(Proteins = amino acids)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?
FIGURE (below)
Therapeutic targets of PPARδ in the metabolic syndrome. Receptor activation improves multiple aspects of the metabolic syndrome through tissue- and cell-specific effects. In skeletal muscle, PPARδ regulates fatty acid transport and oxidation, thermogenesis, and the formation of slow-twitch muscle fibers, resulting in enhanced endurance performance. It likewise activates fatty acid transport and oxidation as well as thermogenesis in adipose tissue, retarding weight gain. PPARδ regulates the availability of BCL-6, an inflammatory suppressor protein released upon ligation of PPARδ, thereby functioning as an “antiinflammatory switch” to control macrophage-elicited inflammation and atherogenesis. In the liver, PPARδ activation suppresses glucose production by upregulating the pentose phosphate shunt. PPARδ activation also improves atherogenic dyslipidemia by raising serum HDL cholesterol levels via unclear mechanisms. Additionally, PPARδ activation in the heart enhances contractile function and may improve cardiomyopathy.
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
"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)."
The key may be perhaps... muscle. Isn't the heart one of the most important muscles? It beats every second of every minute of our lives, right? Nearly 100,000 times per day.
Metabolic 'remodeling' in the muscles activates PPAR-Delta; fasting, exercise training, and diabetes can affect it. The end result is prevention of obesity/weight gain and potently sensitizing glucose uptake.
"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
(41). Oxidative myofibers preferentially express enzymes that oxidize fatty acids and contain slow isoforms of contractile proteins, whereas glycolytic myofibers predominantly metabolize glucose and are composed of fast contractile protein isoforms (41, 42). Skeletal muscle is highly
plastic, adapting to environmental challenges by regulating the composition of slow- and fast-twitch myofibers. Interventions including endurance exercise, physical inactivity, and metabolic diseases such as type 2 diabetes mellitus can induce the trans-differentiation of myofibers (43)."
"PPARδ’s regulation of metabolic and fiber type status has several physiological implications. First, the presence of an increased proportion of oxidative slow-twitch fibers is predicted to decrease skeletal muscle fatigability. For example, increased endurance in marathon runners is linked to a higher proportion of oxidative slow-twitch fibers in their skeletal muscles. Mice with muscle-specific VP16-PPARδ transgenes have strikingly higher treadmill endurance capacity, running twice as long and far as wild-type mice (WOW -- super-mice! PPAR-Delta doubles the distance!) (48). Second, oxidative fibers have a tremendous impact on fatty acid homeostasis. Both obesity and insulin resistance are linked to a decrease in the proportion of oxidative slow-twitch fibers in skeletal muscle (52–56). Muscle-specific VP16-PPARδ transgenic mice, which have a higher proportion of oxidative slow-twitch fibers, are resistant to high-fat diet–induced obesity (48). Activation of PPARδ during high-fat feeding (In Lab language, translates to 'HIGH CARB' lab chow -- c-a-r-b is the context to concentrate on.) increases disposal of lipid in skeletal muscles, preventing the storage of excess fat in adipocytes and weight gain (39, 40, 49)."
PPAR-Delta activation may be the most heart-protective of all the PPAR receptor subtypes -- PPARalpha and PPARgamma have primary tissue expression, however PPARdelta is expressed strongly ubiquitiously.
Undoubtedly, this receptor has the most power to shield the heart from shifting to inferior energy sources (glucose) and developing inelasticity and stiffness in heart muscle fibers. What has been shown to activate PPAR-Delta? Protein intake (see end), fatty acid intake, movement (see end). What has been shown definitely to de-activate PPAR-Delta? The amount of unliganded receptors appears to predict the inflammatory status, according to Takahashi S, et al. (New therapeutic target for metabolic syndrome: PPARdelta. Endocr J. 2007 Jun;54(3):347-57). Paraplegia (see later). In other words, long periods of physical inactivity and sedentary lifestyles allow this pivotal anti-inflammatory 'switch' to be turned off (which can later lead to heart disease, heart failure, MetSyn, insulin resistance, and even cancer in vitro here and here).
