiratory quotient thus suggesting enhanced whole-body fat utilization.…”

Section: Discussionsupporting

confidence: 90%

Correlation guided Network Integration (CoNI) reveals novel genetic regulators of hepatic metabolism

Vs¹,

Kuhn

et al. 2020

Preprint

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ABSTRACTThe steadily increasing amount of newly generated omics data of various types from genomics to metabolomics is a chance and a challenge to systems biology. To fully use its potential, one key is the meaningful integration of different types of omics. We here present a fully unsupervised and versatile correlation-based method, termed Correlation guided Network Integration (CoNI), to integrate multi-omics data into a hypergraph structure that allows for identification of effective regulators. Our approach further unravels single transcripts mapped to specific densely connected metabolic sub-graphs or pathways. By applying our method on transcriptomics and metabolomics data from murine livers under standard chow or high-fat-diet, we isolated eleven genes with a regulatory effect on hepatic metabolism. Subsequent in vitro and ex vivo experiments in human liver cells and human obtained liver biopsies validated seven candidates including INHBE and COBLL1, to alter lipid metabolism and to correlate with diabetes related traits such as overweight, hepatic fat content and insulin resistance (HOMA-IR). Last, we successfully applied our methods to an independent data-set to confirm its versatile and transferable character.

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Section: Discussionsupporting

confidence: 90%

Correlation guided Network Integration (CoNI) reveals novel genetic regulators of hepatic metabolism

Vs¹,

Kuhn

et al. 2020

Preprint

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“…These proteins, often termed hepatokines, are secreted by the liver and mediate interorgan communication through autocrine, paracrine, and endocrine signaling (8,16). Several hepatokines have been identified including fetuin A (17), fetuin B (18), fibroblast growth factor 21 (FGF21) (19), fibrinogen-like protein 1 (FGL1, also known as hepassocin) (20), follistatin (FST) (21)(22)(23), inhibin βE (INHBE) (24,25), leukocyte cell-derived chemotaxin 2 (LECT2) (26), retinol-binding protein 4 (RBP4) (27,28), and selenoprotein P (SEPP1) (29). These hepatokines, whose expression is affected by conditions such as obesity and NAFLD, impact various organs to modulate glucose metabolism, lipid homeostasis, and inflammation.…”

Section: Introductionmentioning

confidence: 99%

The hepatokine Tsukushi is released in response to NAFLD and impacts cholesterol homeostasis

Mouchiroud¹,

Camiré²,

Aldow³

et al. 2019

JCI Insight

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“…as an important modulator of adipocyte browning and insulin sensitivity [28]. Further research is needed to test whether hepatic expression profile correlates with the circulating level of these hormones and to investigate the clinical relevance of these observations.…”

Section: Discussionmentioning

confidence: 99%

Regulation of hepatokine gene expression in response to fasting and feeding: Influence of PPAR-α and insulin-dependent signalling in hepatocytes

Smati

Régnier

Fougeray

et al. 2020

Diabetes & Metabolism

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Aim.-In hepatocyte, PPARa and insulin receptor (IR) are critical for the transcriptional responses to fasting and feeding, respectively. Here we analyzed the effects of the nutritional status (fasting vs feeding) on the expression of a large panel of hepatokines in hepatocytespecific PPARa (Ppara hep−/−) and IR (IR hep−/−) null mice. Methods.-Ppara hep−/− , and IR hep−/− mice and their wild-type littermate were subjected to fasting or feeding metabolic challenges, and then analyzed for hepatokine gene expression. Experiments were conducted in mice of both sexes. Results.-Our data confirmed that PPARa is critical for regulating fasting-induced Fgf21 and Angptl4 expression. In mice lacking PPARa, fasting led to an increased Igfbp1 and Gdf15 expression. In the absence of hepatic IR, feeding induced overexpression of Igfbp1, follistatin (Fst), and adropin (Enho). We also observed reduced activin E (Inhbe) expression in IR hep−/− mice. Sex only had a modest influence on hepatokine gene expression in the liver. Conclusion.-The present results highlight the potential roles of hepatokines as a class of hormones that substantially influence nutritional regulation in both females and males.

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Activin E Controls Energy Homeostasis in Both Brown and White Adipose Tissues as a Hepatokine

Cited by 61 publications

References 39 publications

Correlation guided Network Integration (CoNI) reveals novel genetic regulators of hepatic metabolism

Correlation guided Network Integration (CoNI) reveals novel genetic regulators of hepatic metabolism

The hepatokine Tsukushi is released in response to NAFLD and impacts cholesterol homeostasis

Regulation of hepatokine gene expression in response to fasting and feeding: Influence of PPAR-α and insulin-dependent signalling in hepatocytes

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