ReverseFX weight gain and inflammation

According to studies, several compounds found in ReverseFX upregulate the “HOTSPOT” gene PPAR-Gamma.

This is a MASSIVELY HUGE ORDEAL!

PPAR-gamma has been implicated in the pathology of numerous diseases including obesity, diabetes, atherosclerosis, cancer, neurodegeneration, gut related disorders, lung disease, and immune/inflammatory pathways. 

What is PPARG?

PPARG is essential in the regulation of the expression of genes and is the master regulator of adipose (fat) tissue biology.

Fat has been blamed for many health problems, but it is actually an essential nutrient for optimal health. 

Adipose tissue (stored fat) provides cushion and insulation to internal organs, protects nerves, moves certain vitamins (A, D, E, and K) throughout the body, and is the largest reserve of stored energy available for activity.

PPARs are very important protein for metabolizing fat and for weight loss.

Things that upregulate PPAR-gamma have been used in the treatment of hyperlipidaemia (a condition in which there are high levels of fat particles (lipids) in the blood) and hyperglycemia (high blood glucose). 

PPAR-gamma upregulation decreases the inflammatory response of many cardiovascular cells, particularly endothelial cells.

PPARs are generally anti-inflammatory and block inflammation (MAPK, NF-kappaB, and others). PPARs induce an immune profile more similar to Th2 dominance. PPARG promotes anti-inflammatory M2 macrophage activation.

It’s not surprising then that PPAR gamma activation is one mechanism by which mice can live longer.

Studies show that the activation of PPAR gamma may be responsible for inhibiting the growth of cultured human breast, gastric, lung, prostate and other cancer cell lines.

PPARs play pivotal roles in nutrient sensing, metabolism, and lipid-related processes.

https://www.mdpi.com/ijms/ijms-22-10573/article_deploy/html/images/ijms-22-10573-g001.png

PPAR increases FGF-21. FGF-21 has been shown to benefit insulin sensitivity, blood glucose, and cholesterol profile while decreasing body weight in obese mice and diabetic monkeys, without increased cancer or other side effects. FGF-21 leads to increased energy expenditure, fat utilization, and excretion.

PPARs also cause the browning of white fat (good), which should help combat obesity.

PPAR gamma decreases inflammation in your heart and reduces cholesterol.

PPAR gamma decreases inflammation and can help IBD (Crohn’s, colitis) because PPAR gamma plays a relatively large role in colon cells.

PPAR activation represses NF-κB signaling, which decreases the inflammatory cytokine production by different cell types, such as tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, and Il-1β. 

In this regard, the anti-inflammatory responses induced by PPAR activation might restore the pathological imbalances associated with inflammatory bowel diseases (IBD).

PPAR gamma increases ApoE, which 25% of the population have lower levels of and is implicated in Alzheimer’s. ApoE is an anti-inflammatory, anti-oxidant and junk removal protein. It also lowers cholesterol.

PPAR gamma increases PON1, which is an antioxidant and protects your heart. PON1 is important for handling pesticides.

PPAR agonists promote the cessation of neutrophil recruitment and thus favor the resolution of inflammation.

The resolution of inflammation is an active and dynamic process, mediated in large part by the innate immune system. Resolution represents not only an increase in anti-inflammatory actions, but also a paradigm shift in immune cell function to restore homeostasis. 

PPAR has long been studied for its anti-inflammatory actions. PPAR can shift production from pro- to anti-inflammatory mediators by neutrophils, platelets, and macrophages. 

PPAR and its ligands further modulate platelet and neutrophil function, decreasing trafficking, promoting neutrophil apoptosis, and preventing platelet-leukocyte interactions. 

PPAR alters macrophage trafficking, increases efferocytosis and phagocytosis, and promotes alternative M2 macrophage activation. There are also roles for this receptor in the adaptive immune response, particularly regarding B cells. 

These effects contribute towards the attenuation of multiple disease states, including COPD, colitis, Alzheimer’s disease, and obesity in animal models.

