NRG1-Fc improves metabolic health via dual hepatic and central action

Zhang, Peng; Kuang, Henry; He, Yanlin; Idiga, Sharon O.; Li, Siming; Chen, Zhimin; Zhao, Yanzhi; Cai, Xing; Zhang, Kezhong; Potthoff, Matthew J.; Xu, Yong; Lin, Jiandie D.

doi:10.1172/jci.insight.98522

Cited by 44 publications

(57 citation statements)

References 38 publications

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“…While circulating NRG1 has previously been shown to act directly on the central nervous system [22,55] , liver [36,55] , skeletal muscle [56] , and cardiac muscle [24] here we propose an additional site of action within adipose tissues. We present a model that Type III NRG1 is epigenetically regulated and endogenously produced within adipose as a molecular rheostat controlling adipose expandability.…”

Section: Discussionmentioning

confidence: 64%

Epigenetic regulation of Neuregulin-1 tunes white adipose stem cell differentiation

Cordero

Callihan

Said

et al. 2020

Preprint

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AbstractExpansion of subcutaneous adipose tissue by differentiation of new adipocytes has been linked to improvements in metabolic health. However, an expandability limit has been observed wherein new adipocytes cannot be produced, the existing adipocytes become enlarged (hypertrophic) and lipids spill over into ectopic sites. Inappropriate ectopic storage of these surplus lipids in liver, muscle, and visceral depots has been linked with metabolic dysfunction. Here we show that Neuregulin-1 (NRG1) serves as a regulator of adipogenic differentiation in subcutaneous primary human stem cells. We further demonstrate that DNA methylation modulates NRG1 expression in these cells, and a 3-day exposure of stem cells to a recombinant NRG1 peptide fragment is sufficient to reprogram adipogenic cellular differentiation to higher levels. These results define a novel molecular adipogenic rheostat with potential implications for the expansion of adipose tissue in vivo.

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Section: Discussionmentioning

confidence: 64%

Epigenetic regulation of Neuregulin-1 tunes white adipose stem cell differentiation

Cordero

Callihan

Said

et al. 2020

Preprint

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“…EGF binds EGFR to induce lipogenesis in the liver, and increase TG secretion (Scheving et al, 2014). NRG1 acts on ErbB3 and/or ErbB4 to inhibit gluconeogenesis in the liver (Ennequin et al, 2015;Zhang et al, 2018), and to increase glucose uptake and oxidative phosphorylation in myotubes (Canto et al, 2004(Canto et al, , 2007Suárez et al, 2001). NRG1 also decrease food intake by acting on ErbB4 in the brain (Ennequin et al, 2015;Zhang et al, 2018).…”

Section: Epidermal Growth Factormentioning

confidence: 99%

“…Thus, global deletion of NRG1 results in embryonic lethality, while knockouts of NRG2-4 develop normally (Meyer and Birchmeier, 1995;Britto et al, 2004;Hayes et al, 2016). More recently, several lines of evidence point to a role of NRGs in the control of metabolism via actions on muscle, liver, adipose tissue and the hypothalamus Zhang et al, 2018). The four NRG genes encode for several isoforms, most of which contain a transmembrane domain and an N-terminal extracellular EGF-like domain (Burden and Yarden, 1997).…”

Section: The Neuregulinsmentioning

confidence: 99%

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Regulation of Energy Metabolism by Receptor Tyrosine Kinase Ligands

