EvoMuse Presents: Defuse Perpetua

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I've fielded so many questions about why Defuse needs to be used in a burst type manner. The answer is (usually) the same - homeostasis. If you block mature pathways strongly enough and for a long enough period, the body is unbelievably capable of finding ways around. Not to mention the blowback of blocking these enzymes for long enough, then stopping the Defuse would be......bad.

Anyway, I have been working on something since releasing Defuse that would get around it, and today I found it. While mature cells are "set in their ways" and other than turning them into BRITE cells, preadipocytes and undifferentiated cells (the reason BMP is so effective as well) can be messed with relentlessly without screwing up the body too badly.

I'm putting the final touched on Defuse Prolong (probably need a better name). This will be a version of Defuse that you CAN take for extended periods of time, that blocks so many pathways that trigger rapid lipid droplet accumulation in freshly differentiated 3t3 cells as well as many other pathways that cause fat cells to proliferate.

This throws a huge wrench into the stable production plan that we were finalizing, but I'm going to see about picking up a quick line of credit from my bank to finance this.. Luckily, this product will be effective year round, but especially effective during the holiday/Fall/Winter seasons when we let ourselves indulge a bit because we're dressed like Randy from A Christmas Story so we think people won't notice.

Well, I notice and it's depressing. We're once again creating something that hasn't been seen before. This is no carb blocker, so fat blocker that keeps nutrients from being absorbed.

This is SPARTA!
 
BamBam0319

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I am all in.
 

hsk

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Looking forward to trying this. Any chance of this dropping before 2017 Holiday Season?
 
Tank999

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And as usual - sounds too good to be true......and it'll probably work better than expected!
 
dsade

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Looking forward to trying this. Any chance of this dropping before 2017 Holiday Season?
Yep, I have a few people that have offered some limited funding short term. Again, shooting for September.
 
JDybya

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Sounds very promising. Can't wait to try!
 
Wimsicle

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Yess, sounds awesome
 
cubs1987

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subbed- I'd be all over this (and regular Defuse!)
 
booneman77

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always in for these amazing new products
 
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In. As usual, Matt doing big things!
 
GiftedNatty

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IN!
 
paul56778

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Subbed I'm IN, also need more regular Defuse and DCP before August.
 
dsade

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I'm changing the name to Defuse Perpetua, since you can take it long term. I'm going to post one hint at a few target pathways.

The difficulty of this research vs Defuse is mind blowing. Your body has at least 25 different pathways that it can use to recruit mesenchymal stem cells to preadipocytes, then cram those preadipocytes full of lipid droplets until they burst into fully mature fat cells ready to **** up our physiques.

Well, not on MY watch. I've already spent about 60 hours in the last 5 days on this and I'm just about done.

Geranylgeraniol Suppresses the Expression of Adipogenic Genes and the Differentiation of Murine 3T3-F442A and 3T3-L1 Preadipocytes

Manal Elfakhani1, Sophie Yount2 and Huanbiao Mo1

+
Author Affiliations

1Nutrition, Georgia State University, Atlanta, GA
2Chemistry, Georgia State University, Atlanta, GA

