Adipocyte-secreted BMP8b mediates adrenergic-induced remodeling of the neuro-vascular network in adipose tissue

Pellegrinelli, Vanessa; Peirce, Vivian; Howard, Laura; Virtue, Samuel; Türei, Dénes; Senzacqua, Martina; Frontini, Andrea; Dalley, Jeffrey W.; Horton, Antony R.; Bidault, Guillaume; Severi, Ilenia; Whittle, Andrew J.; Rahmouni, Kamal; Sáez-Rodríguez, Julio; Cinti, Saverio; Davies, Alun M.; Vidal-Puig, António

doi:10.1038/s41467-018-07453-x

Cited by 100 publications

(85 citation statements)

References 62 publications

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“…Of these four candidates, only Bmp8b has been studied in brown adipose. It is secreted by brown adipocytes and amplifies the thermogenic response of cells by increasing sensitivity to adrenergic input [91,92].…”

Section: Discussionmentioning

confidence: 99%

Genetic background and diet affect brown adipose gene co-expression – metabolic associations

Carson

Lawson

2019

Preprint

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28 Adipose is a dynamic endocrine organ that is critical for regulating metabolism and is highly 29 responsive to nutritional environment. Brown adipose tissue is an exciting potential therapeutic 30 target, however there are no systematic studies of gene-by-environment interactions affecting 31 function of this organ. We leveraged a weighted gene co-expression network analysis to identify 32 transcriptional networks in brown adipose tissue from LG/J and SM/J inbred mice fed high or low 33 fat diets, and correlate these networks with metabolic phenotypes. We identified 8 primary gene 34 network modules associated with variation in obesity and diabetes-related traits. Four modules 35 were enriched for metabolically relevant processes such as immune and cytokine response, cell 36 division, peroxisome functions, and organic molecule metabolic processes. The relative 37 expression of genes in these modules is highly dependent on both genetic background and 38 dietary environment. Genes in the immune/cytokine response and cell division modules are 39 particularly highly expressed in high fat-fed SM/J mice, which show unique brown adipose-40 dependent remission of diabetes. The interconnectivity of genes in these modules is also heavily 41 dependent on diet and strain, with most genes showing both higher expression and co-expression 42 under the same context. We highlight 4 candidate genes, Col28a1, Cyp26b1, Bmp8b, and Kcnj14, 43 that have distinct expression patterns among strain-by-diet contexts and fall under metabolic QTL 44 previously mapped in an F 16 generation of an advanced intercross between these two strains.45 Each of these genes have some connection to obesity and diabetes-related traits, but have not 46 been studied in brown adipose tissue. In summary, our results provide important insights into the 47 relationship between brown adipose and systemic metabolism by being the first gene-by-48 environment study of brown adipose transcriptional networks and introducing novel candidate 49 genes for follow-up studies of biological mechanisms of action.50 51 52 3 53 Author Summary 54 Research on brown adipose tissue is a promising new avenue for understanding and potentially55 treating metabolic dysfunction. However, we do not know how genetic background interacts with 56 dietary environment to affect the brown adipose transcriptional response, and how this might 57 affect systemic metabolism. Here we report the first investigation of gene-by-environment 58 interactions on brown adipose gene expression networks associating with multiple obesity and 59 diabetes-related traits. We identified 8 primary networks correlated with variation in these traits in 60 mice, including networks enriched for immune and cytokine response, cell division, organic 61 molecule metabolism, and peroxisome genes. Characterizing these networks and their distinct 62 diet-by-strain expression and co-expression patterns is an important step towards understanding 63 how brown adipose tissue responds to an obesogenic diet, how this response a...

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Section: Discussionmentioning

confidence: 99%

Genetic background and diet affect brown adipose gene co-expression – metabolic associations

Carson

Lawson

2019

Preprint

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“…These mice exhibit reduced adiposity only at RT, suggesting that decreased adaptive thermogenesis can contribute to the development of obesity in these mice at RT [105,106]. Similarly, adipocyte BMP8b transgenic mice have been shown to sustain beige adipocytes at both RT and thermoneutrality due to the remodeling of neuro-vascular network, only manifesting reduced susceptibility to HFD-induced obesity at RT [103].…”

