Human Semaphorin 3 Variants Link Melanocortin Circuit Development and Energy Balance

Klaauw, Agatha A. van der; Croizier, Sophie; Oliveira, Edson Mendes de; Stadler, Lukas Kurt Josef; Park, Soyoung; Kong, Y.; Banton, Matthew C.; Tandon, Panna; Hendricks, Audrey E.; Keogh, Julia M.; Riley, Susanna E.; Papadia, Sofia; Henning, Elana; Bounds, Rebecca; Bochukova, Elena G.; Mistry, Vanisha; O’Rahilly, Stephen; Simerly, Richard B.; Minchin, James E.N.; Barroso, Inês; Jones, E Y; Bouret, Sébastien G.; Farooqi, I. Sadaf

doi:10.1016/j.cell.2018.12.009

Cited by 82 publications

(77 citation statements)

References 53 publications

(68 reference statements)

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“…A variety of signals have been shown to influence hypothalamic axonal outgrowth resulting in metabolic alterations (13,21,23,24). To determine if NNS impact hypothalamic axonal outgrowth, we treated arcuate nucleus (ARH) explants with sucralose, aspartame, ACEK, or rebaudioside A.…”

Section: Acek Reduces Axonal Outgrowth and Tudca Co-treatment Improvementioning

confidence: 99%

Non-nutritive Sweeteners Induce Hypothalamic ER Stress Causing Abnormal Axon Outgrowth

2019

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With the prevalence of obesity, non-nutritive sweeteners (NNS) have been widely used as sugar substitutes as they deliver a sweet taste without excessive caloric load. However, it is increasingly recognized that NNS are not inert compounds and may cause long-term metabolic perturbations. Endoplasmic reticulum (ER) stress has emerged as a critical link in the development of obesity and type 2 diabetes. In this study, we investigated the effects of NNS found in common diet beverages (i.e., sucralose, aspartame, acesulfame potassium) and a natural sweetener (i.e., rebaudioside A) on ER stress in the hypothalamic cell line mHypoE-N43/5 in vivo and on axonal outgrowth ex vivo. Sucralose, aspartame, and acesulfame potassium caused elevated ER stress gene expression in mHypoE-N43/5 cells, with sucralose and acesulfame potassium having the most potent effect. Moreover, acesulfame potassium treatment reduced axon outgrowth from arcuate nucleus explants and this effect was attenuated with the ER stress-relieving drug tauroursodeoxycholic acid. Furthermore, sucralose induced cytotoxicity and acesulfame potassium increases caspase3/7 activity at high concentrations in mHypoE-N43/5 cells. In contrast, rebaudioside A only had moderate effects on hypothalamic ER stress and no adverse effects on axon outgrowth, cytotoxicity, or caspase3/7 activity. Together, our data reveal that commonly consumed NNS cause cellular stress in hypothalamic cells disrupting axon outgrowth and that these biological alterations are not seen with rebaudioside A. These data provide biological plausibility for some NNS to adversely impact metabolic health and identifies rebaudioside A as a sweetener with lower detrimental biological impact on hypothalamic cells.

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Section: Acek Reduces Axonal Outgrowth and Tudca Co-treatment Improvementioning

confidence: 99%

Non-nutritive Sweeteners Induce Hypothalamic ER Stress Causing Abnormal Axon Outgrowth

2019

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“…As already described (52), PVH and ARH nuclei were microdissected under binocular loupe from 200 µm-thick brain sections collected from P8, P10, P12, P14, P16, and P18 C57Bl/6 pups (n=2-4/age, from at least 2 litters/age) and from 16 week-old Pomc -Cre; Efnb2 loxP/loxP and Efnb2 loxP/loxP . Microdissected nuclei were stored at −80°C until RNA extraction using Picopure RNA extraction kit (Applied Biosystems).…”

Section: Methodsmentioning

confidence: 99%

“…P6, P14, and P22 Pomc -Cre;tdTomato male mice (n=2-3 animals/age), 16-18 week-old Pomc -Cre;tdTomato; Efnb1 loxP/0 , Pomc -Cre;tdTomato, Pomc -Cre;tdTomato; Efnb2 loxP/loxP , and Pomc -Cre;tdTomato; Efnb1 loxP/loxP , Pomc -Cre;tdTomato; Efnb2 loxP/loxP , Pomc -Cre;tdTomato female mice were transcardially perfused with 4% PFA (n=3/group). 20 µm-thick brain and pancreas sections were processed for immunofluorescence using standard procedures (10,52,58). The primary antibodies used for IHC were as follows: rabbit anti-vGLUT2 (1:500, Synaptic Systems), rabbit anti-VAChT (1:500, Synaptic Systems), guinea-pig anti-insulin (1:500, Abcam).…”

Section: Methodsmentioning

confidence: 99%

EphrinB1 modulates glutamatergic inputs into POMC neurons and controls glucose homeostasis

Gervais

Picard

Thorens

et al. 2020

Preprint

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Proopiomelanocortin (POMC) neurons are major regulators of energy balance and glucose homeostasis. In addition to being regulated by hormones and nutrients, POMC neurons are controlled by glutamatergic input originating from multiple brain regions. However, the factors involved in the formation of glutamatergic inputs and how they contribute to bodily functions remain largely unknown. Here, we show that during the development of glutamatergic inputs, POMC neurons exhibit enriched expression of the Efnb1 (EphrinB1) and Efnb2 (EphrinB2) genes, which are known to control excitatory synapse formation. In vitro silencing and in vivo loss of Efnb1 or Efnb2 in POMC neurons decreases the amount of glutamatergic inputs into these neurons. We found that mice lacking Efnb1 in POMC neurons display impaired glucose tolerance due to blunted vagus nerve activity and decreased insulin secretion. However, mice lacking Efnb2 in POMC neurons showed no deregulation of insulin secretion and only mild alterations in feeding behavior and gluconeogenesis. Collectively, our data demonstrate the role of ephrins in controlling excitatory input amount into POMC neurons and show an isotype-specific role of ephrins on the regulation of glucose homeostasis and feeding.

