I had said in another thread that I was beginning to wade through Trouble's posts over at IronAddicts.com, on her grand theory involving nuclear receptors. I said that if I found any interesting information I would rehash it for the community. Well I came across a couple interesting papers that Trouble posted, and thought I might begin by posting some quotes from the papers and a little discussion. Hopefully after I gather a few posts worth of papers I will be able to begin to pull some of it together...
I know there has been quite a lot of discussion of the PPAR receptors, particularly α (alpha) and γ (gamma), but there hasn't been much said about β/δ (beta/delta, which I will call delta, δ , from here on). Here are some interesting excerpts from 3-4 different papers:
This is interesting, and I think more or less well known. But it should be noted that these IL's are pro-inflammatory, and that some/many anti-inflammatories are going to inhibit the release of these. There is an article on M&M talking about not taking NSAIDs to reduce DOM after training because you are robbing yourself of some of your growth, well this is part of the reason for why that is. I have looked long and hard to see if PPAR agonists of the various sorts, which are all anti-inflammatory, reduce the levels of these IL's; I have yet to find anything. The only thing I have found is that administration of IL-15 causes increased expression of PPARδ. [see: http://dx.doi.org/10.1016/j.bbalip.2005.12.006]Recent studies demonstrate that skeletal muscle is an endocrine organ. Muscle expresses and releases several cytokines into the circulation, for example, IL-6, IL-8 and IL-15. The autocrine actions are well documented, however, evidence is accumulating that these cytokines exert their effect in other parts of the body. Muscle derived cytokines have been coined "myokines".
Sustained and intense exercise induces skeletal muscle to express and release IL-6 into the circulation, more so when glucose and glycogen stores are low. IL-6 stimulates AMPK activity (in adipose and lean tissue), lipolysis in adipose, inhibits TNFα, and improves insulin sensitivity. Furthermore, IL-6 deficient mice have reduced endurance, energy expenditure, glucose intolerance and develop late onset obesity. [see also: http://www.ncbi.nlm.nih.gov/entrez/query.f...t_uids=16945991]
IL-8 induces localized angiogenesis in response to exercise. [growth of new blood vessels]
IL-15, abundantly expressed in skeletal muscle (and induced by acute exercise) leads to muscle hypertrophy, reduced lipogenesis and enhanced lipolysis in adipose tissue.
I found all of this extraordinarily interesting, as there has been much discussion of the PPAR's here on M&M, but it has been scattered over many years and many threads. This paper pulls together much of the recent research, and illuminates the role of PPARδ. It seems to me that we really really want to have a nice PPARδ agonist at our disposal, maybe even more so than the currently used PPARα agonists.Metabolism, in part, is regulated by nuclear hormone receptors (NRs) which function as hormone regulated transcription factors that bind DNA and control gene expression. Essentially, NRs function as the conduit between environmental stimuli and gene expression, and mediate the physiological response.
NRs involved in control of lipid and cholesterol metabolism, and energy expenditure in skeletal muscle include the peroxisome proliferator activated receptors (PPARs α, γ, and β/δ), liver X receptors (LXRs α and β), thyroid hormone receptors (TRs), glucocorticoid receptor (GR), and farnesoid X receptor (FXR).
PPARα and PPARγ are predominantly, though not exclusively, expressed in liver and adipose tissue, respectively. While PPARδ expression is ubiquitous it is abundantly expressed in brain, intestine, skeletal muscle, spleen, macrophages, lung, fat, and adrenals.
PPARγ promotes adipogenesis and increases lipid storage in adipose tissue. In contrast PPARα enhances the conflicting process of fatty acid oxidation in the liver. Until recently relatively little was known about the specific function of PPARδ. PPARδ regulates glucose tolerance, fatty acid oxidation, and energy expenditure in adipose and skeletal muscle.
PPARα specific agonists stimulate mitochondrial β-oxidation in vivo in both liver and muscle via the up-regulation of genes such as mCPT1, MCAD and MTE1. Furthermore PPARα activation promotes thermogenesis in muscle via the induction of uncoupling proteins-1, -2 and -3. Interestingly PPARα knock-out mice exhibited minimal alteration in skeletal muscle lipid homeostasis or expression of PPARα target genes following a period of starvation or exertion. It was proposed that this observation reflects the ability of PPARδ to compensate for the lack of PPARα representing a potential functional redundancy between these genes.
PPARδ was implicated in fatty acid catabolism and homeostasis from the observation that skeletal muscle from PPARα knock-out (KO) mice has similar oxidative capacity to muscle derived from wild type animals. Unlike in liver and heart, PPARδ is several fold more abundant in skeletal muscle of wild-type mice, than either PPARα or PPARγ, and this high abundance of PPARδ may compensate for the lack of PPARα in the KO-mice. This hypothesis is underscored by the fact that:
(i) exercise induces the classical PPARα target genes, pyruvate-dehydrogenase kinase 4 (PDHK4) and uncoupling protein-3 (UCP3) in skeletal (but not cardiac) muscle from the wild type (WT) and KO mice.
(ii) PPARδ agonists increases fatty acid oxidation and induces the expression of several lipid regulatory genes, including PDHK4 and UCP3.
