Neuregulin-4 is an angiogenic factor that is critically involved in the maintenance of adipose tissue vasculature

Nugroho, Dhite Bayu; Ikeda, Koji; Barinda, Agian Jeffilano; Wardhana, Donytra Arby; Yagi, Kazuichi; Miyata, Keishi; Oike, Yuichi; Hirata, Ken‐ichi; Emoto, Noriaki

doi:10.1016/j.bbrc.2018.06.043

Cited by 35 publications

(27 citation statements)

References 26 publications

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“…We have previously reported that adipose tissue (AT) vasculatures are critically involved in fat functions, and consequently play crucial roles in the maintenance of systemic metabolic health [18][19][20] . Adipocytes actively regulate AT angiogenesis by secreting angiogenic factors to maintain AT vasculatures [19][20][21][22][23] . Impaired AT angiogenesis regulation and/or disproportional adipocyte hypertrophy leads to reduction in AT vasculature, resulting in fat dysfunction.…”

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confidence: 99%

Endothelial progeria induces adipose tissue senescence and impairs insulin sensitivity through senescence associated secretory phenotype

et al. 2020

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Vascular senescence is thought to play a crucial role in an ageing-associated decline of organ functions; however, whether vascular senescence is causally implicated in age-related disease remains unclear. Here we show that endothelial cell (EC) senescence induces metabolic disorders through the senescence-associated secretory phenotype. Senescence-messaging secretomes from senescent ECs induced a senescence-like state and reduced insulin receptor substrate-1 in adipocytes, which thereby impaired insulin signaling. We generated EC-specific progeroid mice that overexpressed the dominant negative form of telomeric repeat-binding factor 2 under the control of the Tie2 promoter. EC-specific progeria impaired systemic metabolic health in mice in association with adipose tissue dysfunction even while consuming normal chow. Notably, shared circulation with EC-specific progeroid mice by parabiosis sufficiently transmitted the metabolic disorders into wild-type recipient mice. Our data provides direct evidence that EC senescence impairs systemic metabolic health, and thus establishes EC senescence as a bona fide risk for age-related metabolic disease.

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confidence: 99%

Endothelial progeria induces adipose tissue senescence and impairs insulin sensitivity through senescence associated secretory phenotype

et al. 2020

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“…These data indicate that Nrg4 is a brown/brown‐in‐white (brite) adipokine that is likely to play a crucial role in the sympathetically mediated activation of BAT thermogenesis . Moreover, Nugroho et al reported that Nrg4 exacerbated angiogenic activity and angiogenesis both in vitro and in vivo. Notably, Nrg4 deficiency led to a decrease in BAT and WAT blood vessels and provoked overweight even on a normal chow diet.…”

Section: Discussionmentioning

confidence: 87%

A systematic review of the association of neuregulin 4, a brown fat–enriched secreted factor, with obesity and related metabolic disturbances

et al. 2019

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Neuregulin 4 (Nrg4), a novel brown fat-enriched hormone, plays a key role in the modulation of glucose and lipid metabolism and energy balance. Recent data have demonstrated that the expression of Nrg4 is substantially down-regulated in mouse and human obesity, making its regulatory aspect intriguing. Because of the close relationship between Nrg4, obesity, and associated metabolic diseases, this systematic review aimed to assess the association of Nrg4 with obesity and related metabolic disturbances, emphasizing its possible mechanisms of action in these disorders. We searched PubMed/Medline, ScienceDirect, Scopus, EMBASE, ProQuest, and Google Scholar up until June 2019. The evidence reviewed here indicates that Nrg4 may contribute to the prevention of obesity and related metabolic complications by elevating brown adipose tissue activity, increasing the expression of thermogenic markers, decreasing the expression of lipogenic/ adipogenic genes, exacerbating white adipose tissue browning, increasing the number of brite/beige adipocytes, promoting hepatic fat oxidation and ketogenesis, inducing neurite outgrowth, enhancing blood vessels in adipose tissue, increasing the circulatory levels of healthy adipokines, and improving glucose homeostasis.Thus, Nrg4 appears to be a novel therapeutic strategy for the treatment of obesity and associated metabolic complications. However, prospective cohort studies are warranted to confirm these outcomes.

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“…Its circulating levels were reported to correlate positively, negatively, or not at all with adiposity and markers of insulin resistance (206)(207)(208)(209)(210)(211), yielding a rather unclear picture of its behavior. NRG4-deficient mice fed a high-fat diet display increased body weight gain, decreased WAT and BAT vessel density, increased WAT inflammation, liver steatosis, and impaired glucose tolerance and insulin sensitivity (201,204,205). While similar effects occur in high-fatchallenged ErbB4-deficient mice, opposite effects can be achieved by adipocyte-or hepatocyte-specific overexpression of NRG4 (201,203,204,212,213).…”

Section: Neuregulinmentioning

confidence: 99%

“…It signals through the EGF receptor 4 (ErbB4) that is expressed by a wide range of cells (200,201). NRG4 is expressed in WAT and BAT where its production increases upon cold exposure and decreases with obesity (201)(202)(203)(204)(205). Its circulating levels were reported to correlate positively, negatively, or not at all with adiposity and markers of insulin resistance (206)(207)(208)(209)(210)(211), yielding a rather unclear picture of its behavior.…”

Section: Neuregulinmentioning

confidence: 99%

Beyond adiponectin and leptin: adipose tissue-derived mediators of inter-organ communication

Funcke

Scherer

2019

Journal of Lipid Research

237

165

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Neuregulin-4 is an angiogenic factor that is critically involved in the maintenance of adipose tissue vasculature

Cited by 35 publications

References 26 publications

Endothelial progeria induces adipose tissue senescence and impairs insulin sensitivity through senescence associated secretory phenotype

Endothelial progeria induces adipose tissue senescence and impairs insulin sensitivity through senescence associated secretory phenotype

A systematic review of the association of neuregulin 4, a brown fat–enriched secreted factor, with obesity and related metabolic disturbances

Beyond adiponectin and leptin: adipose tissue-derived mediators of inter-organ communication

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