Abstract

Fundamental to the pathology of obesity is the hypertrophy and hyperplasia of adipocytes. Lipid accumulation in differentiated adipocytes is part of the adipocyte lifecycle that eventually leads to recruitment of macrophages and inflammation. We have previously shown that lovastatin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, suppresses the differentiation of murine 3T3-F442A adipocytes via mevalonate deprivation. Tocotrienols, down-regulators of HMG CoA reductase, inhibit adipocyte differentiation via suppression of peroxisome proliferator-activated receptor γ (PPARγ). We hypothesize that geranylgeraniol, a diterpene known to accelerate the degradation of HMG CoA reductase, mimics the impact of lovastatin and tocotrienol in suppressing adipocyte differentiation and the expression of adipogenic genes. Oil Red O staining and Adipo-Red assay showed that a 7-d incubation with 2.5 – 20 μmol/L geranylgeraniol decreased the intracellular triglyceride content of murine 3T3-F442A and 3T3-L1 adipocytes in a concentration-dependent manner. Geranylgeraniol also down-regulated the expression of PPARγ, a key regulator of adipocyte differentiation, as well as the expression of adipocyte marker genes comprising adiponectin, leptin, fatty acid binding protein 4 (FABP4) and lipoprotein lipase, as measured by real-time qPCR. Concurrently, Western-blot showed that geranylgeraniol reduced the levels of PPARγ, FABP4 and C/EBPα proteins. No cytotoxicity was observed in preadipocyte cells incubated with geranylgeraniol (0–400 μmol/L) for 24 and 48 h. Mevalonate-derived metabolites have crucial roles in promoting adipocyte differentiation by regulating the expression of adipogenic genes. Dietary mevalonate suppressors as anti-adipogenesis compounds may have potential in the prevention of obesity.

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ma70

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Came back to the forums just in time. The real question is....what's nice to stack with this? :)
 
dsade

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Came back to the forums just in time. The real question is....what's nice to stack with this? :)
BMP and EP4
 
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This one is about 10 times more complicated than BMP.
 

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Awesome matt!! Keep it going!! Your stuff kicks ass!! Starting prep august 1st for nationals and im def going to need some more supernova soon, got 2 bottles left of my 5! Started day 1 of prep on my ass cheeks!! haha
 
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subbed
 
ZachH

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Definitely in on this. Please respond to my PM brother only got a week and a half left until vacation!!!
 
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EP4 is a muscle building oathway downstream fro PGE2. In working on blocking the undesirable effects of PGE2, increasing expression of EP4 in muscle, then directly agonizing it.
 
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Sorry guys, been updating Facebook and neglecting this thread.... formula is complete and we are hitting the writeup hard. SHould have final product cost and ETA soon.....this one is a beast.

https://www.ncbi.nlm.nih.gov/pubmed/22678810

J Cell Biochem. 2012 Nov;113(11):3436-45. doi: 10.1002/jcb.24220.
Wedelolactone inhibits adipogenesis through the ERK pathway in human adipose tissue-derived mesenchymal stem cells.
Lim S1, Jang HJ, Park EH, Kim JK, Kim JM, Kim EK, Yea K, Kim YH, Lee-Kwon W, Ryu SH, Suh PG.
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Abstract

Wedelolactone is an herbal medicine that is used to treat septic shock, hepatitis and venom poisoning. Although in differentiated and cancer cells, wedelolactone has been identified as anti-inflammatory, growth inhibitory, and pro-apoptotic, the effects of wedelolactone on stem cell differentiation remain largely unknown. Here, we report that wedelolactone inhibits the adipogenic differentiation of human adipose tissue-derived mesenchymal stem cells (hAMSCs). Wedelolactone reduced the formation of lipid droplets and the expression of adipogenesis-related proteins, such as CCAAT enhancer-binding protein-α (C/EBP-α), peroxisome proliferator-activated receptor-γ (PPAR-γ), lipoprotein lipase (LPL), and adipocyte fatty acid-binding protein aP2 (aP2). Wedelolactone mediated this process by sustaining ERK activity. In addition, inhibition of ERK activity with PD98059 resulted in reversion of the wedelolactone-mediated inhibition of adipogenic differentiation. Taken together, these results indicate that wedelolactone inhibits adipogenic differentiation through ERK pathway and suggest a novel inhibitory effect of wedelolactone on adipogenic differentiation in hAMSCs.

Copyright © 2012 Wiley Periodicals, Inc.

PMID:
22678810
DOI:
10.1002/jcb.24220


I've managed to block most of the pathways triggering differentiation of fat cells, as well as increasing expression of some pathways that actively block adipogenesis. Defuse Perpetua is going to be a wonder to behold, and the most effective formula to block fat formation that you will ever see.
 