Upregulating PPARG also decreases airway inflammation.

Inflammation as the body’s response to an injury at first would be beneficial, because there would be a mobilization of the innate and adaptive immune system, and this would help to contain the cause of the inflammation, and consequently, the healing of damaged tissues. 

The “good” side of inflammation will depend on the activity of endogenous suppressors of the inflammatory signaling pathways. Nevertheless, when these physiological suppressors do not work correctly, acute or chronic uncontrolled inflammation can lead to apoptosis, necrosis, fibrosis and ultimately, organ dysfunction at the end of the process.

Studies have already demonstrated that PPAR has anti-inflammatory effects through innate immune signaling by NFκB, particularly in macrophages. These cells are furthermore capable of producing several PPAR ligands, which can potentiate the anti-inflammatory pro-resolving actions of this receptor on other cells.

PPAR agonist could alleviate inflammation by regulating macrophage polarization and the suppressor of cytokine signaling proteins (SOCS)/JAK2/STAT signaling pathway.

Also, PPARγ agonists were linked to reduced chronic obstructive pulmonary disease (COPD) exacerbation rate in diabetic patients, showing PPARs role in lung diseases.

In one study a synthetic PPAR agonist showed a potent anti-inflammatory action modulating cytokine overproduction, proving to be a good candidate for COVID-19 infections and lung inflammation with edema.

PPARs role in cancer has excelled. PPAR was shown to hamper tumor development and progression, and controlled the tumor microenvironment, ameliorating tumor growth and metastasis.

PPAR activation transrepressed the NFkB pathway, blocking cell proliferation, differentiation and apoptosis in non-small cell lung carcinoma.

PPAR has been considered a molecular target for effective asthma therapy. 

PPARγ negatively regulated the production of mucin and inflammatory mediators by repressing gene expression in primary human bronchial epithelial cells during allergic airway inflammation.

In lung inflammatory disorders, reactive oxygen species (ROS) is a protagonist in diseases such as chronic obstructive pulmonary disease (COPD) and acute respiratory distress syndrome (ARDS). 

Cytokines with pro-inflammatory activities are considered biomarkers, predictors of morbidity and mortality during ARDS. Higher levels of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) expression promote the recruitment of leukocytes to the lung, leading to the production of proinflammatory cytokines in the tissue.

PPAR upregulation was shown to inhibit this occurrence.

PPAR inhibited NF-κB in COPD, decreasing inflammatory mediator production, ameliorating cigarette smoke extract-induced inflammation in vivo and in vitro. The activation of PPAR may be an effective therapeutic approach in COPD, as it reduced cigarette smoke-induced inflammation and decreased the magnitude of bacterial infection-caused exacerbations.

Cystic fibrosis is an inherited disease with mutations on the cystic fibrosis transmembrane conductance regulator (CFTR) gene.

Cystic fibrosis epithelial cells present lower FOXO1 expression and deficiency in PPAR.

HO-1 (heme oxygenase-1), an antioxidant enzyme, is induced by PPAR ligands. PPAR activation and HO-1 can exert therapeutic effects on lung inflammation. 

PPARγ directly regulates HO-1 transcription, impacting inflammation, ROS production and apoptosis. The upregulation of HO-1 by PPAR agonists also inhibits pulmonary cell proliferation and remodeling.

Therefore, PPAR agonists may be useful for protection against pulmonary inflammation.

PPAR is also a therapeutic target to rescue mitochondrial function in neurological disease.

The is a growing number of evidence for potential beneficial effects of PPAR agonists in a number of neurological disorders, including Parkinson’s disease, Alzheimer’s disease, Amyotrophic lateral sclerosis and Huntington’s disease, ischaemia, autoimmune encephalomyelitis and neuropathic pain.

Studies revealed 14 PPAR-regulated proteins are also linked to anxiety.

Anxiety disorders (including generalized anxiety disorders or panic disorders) are the most widespread mental diseases which are at the same time difficult to treat.