et al. 2020

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Integrative Physiology, a section of the journal Frontiers in PhysiologyMetabolic diseases, such as diabetes, obesity, and fatty liver disease, have now reached epidemic proportions. Receptor tyrosine kinases (RTKs) are a family of cell surface receptors responding to growth factors, hormones, and cytokines to mediate a diverse set of fundamental cellular and metabolic signaling pathways. These ligands signal by endocrine, paracrine, or autocrine means in peripheral organs and in the central nervous system to control cellular and tissue-specific metabolic processes. Interestingly, the expression of many RTKs and their ligands are controlled by changes in metabolic demand, for example, during starvation, feeding, or obesity. In addition, studies of RTKs and their ligands in regulating energy homeostasis have revealed unexpected diversity in the mechanisms of action and their specific metabolic functions. Our current understanding of the molecular, biochemical and genetic control of energy homeostasis by the endocrine RTK ligands insulin, FGF21 and FGF19 are now relatively well understood. In addition to these classical endocrine signals, non-endocrine ligands can govern local energy regulation, and the intriguing crosstalk between the RTK family and the TGFβ receptor family demonstrates a signaling network that diversifies metabolic process between tissues. Thus, there is a need to increase our molecular and mechanistic understanding of signal diversification of RTK actions in metabolic disease. Here we review the known and emerging molecular mechanisms of RTK signaling that regulate systemic glucose and lipid metabolism, as well as highlighting unexpected roles of non-classical RTK ligands that crosstalk with other receptor pathways.

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“…Nrg4 acts via paracrine, autocrine or endocrine mechanisms by releasing the epidermal growth factor (EGF)-like domain after photolytic cleavage [3,4]. Numerous studies showed that decreased Nrg4 levels were closely associated with obesity, insulin resistance, diabetes mellitus, dyslipidemia, metabolic syndrome, non-alcoholic fatty liver disease, inflammation, oxidative stress, and macrovascular disease such as coronary artery disease, myocardial infarcts, subclinical cardiovascular disease (CVD) in rodents and humans [3,[5][6][7][8][9][10][11][12][13][14][15], while all above factors have been reported to contribute to the development of DNP [1-3, 16, 17], suggesting indirectly that Nrg4 appears to play a crucial role in the development of DNP.…”

mentioning

confidence: 99%

Changes of circulating neuregulin 4 and its relationship with 25-hydroxy vitamin D and other diabetic vascular complications in patients with diabetic peripheral neuropathy

Yan

Miao

et al. 2020

Diabetol Metab Syndr

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Background: Neuregulin 4 (Nrg4) is a novel neurotrophic adipokine associated with the development of diabetic peripheral neuropathy (DPN), however, the pathological mechanism remains poorly understood. The purpose of our study was to investigate the association of circulating Nrg4 with DPN and 25-hydroxy vitamin D [25(OH)D], a multifunctional secosteroid hormone that regulates other neurotrophic factors and adipokines gene expression, and other diabetic vascular complications. Methods: Circulating Nrg4 levels were measured with an ELISA kit in 164 newly diagnosed type 2 diabetes mellitus (nT2DM) patients. The relationship between circulating Nrg4 and DPN and other parameters was analyzed. Results: Circulating Nrg4 levels were significantly lower in nT2DM patients with DPN than those without, and subjects in the highest quartile of circulating Nrg4 had significantly lower vibration perception threshold (VPT), the prevalence of DPN, the proportion of persons with VPT > 25 V, and significantly higher circulating 25(OH)D (all P < 0.01). Moreover, circulating Nrg4 was positively and independently associated with 25(OH)D, and was negatively with VPT (P < 0.01 or P < 0.05), but showed no associations with the prevalence of peripheral arterial disease, diabetic nephropathy, and diabetic retinopathy (all P > 0.05). Additionally,the prevalence of DPN and risk of DPN development were progressively decreased with increasing circulating Nrg4 quartiles, independently of potential confounding factors. Conclusions: These data demonstrate that decreased levels of circulating Nrg4 might lead to the development of DPN through its close interaction with circulating 25(OH)D not with other diabetic vascular complications. Further prospective studies are needed to identify our findings in these populations.

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NRG1-Fc improves metabolic health via dual hepatic and central action

Cited by 44 publications

References 38 publications

Epigenetic regulation of Neuregulin-1 tunes white adipose stem cell differentiation

Epigenetic regulation of Neuregulin-1 tunes white adipose stem cell differentiation

Regulation of Energy Metabolism by Receptor Tyrosine Kinase Ligands

Changes of circulating neuregulin 4 and its relationship with 25-hydroxy vitamin D and other diabetic vascular complications in patients with diabetic peripheral neuropathy

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