PPAR-Delta is part of the family of peroxisome proliferator-activated receptors (PPARs). This receptor family is responsible for cueing in environmental nutrients. In evolutionary terms, survival depended on nutrients in the environment and the ability for the human body to adapt to low nutrients vs. plentiful nutrients it is hypothesized to determine inflammatory status, growth, reproduction and development. Nutrient factors like dietary fats and protien bind or regulate PPAR receptors, thus these receptors have been termed 'nutrient sensors.'
How is this wonderful transcriptional 'switch' turned on? What degrades its amazing anti-inflammatory and muscle/metabolism-building functions? PPAR-Delta works through the mTOR pathway which reminds me enormously of the Norse god THOR which shares similar attributes -- invincibility, strength and virility. Can PPAR-Delta be the dagger in the heart of heart disease?
PPAR delta: a dagger in the heart of the metabolic syndrome .
Barish GD , et al. Howard Hughes Medical Institute, Salk, La Jolla CA. J Clin Invest. 2006 Mar;116(3):590-7.
Obesity is a growing threat to global health by virtue of its association with insulin resistance, glucose intolerance, hypertension, and dyslipidemia, collectively known as the metabolic syndrome or syndrome X. The nuclear receptors PPARalpha and PPARgamma are therapeutic targets for hypertriglyceridemia and insulin resistance, respectively, and drugs that modulate these receptors are currently in clinical use. More recent work on the less-described PPAR isotype PPARdelta has uncovered a dual benefit for both hypertriglyceridemia and insulin resistance, highlighting the broad potential of PPARdelta in the treatment of metabolic disease. PPARdelta enhances fatty acid catabolism and energy uncoupling in adipose tissue and muscle, and it suppresses macrophage-derived inflammation. Its combined activities in these and other tissues make it a multifaceted therapeutic target for the metabolic syndrome with the potential to control weight gain, enhance physical endurance, improve insulin sensitivity, and ameliorate atherosclerosis. PMID: 16511591
Synthetic analogues of chemicals that bind PPAR-Delta are being elucidated. In animal (and human) studies, their extreme benefits have been shown on lipids as well as reductions in insulin and improvement in insulin sensitivity . Barish et al summarize much of the current research on PPAR-Delta, including astounding trends in reductions in small dense atherogenic LDL, increases HDL, lowering of TGs, as well as the drops in insulin.
"High-affinity PPARδ ligands have revealed an important role for PPARδ in lipoprotein metabolism. Treatment of insulin-resistant obese rhesus monkeys with the PPARδ-selective agonist GW501516 resulted in a dramatic 79% increase in HDL-C , a 56% decrease in triglycerides, and a 29% decrease in LDL cholesterol ( 33 ). The profound increase in HDL cholesterol levels correlated with an increase in number, not size, of HDL particles and was accompanied by increased serum levels of the HDL-associated apolipoproteins apoA-I, apoA-II, and apoC-III ( 33 ). In addition, fasting insulin levels declined by up to 48% in the PPARδ drug–treated animals ( 33 ). Obese and nonobese mice similarly develop an increase of up to 50% in HDL cholesterol levels when treated with PPARδ agonists ( 34 , 35 ). The mechanism by which PPARδ activation raises HDL cholesterol levels remains to be elucidated, but studies to date indicate that expression of the reverse cholesterol transporter ABCA1 is enhanced in some tissues upon exposure to PPARδ agonists, including human and mouse macrophages as well as human intestinal cells and fibroblasts ( 33 , 35 ). Additional work suggests that PPARδ activation reduces intestinal cholesterol absorption via downregulation of the Niemann-Pick C1–like 1 gene (NPC1L1) ( 35 ). NPC1L1 is a key mediator of intestinal cholesterol absorption and a putative target for the clinically used cholesterol absorption inhibitor ezetimibe (ZETIA). "
However, like all synthetic, fake analogues which try to copy and mimic our own natural endogenous nutritional factors (Dr. Davis recently discussed) that we consume or make on our own, these agents so far are not the 'magic bullet' researchers hoped for. In this trial, there are questionable effects on colon carcinogenesis in APCmin mice with one synthetic analogue GW501516 (and other cancer lines). This reminds me of other failed clinical trials where synthetic vitamins or hormones caused poor outcomes (CARET, WHI, etc). Natural ligands seem to be the most optimal binders to our natural receptors.
"Moreover, PPARδ agonists enhanced β-oxidation in 3T3-L1 preadipocytes by 50% (39 ). Most importantly, PPARδ ligands retard weight gain in models of high-fat diet–induced obesity ( 39 , 40 ). These results suggest that PPARδ synthetic drugs may be therapeutic as antiobesity agents. Short-term (4-month) treatment of obese rhesus monkeys with variable doses of GW501516 did not affect body weight, however, so it remains to be determined whether long-term administration of PPARδ drugs will control body weight in monkeys and humans ( 33 )."
" Skeletal muscle is a key metabolic tissue, accounting for approximately 80% of insulin-stimulated glucose uptake. It is composed of heterogeneous myofibers that differ in their metabolic and contractile properties, including oxidative slow-twitch (type I), mixed oxidative/glycolytic fast-twitch (type IIA), and glycolytic fast-twitch (type IIB) forms
FIGURE. PPARδ: an inflammatory switch . In the absence of ligand, PPARδ-RXR heterodimers bind to consensus PPAR DNA response elements (PPREs) and repress target gene expression by recruiting corepressors and associated repressive proteins including B cell lymphoma-6 (BCL-6) (top). (VITAMIN A, RETINOIDS, CAROTENOIDS BIND RXR) Upon addition of PPARδ ligand (bottom left), PPARδ-RXR heterodimers undergo a conformational shift. This dismisses the corepressor complex, including BCL-6, in exchange for a complex of coactivator proteins and results in enhanced PPARδ target gene expression. BCL-6, an inflammatory suppressor protein, is thereby liberated to repress inflammatory gene expression .
Some natural nutrients and endogenous substances that bind or activate PPARdelta are listed below. What are the side effects of these receptor agonists? Vitality, strength and virility. No cancer, no heart disease, etc.
Fish oil (yeah my favorite) -- DHA, EPA -- n-3 PUFAs
Vitamin D, Vitamin A -- heterodimer with PPARs via VDR and RAR/RXR
Monounsaturated fatty acids (ie, olive oil)
Walnuts, Almonds (n-3 PUFAs, MUFAs)
Saturated fatty acids (our own adipose depots as burned with resistance training/exercise; consumed)
Eicosanoids -- Prostacyclin (PGI2), carbaprostacycline (cPGI2)
Protein -- indirectly activates PPARdelta via mTOR signalling
Physical movement -- especially resistance training with weights
Eat protein... MAKE PROTEIN, ie, muscles!
Dreyer HC, Drummond MJ, Pennings B, Fujita S, Glynn EL, Chinkes DL, Dhanani S, Volpi E, Rasmussen BB. Leucine-enriched essential amino acid and carbohydrate ingestion following resistance exercise enhances mTOR signaling and protein synthesis in human muscle. Am J Physiol Endocrinol Metab. 2008 Feb;294(2):E392-400. PMID: 18056791
Inactivity trains our muscles to degrade and die off. Eight hours of sedentary activity can lead to our most important muscle, the heart, to effectively atrophy. Whereas, use of muscles signals to the body to build m-o-r-e muscles. The resulting adaptations to movement are (1) muscle growth (2) increased synthesis of more mitochrondria (fuel-burning furnaces) (3) higher increases in glucose uptake and transporters for glucose (which thereby ameliorate insulin resistance).