Main characteristic of panic disorder is presence of repetitive sudden panic attacks. According to large scale surveys, percentage of population suffering from the anxiety disease throughout lifetime is up to 33.7%.

Common targets of anxiety and PPARs

https://static-01.hindawi.com/articles/ppar/volume-2020/8859017/figures/8859017.fig.002.svgz

https://static-01.hindawi.com/articles/ppar/volume-2020/8859017/figures/8859017.fig.004.svgz

Additionally, PPAR is engaged in metabolism of amyloid beta precursor protein (APP) in the brain and directly or indirectly through Aβ it may also influence Tau protein phosphorylation. 

PPAR and its coactivator PGC-1α play an important role in cell differentiation and mitochondria biogenesis in neurodegeneration and neuroinflammation.

https://link.springer.com/article/10.1007/s11064-020-02993-5/figures/1

The PPAR-RXR Transcriptional Complex

The peroxisome proliferator-activated receptors (PPARs) and the retinoid X receptors (RXRs) are ligand-activated transcription factors that coordinately regulate gene expression. This PPAR-RXR transcriptional complex plays a critical role in energy balance, including triglyceride metabolism, fatty acid handling and storage, and glucose homeostasis: processes whose dysregulation characterize obesity, diabetes, and atherosclerosis. PPARs and RXRs are also involved directly in inflammatory and vascular responses in endothelial and vascular smooth muscle cells.

Retinoid Receptors and Retinoid Mediators

A central and perhaps somewhat overlooked factor in determining PPAR responses is RXR activity. Because PPARs are obligate RXR heterodimeric partners, the biology of RXR (including its ligands, expression levels, accessory molecules) all become important determinants of not only RXR but also PPAR responses. Many aspects of RXR biology—including genetic variation, how specific retinoid molecules modulate its activity, the enzymes involved in generating retinoid modulators, the binding proteins that handle retinoid transport and delivery, and even dietary aspects of retinoid intake—may influence RXR responses and functional PPAR effects, including those seen with PPAR agonists.

https://media.springernature.com/lw685/springer-static/image/art%3A10.1007%2Fs12035-021-02709-y/MediaObjects/12035_2021_2709_Fig6_HTML.png

RXR may facilitate the nuclear import of VDR (Vitamin D Receptor). 

The VDR gene provides instructions for making a protein called vitamin D receptor (VDR), which allows the body to respond to vitamin D. This vitamin can be acquired from foods in the diet or made in the body with help from sunlight exposure. Vitamin D is involved in maintaining the proper balance of several minerals in the body, including calcium and phosphate, which are essential for the normal formation of bones and teeth. One of vitamin D's major roles is to control the absorption of calcium and phosphate from the intestines into the bloodstream. Vitamin D is also involved in several processes unrelated to bone and tooth formation.

https://www.ommegaonline.org/articles/articleimages/16336_9251.png

The VDR protein attaches (binds) to the active form of vitamin D, known as calcitriol. This interaction allows VDR to partner with another protein called retinoid X receptor (RXR). The resulting complex then binds to particular regions of DNA, known as vitamin D response elements, and regulates the activity of vitamin D-responsive genes. By turning these genes on or off, the complex helps control calcium and phosphate absorption and other processes.

https://www.researchgate.net/profile/Robert-Mak/publication/44692302/figure/fig2/AS:277346297892865@1443135918264/Non-classical-actions-of-vitamin-D-VDR-RXR-Nuclear-vitamin-D-receptor-retinoid-X.png

Vitamin D may fight disease

In addition to its primary benefits, research suggests that vitamin D may also play a role in:

  • Reducing the risk of multiple sclerosis (MS). A 2018 review of population-based studies found that low levels of vitamin D are linked with an increased risk of MS.
  • Decreasing the chance of heart disease. Low vitamin D levels have been linked to increased risk of heart diseases such as hypertension, heart failure, and stroke. But it’s unclear whether vitamin D deficiency contributes to heart disease or simply indicates poor health when you have a chronic condition.
  • Reducing the likelihood of severe illnesses. Although studies are mixed, vitamin D may make severe flu and COVID-19 infections less likely. A recent review found that low vitamin D levels contribute to acute respiratory distress syndrome.
  • Supporting immune health. People who do not have adequate vitamin D levels might be at increased risk of infections and autoimmune diseases, such as rheumatoid arthritis, type 1 diabetes, and inflammatory bowel disease.

