Melting Point/Sesamin Stack

Introduction

Peroxisome profilerator-activated receptors (PPARs) are nuclear hormone receptors that belong to the steroid/thyroid/retinoid superfamily of receptors (Keller et al. 2000). PPARs form heterodimers with the retinoid-X receptors (RXR). The PPAR/RXR dimer then binds to a peroxisome proliferators-response element (Staels and Fruchart 2005), a DNA-specific sequence of which many types exist. This binding activates a change in gene transcription.

There exist three different PPAR isoforms, alpha, beta/delta, and gamma, which when activated stimulate expression of genes involved in energy homeostasis, specifically the metabolism of glucose and fatty acids (Blaschke et al. 2006). These different isoforms vary in their affinity to ligands, distribution throughout the body, and cofactors proteins they bind to. Each isoform has distinct properties and actions when activated.


PPAR-Alpha

PPAR-alpha is found in metabolically active tissues, the liver, adipocytes, skeletal muscle, the heart, and the kidneys, where it is involved in lipid metabolism, and in vascular endothelium, vascular smooth muscle, and macrophages.

PPAR-alpha activation increases the expression of lipoprotein lipase and apolipoprotein A-V (apoA-V) while simultaneously decreasing expression of apoC-III in the liver, which decreases VLDL particles and lowering plasma triglycerides in chylomicrons (Staels and Fruchart 2005). These changes liberate fatty acids, allowing them to either be oxidized or stored. This suggests that use of a PPAR-alpha agonist may be beneficial in aiding fat loss.

In addition to the change in plasma fatty acid levels, hepatic apoA-I andapoA-II are increased by PPAR-alpha activation, which improves cholesterol levels by increasing HDL levels (Chinetti et al. 2001).


PPARbeta/delta

The exact actions of PPARbeta/delta are still being researched, though in obese animals it appears to decrease adiposity. Some feel that PPARbeta/delta may serve as a “back-up” to PPARalpha or have more specific actions in skeletal muscle than PPARalpha does (Tenenbaum et al. 2005).


PPAR-Gamma

PPARgamma is found primarily in adipocytes, vascular endothelium, vascular smooth muscle, and macrophages, but also in smaller number in skeletal muscle and the heart (Staels and Fruchart 2005). It is involved in the storage of fatty acids and is activated by leukotrienes, prostaglandins, and fatty acids. Activation of PPAR-gamma can either increases or decreases the transcription of genes and enzymes involved in insulin sensitivity and adipogenesis, adipocyte differentiation, cell proliferation, and the inflammatory process (Kodera et al. 2000), all of which play a role in obesity and metabolic syndrome X (abdominal obesity, insulin resistance, and elevated blood pressure). Obesity and insulin resistance lead to elevated plasma fatty acid levels. Activation of PPAR-gamma increase fatty acid storage, therefore obesity and insulin resistance suppress PPAR-gamma activation (Guo and Tabrizchi 2005).

Activation of PPAR-gamma should decrease insuling resistance. The anti-diabetic drug thiazolidinediones has been used to treat type-2 diabetes, though possible hepaotoxicity and congestive heart failure due to use of this drug has limited its use (Guo and Tabrizchi 2005).


Natural Dietary Supplements Targeting PPAR (Lignans and Fatty Acids)

Due to the potential side effects associated with the current pharmaceutical drugs that target PPAR receptors, safe alternatives are being searched for. New research is being done with various lignans and fatty acids to measure their ability to activate the PPAR receptors.


Sesamin

Sesamin is a naturally occurring lignan found in sesame seeds and oil. A lignan is a molecule that combines with a receptor or another entity acting as an “activator.” sesamin has been shown to be a potent PPAR-alpha agonist (Ide et al. 2003). The majority of sesamin research has been done on rats, but the results are very promising for use of sesamin to treat type-2 diabetes and obesity.