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“…It suggest sympathetic nerve implicate lipid metabolism, it also suggest SEMA3F maybe has potential role in energy availability. The other studies demonstrate the epigenetics may control differentiation and fatty acid metabolism of LECs ( Wong et al , 2017; van der Klaauw et al , 2019). So, We hypothesize that SEMA3F binding NRP2 to reduce lymphangiogenesis of CRCs maybe has other mechanisms, SEMA3F may bind NRP2 to disturb lipid metabolism of LECs and repress lymphangiogenesis of CRCs.…”

Section: Introductionmentioning

confidence: 99%

SEMA3F-deficient colorectal cancer cells Promote lymphangiogenesis: fatty acid metabolism replace glycolysis for energy supply during lymphatic endothelial cells proliferation in tumor hypoxia microenvironment

Tao

et al. 2019

Preprint

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22 30 tubulogenesis capacity and hLECs migration were escalated in the 31 hypoxia, the hLECs mainly relied on fatty acid metabolism not aerobic 32 glycolysis during lymphangiogenesis. SEMA3F-deficient CRCs 33 up-regulated PMAKP expression and phosphorylation of hLECs, and 34 activated its peroxisome proliferator-activated receptor (PPARs) and 35 Peroxisome proliferator-activated receptor gamma coactivator-1 alpha 36 (PGC-1a) facilitated their switched toward fatty acids (FA) catabolism. 37Furthermore, we observed that activation of the PGCI-PPAR lipid 38 oxidation signaling pathway in hLECs was caused by the secretion of 39 interleukin-6 by tumor cells.Taken together, this study indicates that 40 CRCs with SEMA3F expression depletion significantly promotes 41 lymphangiogenesis in hypoxia and faciliates the secretion of IL-6 in 42 tumor cell, and activates mitochondria fatty acids oxidation (FAO) 43 reaction in the hLECs by PGCI-PPAR signaling pathways to support its 44 growth. 45 46 acid metabolism; hypoxia 48 49 104 CRCs promotion hLECs lipid metabolism and lymphangiogenesis under 105 hypoxemia.We demonstrated that SEMA3F plays a crucial role in hLECs 106 energy metabolism. CRCs with SEMA3F expression depletion 107 significantly promotes hLECs migration and tubulogenesis capacity in 108 hypoxia, and enhance the lipid metabolism via suppressing aerobic 109 glycolysis of hLECs, and the lipid metabolism to induce the PGCI-PPAR 110 signaling pathway in hLECs. Further evidence demonstrated that CRCs 111 cell with SEMA3F expression depletion up-regulated its IL-6 secretion, 112 to activate the PGCI-PPAR signaling pathway and induces the lipid 113 metabolismin of hLECs in hypoxia. Our findings for the first time 114 revealed a novel role and the underlying mechanism, the CRCs cell with 115 SEMA3F expression deficiency was involved the energy metabolism 116 with hLECs in the hypoxia environment, and induce tumor 117 lymphangiogenesis of CRCs to promote lymphatic metastasis. 118 119 Result 120 1.SEMA 3F-deficient CRCs further enhance lymphangiogenesis 121 under hypoxic conditions 122 In our previous study, loss of SEMA3F expression, the inhibitory ligand 123 of NRP2, critically contributes to CRCs metastasis and 124 lymphangiogenesis in normoxia(Wu et al, 2011; Ou et al, 2015). To 125 examine whether SEMA3F loss expression plays any roles in induce 126 lymphangiogenesis of colorectal cancer cell in hypoxia, We used 127 supernatants of the colorectal adenocarcinoma cell line HCT116 with 128 SEMA3F expression and SEMA3F knockout (SEMA3F KD), to culture 129 hLECs three-dimensionally on matrigel substrate under normoxia and 130 hypoxia to induce tubule formation of hLECs. The tubulogenesis of 131 hLECs was improved in hypoxia than that in normoxia (p < 0.001; Figure 132 1A and B). Strikingly, comparing with control cells, SEMA3F KD groups 133 displayed significantly enhancement of tubulogenesis ability of hLECs 134 under normoxic conditions. Consistent with normoxic conditions 135 culture, SEMA3F KD groups had stronger abili...

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Human Semaphorin 3 Variants Link Melanocortin Circuit Development and Energy Balance

Cited by 82 publications

References 53 publications

Non-nutritive Sweeteners Induce Hypothalamic ER Stress Causing Abnormal Axon Outgrowth

Non-nutritive Sweeteners Induce Hypothalamic ER Stress Causing Abnormal Axon Outgrowth

EphrinB1 modulates glutamatergic inputs into POMC neurons and controls glucose homeostasis

SEMA3F-deficient colorectal cancer cells Promote lymphangiogenesis: fatty acid metabolism replace glycolysis for energy supply during lymphatic endothelial cells proliferation in tumor hypoxia microenvironment

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