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With an ideal dosage of 10mg/kg in rats, the extract i was able to get is PLENTY potent. It's also a really great PPAR-a agonist.
 
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And this is one of the main reasons why my BMP is such a badass recomposition product, and why combining it with BRITE yields such incredible results.

There are many other bioactive molecules regulating adipogenic differentiation and adipogenic key transcription factors. For example, ginsenosides, the major active molecules of Panax ginseng, have shown potential anti-obesity and anti-adipogenic effects [175]. Ginsenosides (25–100 µM) significantly reduced lipid accumulation and expression of key adipogenic genes (PPARγ and C/EBPα) [175]. Moreover, it has been shown that ginseng supplementation prevented high-fat diet induced hyperglycemia and obesity in mice [176]. Adipokines, which are secreted from adipose tissues, are important regulators for adipogenesis, insulin sensitivity, and obesity [177,178]. Among those adipokines, adiponectin increases insulin sensitivity, PPARα activity through PPAR coactivator-1α, and SIRT1-AMPK signaling system, resulting in fat oxidation, reduced lipid synthesis and prevention of hepatic steatosis [177,178]. BMPs are the transforming growth factor-β superfamily and are key regulators for adipogenesis [179,180]. In rodent and human adipose stem cells, BMP4 and BMP7 have been shown to promote transition of white adipocytes to brown adipocytes which metabolizes triglycerides to produce heat and increase energy expenditure through the expression of uncoupling protein 1 (UCP1) [179,180]. Thus, these secreted proteins can be potential molecules regulating adipogenesis and obesity in humans and animals.
 
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Now that the formula is complete and out for quotation, it's time to start teasing you with ingredients....

Cirsium setidens Nakai extract suppresses adipogenesis and regulates lipid metabolism genes in 3T3-L1 cells

Bong-Yeon Cho1, Jin-Ha Lee1, Jae-Min Kim1, Sun-Il Choi1, Tae-Dong Jung1, Seung-Hyun Choi1, Moon-Jin Ra2, Sun-Young Kim2, Il-Jun Kang3, Kyoung Chan Han4 and Ok-Hwan Lee1

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Author Affiliations

1Kangwon National University, Chuncheon-si, Gangwon-do, Korea, Republic of
2Hongcheon Institute of Medicinal Herb, Hongcheon-eup, Hongcheon-gun, Korea, Republic of
3Hallym University, Chuncheon-si, Gangwon-do, Korea, Republic of
4Hatti Co. Ltd., Hongcheon-eup, Hongcheon-gun, Korea, Republic of

Abstract

Cirsium setidens Nakai, a wild perennial herb, grows mainly in Kangwon province, Korea, and it has been reported to contain bioactive ingredients with various medicinal activities including treat edema, bleeding and hemoptysis. However, the potentiality of anti-obesity effects of C. setidens Nakai has not been fully investigated. To characterize anti-obesity effect of C. setidens Nakai extract (CNE) and to evaluate its potential as a functional food, we performed various obesity-related in vitro experiments. In adipogenesis assay, CNE blocked the differentiation of 3T3-L1 preadipocyte in a dose-dependent manner. Exposure 200 μg/mL, CNE significantly reduced lipid accumulation (~40%). In addition, CNE suppressed the expression of lipogenic genes, while increasing the expression of lipolytic genes. The anti-adipogenic and anti-lipogenic effect of CNE seems to be mediated by the inhibition of PPARγ and C/EBPα, C/EBPβ, C/EBPδ expression. Moreover, CNE stimulated fatty acid oxidation in an AMPK-dependent manner. These results showed anti-obesity effects of CNE on adipogenesis and lipid metabolism in vitro and raised a possibility of developing the treatment of obesity as non-toxic natural resources.
 