Vitamin D may regulate mood and reduce depression

Research has shown that vitamin D might play an important role in regulating mood and decreasing the risk of depression.

A review of 7,534 people found that those experiencing negative emotions who received vitamin D supplements noticed an improvement in symptoms. Vitamin D supplementation may help people with depression who also have a vitamin D deficiency.

Another study identified low vitamin D levels as a risk factor for more severe fibromyalgia symptoms, anxiety, and depression.

It might support weight loss

People with higher body weights have a greater chance of low vitamin D levels.

In one study, people with obesity who received vitamin D supplements in addition to following a weight loss diet plan lost more weight and fat mass than the members of the placebo group, who only followed the diet plan.

In an older study, people taking daily calcium and vitamin D supplements lost more weight than subjects taking a placebo supplement. The researchers suggest that the extra calcium and vitamin D may have had an appetite-suppressing effect.

The current research doesn’t support the idea that vitamin D would cause weight loss, but there appears to be a relationship between vitamin D and weight.

So by upregulating the expression of PPARG, the expression of VDR is also upregulated via RXR.

RXR also promotes myelin debris phagocytosis and remyelination by macrophages. It plays a role in the attenuation of the innate immune system in response to viral infections, possibly by negatively regulating the transcription of antiviral genes such as type I IFN gene.

Upregulating the expression of this gene may help improve your health on a MASSIVE SCALE because PPAR Gamma is a HOTSPOT found in our genome. Its dysregulation has been implicated in NUMEROUS health conditions.

ReverseFX contains the following compounds that have been shown to modulate PPARG:

  • MCT oil powder – Caprylic, Capric, Palmitic, Myristic, and Lauric Acid (RR, R)
  • Resveratrol (R, R, R)
  • Pomegranate/Ellagic acid (R)
  • Dan shen (R)
  • Ginger (R)
  • Licorice (R) (R)
  • Chinese Skullcap (R, R)
  • N-Acetylglucosamine (R)
  • Kudzu/Daidzein (R)
  • Seabuckthorn/Isorhamnetin (Vitamin E, Emodin) (R)
  • Nattokinase/Glycine max (R)
  • Phosphatidylcholine (R)

* These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease.

Sources:

https://www.genecards.org/cgi-bin/carddisp.pl?gene=PPARG

https://en.wikipedia.org/wiki/Peroxisome_proliferator-activated_receptor_gamma

https://selfhack.com/blog/ppargamma-role-weight-gain-inflammation-natural-activators/

https://www.frontiersin.org/articles/10.3389/fendo.2021.624112/full

https://pubmed.ncbi.nlm.nih.gov/17418635/

https://www.hindawi.com/journals/ppar/2015/549691/

https://www.science.org/doi/10.1126/sciimmunol.aal5196

https://www.frontiersin.org/articles/10.3389/fphar.2020.00730/full

https://www.mdpi.com/1422-0067/22/19/10573/htm

https://www.sciencedirect.com/science/article/pii/S0891584916303112

https://www.hindawi.com/journals/ppar/2020/8859017/

https://www.nature.com/articles/srep07749

https://www.ahajournals.org/doi/10.1161/circresaha.110.226860

https://link.springer.com/article/10.1007/s12035-021-02709-y

https://www.genecards.org/cgi-bin/carddisp.pl?gene=RXRA

https://medlineplus.gov/genetics/gene/vdr/

https://www.healthline.com/health/food-nutrition/benefits-vitamin-d#1.-Vitamin-D-may-fight-disease

https://www.ommegaonline.org/article-details/Role-of-vitamin-D-receptor-VDR-genetic-polymorphism-in-onset-of-type-2-diabetes-mellitus/2458

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