Fat can be oxidized in the mitochondria and the peroxisomes of cells, the majority of this oxidation occurring in skeletal muscle cells and the liver. PPARalpha activation by sesamin increases fat oxidation in mitochondria and peroxisomes by increasing the expression of enzymes involved in beta-oxidation of fatty acids (Sirato-Yasumoto et al. 2001). Of vital important, sesamin increases the expression of the mitochondrial enzyme carnitine palmitoyl transferase (CPT) (Sirato-Yasumoto et al. 2001). CPT, the rate-limiting enzyme in beta-oxidation of fatty acids in skeletal muscle and liver cell mitochondria, is found on the outer membrane of mitochondria and carries fatty acids across the membrane into the mitochondria by binding to them. Increasing the expression of CPT will allow more fatty acids to be transported into the mitochondria where they can be oxidized.

In addition to increasing the oxidation of fat, sesamin supplementation has also been shown to decrease lipogenesis by decreasing lipogenic enzymes in the liver. sesamin has been shown to decrease the gene expression of sterol regulatory element binding protein-1 (SREBP-1), acetyl-CoA carboxylase, and fatty acid synthase, among other lipogenic enzymes (Ide et al 2001), which means less fat is esterifized in the liver and therefore less fat is stored in adipose tissue.


TetradecylThioacetic Acid (TTA)

TetradecylThioacetic Acid (TTA), a non beta-oxidizable fatty acid analog, has been shown to activate all three of the PPAR receptors in rats, in the ranking order of alpha > beta/delta > gamma (Madsen et al. 2002). TTA has been shown to increase insulin sensitivity by increasing hepatic fat oxidation and ketogenesis while draining fatty acids from the blood and extrahepatic tissues. This drainage of fatty acids by the liver increases the ability of adipocytes and skeletal muscle in uptake glucose (Grav et al. 2003).

TTA has been shown to cause mitochondrial and peroxisomal proliferation in rats (Kryvi et al. 1990), leading to increased beta-oxidation of fatty acids in the liver, along with increasing uncoupling protein-2 (UCP-2) expression (Grav et al. 2003). UCP-2, and UCP-3, is involved in preventing the accumulation of oxygen-specific free radicals and in regulating lipogenesis and ketogenesis. UCP-2 is found throughout the body (Grav et al. 2003). These three adaptations, increased mitochondria, peroxisomes, and UCP-2 concentrations, all aid in increasing insulin sensitivity and reducing adiposity.


Scivation Sesamin + Designer Supplements Melting Point

Sesamin (found in Scivation’s Sesamin) and TTA (found in Designer Supplements Melting Point) compliment each other very well with regards to fat loss and health enhancement. The dual action of PPARalpha and PPARbeta agonist creates a huge increase in fat oxidation. This non-stimulant fat oxidation stack is a potent combo guaranteed to melt the fat off your body.


References:

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Guo L, Tabrizchi R. Peroxisome proliferator-activated receptor gamma as a drug target in the pathogenesis of insulin resistance. Pharmacol Ther. 2005 Nov 20

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Ide T., et al. 2003. Sesamin, a Sesame Lignan, as a Potent Lipid-Lowering Food Component. JARQ 37 (3), 151 - 158.

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Kodera, Y., Takeyama, K., Murayama, A., Suzawa, M., Masuhiro ,Y. and Kato, S. (2000) Ligand type-specific interactions of peroxisome proliferator-activated receptor with transcriptional coactivators. J. Biol. Chem.,275, 33201-33204

Kryvi H, Aarsland A, Berge RK. Morphologic effects of sulfur-substituted fatty acids on rat hepatocytes with special reference to proliferation of peroxisomes and mitochondria.J Struct Biol. 1990 May;103(3):257-65.

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PPARbeta: studies using null mice. Biochim Biophys Acta1632 :80 –89,2003

Sirato-Yasumoto S, Katsuta M, Okuyama Y, et al. Effect of sesame seeds rich in sesamin and sesamolin on fatty acid oxidation in rat liver. J Agric Food Chem 2001 May;49(5):2647-51.