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Myricetin

Nutr Res. 2015 Apr;35(4):317-27. doi: 10.1016/j.nutres.2014.12.009. Epub 2015 Jan 8.
Myricetin suppresses differentiation of 3 T3-L1 preadipocytes and enhances lipolysis in adipocytes.
Wang Q1, Wang ST1, Yang X1, You PP1, Zhang W2.
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Abstract

Myricetin (MyR), a naturally occurring flavonol widely distributed in fruits, vegetables, and medicinal plants, has anticancer, anti-inflammatory, antihyperlipidaemic, and antiobesity activities. In the present study, we hypothesized that the antiobesity property of MyR is mediated via suppression of differentiation of preadipocytes into adipocytes and promotion of lipolysis of mature adipocytes, which effectively decrease the intracellular triglyceride concentration of adipocytes. Accordingly, the aim of this work was to investigate the effects of MyR on adipocyte differentiation and lipolysis in differentiated 3 T3-L1 adipocytes. Our results showed that MyR inhibited differentiation of 3 T3-L1 preadipocytes in a concentration-dependent manner. Myricetin downregulated the mRNA and protein levels of CCAAT/enhancer-binding protein α and peroxisome proliferator-activated receptor γ, both of which are major adipogenic transcription factors. Furthermore, the mRNA levels of other adipogenesis-related transcription factors, namely, CCAAT/enhancer-binding protein β, sterin regulatory element binding protein 1-c, peroxisome proliferator-activated receptor γ coactivator-1, adipocyte protein 2, lipoprotein lipase and glucose transporter 4, were also reduced by MyR treatment. Moreover, MyR significantly inhibited the phosphorylation of extracellular signal-regulated kinase, Jun N-terminal kinase, and p38 during the differentiation process. On the other hand, MyR induced a dose-dependent increase in glycerol release in fully differentiated adipocytes, indicating its stimulatory effect on adipocyte lipolysis. Furthermore, MyR downregulated mRNA level of perilipin A and enhanced the phosphorylation level of extracellular signal-regulated kinase, Jun N-terminal kinase, and p38 during lipolysis. Taken together, these findings indicate that MyR exerts antiobesity activity in adipocytes.

Copyright © 2015 Elsevier Inc. All rights reserved.
KEYWORDS:

3 T3-L1 adipocyte; Differentiation; Lipolysis; MAPK; Myricetin

PMID:
25724338
DOI:
10.1016/j.nutres.2014.12.009

Tackling both differentiation as well as lipolysis in mature adipocytes. You won't be able to stop the lean!!!
 
Wimsicle

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Damn.. Based on those 2 my hype meter is skyrocketing ha
 
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Damn.. Based on those 2 my hype meter is skyrocketing ha
I'm barely getting started. This is almost 200 hours of work by me, and quite a bit by Marc as well.
 
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Note the words used carefully....irreversibly.

PLoS One. 2012;7(1):e30831. doi: 10.1371/journal.pone.0030831. Epub 2012 Jan 24.
Inhibition of adipogenesis and induction of apoptosis and lipolysis by stem bromelain in 3T3-L1 adipocytes.
Dave S1, Kaur NJ, Nanduri R, Dkhar HK, Kumar A, Gupta P.
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Abstract