Section: Beige Adipocytes In Metabolic Diseasesmentioning

confidence: 97%

Towards a Better Understanding of Beige Adipocyte Plasticity

Paulo

Wang

2019

Cells

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Beige adipocytes are defined as Ucp1 + , multilocular adipocytes within white adipose tissue (WAT) that are capable of thermogenesis, the process of heat generation. In both mouse models and humans, the increase of beige adipocyte population, also called WAT browning, is associated with certain metabolic benefits, such as reduced obesity and increased insulin sensitivity. In this review, we summarize the current knowledge regarding WAT browning, with a special focus on the beige adipocyte plasticity, collectively referring to a bidirectional transition between thermogenic active and latent states in response to environmental changes. We further exploit the utility of a unique beige adipocyte ablation system to interrogate anti-obesity effect of beige adipocytes in vivo.It has been well established that activity of beige adipocytes is dominantly regulated by the sympathetic nervous system, induced by the cold or just the feeling of cold ( Figure 1) [6][7][8]. Chemical denervation with 6-hydroxydopamina, prior to 3-week-old age or prior to cold exposure, impairs beige adipocyte formation, indicating the importance of sympathetic nerves during WAT browning [21]. Previous studies on anatomical positioning of sympathetic nerves in the subcutaneous inguinal white adipose tissue (iWAT), for example, by staining the tyrosine hydrolase + (Th + ) sympathetic nerves in fixed tissues [22,23], lack spatial and temporal precision [21,24,25]. Th + -sympathetic nerves and beige adipocytes are not distributed evenly across iWAT [22], suggesting that anatomic positioning of sympathetic nerves may also contribute to beige adipocyte formation. However, the actions of sympathetic nerves, the engagement of neurotransmitters, and their receptors at the contact sites of the sympathetic nerve and receiving cell in live mice are most unknown, and functional relevance of sympathetic nerve neurotransmission in beige adipocyte plasticity, especially during the postnatal period, is not fully elucidated yet.Cells 2019, 8, 1552 2 of 16 environment, but their appearances are also negatively correlated with aging and obesity, suggesting a potential role of beige adipocytes in regulating energy homeostasis. Beige Adipocyte Formation: Different PlayersIt has been well established that activity of beige adipocytes is dominantly regulated by the sympathetic nervous system, induced by the cold or just the feeling of cold (Figure 1) [6][7][8]. Chemical denervation with 6-hydroxydopamina, prior to 3-week-old age or prior to cold exposure, impairs beige adipocyte formation, indicating the importance of sympathetic nerves during WAT browning [21]. Previous studies on anatomical positioning of sympathetic nerves in the subcutaneous inguinal white adipose tissue (iWAT), for example, by staining the tyrosine hydrolase + (Th + ) sympathetic nerves in fixed tissues [22,23], lack spatial and temporal precision [21,24,25]. Th + -sympathetic nerves and beige adipocytes are not distributed evenly across iWAT [22], suggesting that anatomic positioning of sympatheti...

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“…Most likely, NRG4 exerts its effects on other target cells and tissues expressing ErbB/HER receptors. The figure was modified from Pfeifer and is based on data from Wang et al , Rosell et al , Guo et al , and Pellegrinelli et al .…”

Section: Nrg4 Links Bat To Livermentioning

confidence: 99%

“…In this context, it has been suggested that adipocyte‐derived NRG4 induces neurite outgrowth and could thereby regulate activation of BAT by sympathetic neurons (Figure ). Bone morphogenetic protein 8b may play an important role as an activator of NRG4 secretion and as an interconnected regulator . In addition, effects of NRG4 on the liver, but also on BAT and white adipose tissue, may be related to increased sympathetic innervation, which drives neurovascular remodeling in these tissues .…”

Section: Role Of Nrg4 In Neurite Outgrowthmentioning

confidence: 99%

“…Bone morphogenetic protein 8b may play an important role as an activator of NRG4 secretion and as an interconnected regulator . In addition, effects of NRG4 on the liver, but also on BAT and white adipose tissue, may be related to increased sympathetic innervation, which drives neurovascular remodeling in these tissues . Whether increased innervation mediated by NRG4 also contributes to the observed metabolic effects and may lead to increased lipolysis has not been directly investigated.…”

Section: Role Of Nrg4 In Neurite Outgrowthmentioning

confidence: 99%

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Neuregulin 4: A “Hotline” Between Brown Fat and Liver

Blüher

2019

Obesity

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The discovery that functional brown adipose tissue (BAT) in adult humans is inversely related to body fat mass and may reflect metabolic health has stimulated adipose tissue research to explore activation of BAT as a potential target for antiobesity treatments. In addition to the capacity of BAT to increase energy expenditure and glucose and lipid uptake, BAT secretes factors that may contribute to the regulation of whole‐body metabolism. Among signals released from BAT, neuregulin 4 (NRG4) has been recently identified as an endocrine factor that may link the activation of BAT to protection against diet‐induced obesity, insulin resistance, and hepatic steatosis. NRG4 was shown to directly reduce lipogenesis in hepatocytes, and it could indirectly activate BAT via sympathetic neurons or via inducing brown adipocyte–like signatures in white adipocytes in a paracrine manner. However, the potential relevance of NRG4 as a diagnostic tool or target for the treatment of obesity‐related diseases remains to be explored.

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Adipocyte-secreted BMP8b mediates adrenergic-induced remodeling of the neuro-vascular network in adipose tissue

Cited by 100 publications

References 62 publications

Genetic background and diet affect brown adipose gene co-expression – metabolic associations

Genetic background and diet affect brown adipose gene co-expression – metabolic associations

Towards a Better Understanding of Beige Adipocyte Plasticity

Neuregulin 4: A “Hotline” Between Brown Fat and Liver

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