Scivation Melting Point/Sesamin Stack, Stack
Peroxisome Profilerator-Activated Receptors
(PPARs) and their use in
Improving Health and Wellness
By Derek Charlebois
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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proliferator-activated receptor, and atherosclerosis in type 2
diabetes. Arterioscler Thromb Vasc Biol. 2006 Jan;26(1):28-40. Epub
2005 Oct 20. Review.
Cabrero A, Laguna JC, Vazquez M: Peroxisome proliferator-activated
receptors and the control of inflammation. Curr Drug Targets Inflamm
Allergy1 :243 –248,2002
Chinetti G, Lestavel S, Bocher V, Remaley AT, Neve B, Torra IP,
Teissier E, Minnich A, Jaye M, Duverger N, Brewer HB, Fruchart JC,
Clavey V, Staels B: PPAR-alpha and PPAR-gamma activators induce
cholesterol removal from human macrophage foam cells through
stimulation of the ABCA1 pathway. Nat Med7 :53 –58,2001
Grav HJ, Tronstad KJ, Gudbrandsen OA, Berge K, Fladmark KE, Martinsen
TC, Waldum H, Wergedahl H, Berge RK. Changed energy state and increased
mitochondrial beta-oxidation rate in liver of rats associated with
lowered proton electrochemical potential and stimulated uncoupling
protein 2 (UCP-2) expression: evidence for peroxisome
proliferator-activated receptor-alpha independent induction of UCP-2
expression. J Biol Chem. 2003 Aug 15;278(33):30525-33. Epub 2003 May 19.
Guo L, Tabrizchi R. Peroxisome proliferator-activated receptor gamma as
a drug target in the pathogenesis of insulin resistance. Pharmacol
Ther. 2005 Nov 20
Ide T., et al. 2001. Sesamin, a sesame lignan, decreases fatty acid
synthesis in rat liver accompanying the down-regulation of sterol
regulatory element binding protein-1. Biochim Biophys Acta. Nov
30;1534(1):1-13.
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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proliferator-activated receptors (PPARS) in development, cell life
status and disease. Int J Dev Biol. 2000 Aug;44(5):429-42. Review.
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
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Biol. 1990 May;103(3):257-65.
Madsen L, et al. Tetradecylthioacetic acid prevents high fat diet
induced adiposity and insulin resistance. J Lipid Res. 2002
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Maeda N, Takahashi M, Funahashi T, Kihara S, Nishizawa H, Kishida K,
Nagaretani H, Matsuda M, Komuro R, Ouchi N, Kuriyama H, Hotta K,
Nakamura T, Shimomura I, Matsuzawa Y: PPAR-gamma ligands increase
expression and plasma concentrations of adiponectin, an adipose-derived
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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. |
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