These results indicate somehow a redundancy in the functions of PPARα and PPARδ as regulators of fatty acid metabolism in skeletal muscle. Starvation induces PPARδ mRNA expression in murine gastrocnemius muscle with concomitant activation of fatty acid translocase/CD36 (FAT/CD36), muscle carnitine palmitoyl transferase (M-CPT1 or CPT-1β) and heart fatty acid binding protein (FABP). Similarly the PPARδ agonist induced the expression of acyl-CoA synthetase (ACS), CPT1, UCP2, and UCP3 in rodent neonatal cardiomyocytes in concordance with an increase in fatty acid oxidation.
PPARδ is predominantly expressed in mitochondrial rich type I (oxidative, slow twitch), relative to type-II (glycolytic, fast twitch) skeletal muscle. Endurance training promotes conversion into type-I muscle, accompanied by an increased expression of PPARδ. Muscle specific expression of PPARδ in mice lead to an increase in type-I muscle fibres. Concordantly, increased activity of enzymes involved in oxidative (not glycolytic) metabolism has been reported. Expression analysis also revealed an induction of the genes involved in increased oxidative metabolism, glucose tolerance, preferential lipid utilization, energy expenditure (i.e. troponin-I-slow, cytochrome-C, UCP2, UCP3, and CPT1), and increased endurance.
Numerous studies demonstrated that GW501516 treatment and skeletal muscle specific PPARδ expression in mice ameliorated diet induced obesity, enhanced metabolic rate, lipid oxidation, reduced intramuscular triglycerides and increased mitochondria in skeletal muscle. Moreover, anatomical analysis revealed the resistance to increased body weight was largely due to reduced mass of visceral and epidermal fat depots. The drug treatment ameliorated the diet induced:
(i) hypertrophy in epidermal white adipose, and brown fat.
(ii) hepatic steatosis.
(iii) accumulation of intramuscular lipid droplets.
Interestingly, these mice have profoundly increased endurance capabilities, and resistance to fatigue relative to their wild-type littermates, hence the term "marathon mouse" is used in the press.
Studies involving pharmacological treatment with PPARδ agonists in primates and rodents, and/or genetic manipulation clearly demonstrate the utility of this receptor in the treatment of diabetes. For example, dose dependent decrease in serum insulin levels (not, vert, similar50%), improved glucose tolerance, and lower fasting glucose levels.
[see also: http://www.jbc.org/cgi/content/full/277/29/26089]
I liked this paper because it talks about how PPARα agonists actually improve insulin sensitivity, contrary to what has been discussed in most threads here at M&M. It even discusses a possible mechanism for such an improvement and cites research to back it up.Recently, there has been heightened interest in the lipid oversupply hypothesis that links increased muscle lipid content with the development of insulin resistance. Several rodent studies have shown that insulin sensitivity indexes correlate inversely with changes in muscle lipid content. Similarly, in humans, studies have demonstrated that intramyocellular TAG content correlates inversely with insulin resistance, and that multiple regression analyses select muscle TAG as the strongest predictor of insulin resistance, independent of BMI, adiposity, and waist-to-hip ratio.
These data suggest that muscle lipid dysregulation, which is marked by increased muscle TAG content, is causally related to insulin resistance. The underlying factors contributing to muscle lipid accumulation are still obscure but may be related to reduced oxidative capacity. We and others have reported that fatty acid oxidation rates and fatty acid oxidative enzyme activities are up to 50% lower in muscle from obese compared with lean subjects, and that markers of fatty acid oxidative capacity, including CPT1, correlate inversely with insulin resistance. These reports imply that diminished lipid oxidation precedes muscle lipid accumulation and insulin resistance; thus, pharmacological interventions designed to enhance muscle lipid oxidation might facilitate weight loss, lower muscle lipid content, and promote insulin sensitivity.
Although this prediction contradicts the classic model by Randle et al., which hypothesizes that increased fatty acid oxidation contributes to insulin resistance through product inhibition of hexokinase, recent studies have challenged this convention by showing that glucose-6-phosphate does not accumulate during increased fatty acid substrate utilization. Moreover, in rodent models of obesity and insulin resistance, administration of PPARα agonists has been shown to increase whole-body lipid catabolism while improving glucose tolerance. Clinical trials in humans have shown either improvement or no change in insulin sensitivity indexes.
This last one just caught me completely off guard, but in hindsight it makes a lot of sense considering how good the PPAR agonists are as anti-inflammatory agents.In addition to fibrates and glitazones, other pharmacological compounds have been identified as PPAR activators. Inhibition of cycloxygenase by NSAIDs (Non Steroidal Anti-Inflammatory Drugs) constitutes a clinical approach for the treatment of inflammatory states. Lehmann et al. have demonstrated that certain NSAIDs, including indomethacin and ibuprofen, are activators of PPARγ acting in the micromolar range. These data are consistent with the observation that indomethacin can promote terminal adipocyte differentiation of various preadipocyte cell lines in vitro. The molecular basis underlying this adipogenic action could thus be mediated via activation of PPARγ, a transcription factor with a pivotal role in adipogenesis. In addition, certain NSAIDs are also ligands for the PPARα form. Several NSAIDs have marked effects on peroxisome activity in rodent hepatocytes when used either in vitro or in vivo and it appears likely that these effects are mediated by PPARα activation.