A future blog topic is cardiac energetics (and other laws of physics). Our heart and skeletal muscles prefer combusting fatty acids, not glucose, for energy. Glycogen (glucose stored in muscles) is more like kindling and twigs to a fire. What fuels a nice roaring fire? Nice l-o-g-s... For burning PHAT (!!) flaming fires, our bodies go to temporarily-stored fatty acids in skeletal muscles... then next it goes to WAT (white adipose tissue) found in centrally-located fat, ie toxic wheat-bellies (that Dr. Davis frequently refers to). PPAR-Delta again is responsible for regulating the 'switch' to preferred fuel metabolism!"Fatty acid oxidation is the primary source of energy in the postnatal heart (67). Impaired fatty acid oxidation and a shift to reliance on glucose metabolism are hallmarks of myocardial diseases such as cardiac hypertrophy and congestive heart failure (67). As in skeletal muscle, PPARδ is a critical regulator of fatty acid oxidation in cardiac tissue. Cheng et al. showed that cardiac-specific deletion of PPARδ suppresses the expression of oxidative genes (68). This leads to impaired fatty acid oxidation and a reciprocal increase in glucose oxidation, along with fat accumulation in cardiomyocytes (68). Moreover, PPARδ-selective agonists increase fatty acid oxidation via the induction of oxidative genes in isolated neonatal as well as adult rat cardiomyocytes (69) (Table 1). The PPARδ-dependent maintenance of basal fatty acid oxidation is crucial for normal cardiac mechanics. PPARδ-null hearts are characterized by decreased rates of contraction and relaxation, increased left ventricular end-diastolic pressure, and decreased cardiac output, factors associated with the onset of cardiac failure (68). Indeed, mice with cardiac-specific deletion of PPARδ develop age-dependent cardiac lipotoxicity, cardiac hypertrophy, end-stage dilated cardiomyopathy, and decreased survival (68). The protective role of PPARδ in the heart has been confirmed by in vitro studies showing that PPARδ agonists attenuate phenylephrine-induced cardiac hypertrophy. While phenylephrine suppresses fatty acid oxidation in cardiomyocytes, concomitant activation of PPARδ reverses these effects (70). Although PPARδ may directly increase the transcription of fatty acid oxidative genes, at least 1 study suggests that effects could also be indirect. Planavila and colleagues showed that PPARδ interacts with and blocks NF-κB–mediated suppression of fatty acid oxidation in cardiomyocytes (71). PPARδ-dependent antagonism of NF-κB could be particularly important during sepsis, when endotoxins decrease cardiac fatty acid oxidation and initiate cardiac failure (71, 72)."
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.
Eat protein... MAKE PROTEIN, ie, muscles!
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).
- Dreyer HC, Glynn EL, Lujan HL, Fry CS, DiCarlo SE, Rasmussen BB. Chronic paraplegia-induced muscle atrophy downregulates the mTOR/S6K1 signaling pathway. J Appl Physiol. 2008 Jan;104(1):27-33. Epub 2007 Sep 20. PMID: 17885021
- Röckl KS, Witczak CA, Goodyear LJ. Signaling mechanisms in skeletal muscle: acute responses and chronic adaptations to exercise. IUBMB Life. 2008 Mar;60(3):145-53. Review. PMID: 18380005 Link to full article here (see below for 2 great figures).
SUMMARY by Rockl et al: "Exercise is of critical importance for people with insulin resistance or diabetes. Our current understanding is that one of the many benefits of an acute bout of exercise is an insulin-independent increase in the glucose uptake capacities of skeletal muscle. Important chronic
adaptations to exercise training are the increase of mitochondria and thus oxidative capacities in skeletal muscle, the transformation of muscle fiber types, and the increase in GLUT4 protein expression.
Contractile activity and insulin are the most potent and physiologically relevant stimuli of glucose transport in skeletal muscle. While significant progress has been made in elucidating the insulin signaling pathway leading to GLUT4 translocation, identification of the signals mediating contraction-stimulated glucose transport has proved challenging. A growing body of data suggests that multiple signaling cascades mediate the metabolic effects of contraction. While the proximal signals leading to contraction- and insulin-stimulated glucose transport are clearly distinct, emerging studies have shown a reconnection or convergence of these signals at AS160.
Exercise training induces an increase of oxidative capacity, fiber type changes, and elevated GLUT4 protein levels in skeletal muscle; adaptations which are of critical importance to lower free fatty acids, improve glucose uptake, and decrease the risk of insulin resistance and diabetes. Again, multiple signaling pathways appear to act synergistically to mediate adaptive responses to exercise training. In particular, AMPK and calcineurin have evolved as major candidates for mediating exercise-training adaptations. PGC-1 may be a point of convergence for both pathways. While considerable progress has been made in decoding molecular mechanisms around these molecules, more research will be needed to test their physiological role in skeletal muscle adaptations to exercise training. "
Figure: Proposed model for the signaling pathways mediating insulin and contraction-induced skeletal muscle glucose transport. Insulin and contraction-mediated glucose transport occurs by translocation of glucose transporter 4 (GLUT4) from intracellular locations to the plasma
membrane. Insulin binding leads to phosphorylation of the insulin receptor with subsequent activation of insulin receptor substrate 1/2 (IRS-1/2) and phosphatidylinositol 3-kinase (PI3-kinase). Downstream of PI3-kinase the protein kinases, Akt, which then regulates activation of Akt Substrate of 160 kD (AS160), and atypical protein kinase C (aPKC), have been identified to mediate insulin stimulated GLUT4 translocation. Contraction stimulated glucose uptake is mediated by multiple signaling pathways including aPKC, Ca2+/calmodulin-dependent protein kinase II (CaMKII), Ca2+/calmodulin-dependent protein kinase kinase (CaMKK), LKB1, and AMP-activated protein kinase (AMPK).