The phytotherapeutic protein stem bromelain (SBM) is used as an anti-obesity alternative medicine. We show at the cellular level that SBM irreversibly inhibits 3T3-L1 adipocyte differentiation by reducing adipogenic gene expression and induces apoptosis and lipolysis in mature adipocytes. At the molecular level, SBM suppressed adipogenesis by downregulating C/EBPα and PPARγ independent of C/EBPβ gene expression. Moreover, mRNA levels of adipocyte fatty acid-binding protein (ap2), fatty acid synthase (FAS), lipoprotein lipase (LPL), CD36, and acetyl-CoA carboxylase (ACC) were also downregulated by SBM. Additionally, SBM reduced adiponectin expression and secretion. SBM's ability to repress PPARγ expression seems to stem from its ability to inhibit Akt and augment the TNFα pathway. The Akt-TSC2-mTORC1 pathway has recently been described for PPARγ expression in adipocytes. In our experiments, TNFα upregulation compromised cell viability of mature adipocytes (via apoptosis) and induced lipolysis. Lipolytic response was evident by downregulation of anti-lipolytic genes perilipin, phosphodiestersae-3B (PDE3B), and GTP binding protein G(i)α(1), as well as sustained expression of hormone sensitive lipase (HSL). These data indicate that SBM, together with all-trans retinoic-acid (atRA), may be a potent modulator of obesity by repressing the PPARγ-regulated adipogenesis pathway at all stages and by augmenting TNFα-induced lipolysis and apoptosis in mature adipocytes.

PMID:
22292054
PMCID:
PMC3265525
DOI:
10.1371/journal.pone.0030831

Your fat cells are gonna get beat worse than MacGregor.
 
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What? Anti-adipogenic AND ProApoptotic in mature fat cells? So kill them and their unborn children, then hear the lamentation of their women.

J Nutr. 2007 Dec;137(12):2668-73.
Resveratrol potentiates genistein's antiadipogenic and proapoptotic effects in 3T3-L1 adipocytes.
Rayalam S1, Della-Fera MA, Yang JY, Park HJ, Ambati S, Baile CA.
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Abstract

Genistein (G) and resveratrol (R) individually inhibit adipogenesis in 3T3-L1 adipocytes and induce apoptosis in cancer cells. We investigated whether the combination of G and R resulted in enhanced effects on adipogenesis, lipolysis, and apoptosis in 3T3-L1 cells. Preadipocytes and mature adipocytes were treated with G and R individually at 50 and 100 micromol/L (G100; R100) and in combination. Both in preadipocytes and mature adipocytes, G and R individually decreased cell viability dose-dependently, but G100 + R100 further decreased viability by 59 +/- 0.97% (P < 0.001) and 69.7 +/- 1.2% (P < 0.001) after 48 h compared with G100 and R100, respectively. G100 + R100 induced apoptosis 242 +/- 8.7% (P < 0.001) more than the control after 48 h, whereas G100 and R100 individually increased apoptosis only 46 +/- 9.2 and 46 +/- 7.9%, respectively. G and R did not modulate mitogen-activated protein kinase expression by themselves, but G100 + R100 increased Jun-N-terminal kinase phosphorylation by 38.8 +/- 4.4% (P < 0.001) and decreased extracellular signal-regulating kinase phosphorylation by 48 +/- 3.4% (P < 0.001). Individually, G and R at 25 micromol/L (G25; R25) decreased lipid accumulation by 30 +/- 1.7% and 20.07 +/- 4.27%, respectively (P < 0.001). However, G25 + R25 decreased lipid accumulation by 77.9 +/- 3.4% (P < 0.001). Lipolysis assay revealed that neither G25 nor R25 induced lipolysis, whereas G25 + R25 significantly increased lipolysis by 25.5 +/- 4.6%. The adipocyte-specific proteins PPARgamma and CCAAT/enhancer binding protein-alpha were downregulated after treatment with G + R, but no effect was observed with individual compounds. These results indicate that G and R in combination produce enhanced effects on inhibiting adipogenesis, inducing apoptosis, and promoting lipolysis in 3T3-L1 adipocytes. Thus, the combination of G and R is more potent in exerting antiobesity effects than the individual compounds.

PMID:
18029481

[Indexed for MEDLINE]
 
ZachH

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Can this be used in conjuction with your regular defuse? Or does this make regular defuse (on the rare occasion of huge cheat meal days) not needed anymore?
 
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You can use this with regular Defuse, of course
 
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Subbed to read later
 

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So resveratrol is an ingredient? What about its bioavailability?
 

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