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    Senior Member Mr.Kite's Avatar
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    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:



    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.

    http://dx.doi.org/10.1016/j.biocel.2005.03.002
    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]



    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.

    http://dx.doi.org/10.1016/j.biocel.2005.03.002

    [see also: http://www.jbc.org/cgi/content/full/277/29/26089]
    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.



    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.

    http://diabetes.diabetesjournals.org/cgi/c...t/full/51/4/901
    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.



    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.

    http://www.springerlink.com/content/cq77q1...30234f&pi=0
    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.

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    Yeah, but its in brain health that PPAR delta looks really interesting too.



    Interesting that NSAIDS are gamma/alpha agonists - the NSAIDS are pretty good in alzheimers as well.



    I've wondered if nigella sativa is a delta agonist because one study showed remarkable effects on improving insulin sensitivity, its already shown to be a gamma agonist.
    ------



    These ideas are released under a Creative Commons Share and Share alike license

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    I have a theory that T,progesterone are PPAR antagonists. estrogen? not sure
    Man on a mission

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    Senior Member razg's Avatar
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    Great roundup of the literature. Is this an exploratory post or do you have a theory going?



    Liorrh: why?
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    just a hunch, can't back ot up with logic yet. I can back it up with all sorts of pseudo-leaps
    Man on a mission

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    Senior Member Mr.Kite's Avatar
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    Quote Originally Posted by razg' post='396405' date='Apr 8 2007, 11:36 AM
    Great roundup of the literature. Is this an exploratory post or do you have a theory going?



    Liorrh: why?
    This is still an exploratory post at the moment. Trouble had some theories that she hinted at about generalized differences in metabolism leading to different soma types. She also thought that much of this could be resolved at the level of nuclear receptors through modification of the diet and, possibly, various drugs.



    As of now I will continue to post papers relevant to nuclear receptors and their roles in metabolism and connections to soma types to see if I can actually get evidence for such connections. Anyone who wants to join in this project, I am more than happy to collaborate. Feel free to just post any relevant findings and/or discussion. A good place to start is the Cutting Edge subforum on IA.com, and Trouble's Q&A subforum.



    In fact, I think that the more people we can get contributing to this topic the more progress we are likely to make. ATB, Frangible, Liorrh (as promised?), etc... want to dive into the realm of Nuclear Receptors?

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    HA!



    I was right, I think.



    here's the deal.



    feedback loops in the body... and general "nature" of action of comounds... hear me out.

    there must be some kind of action by T on the PPAR because the other way we allready know exists. and usually that's how it works in the body - things are always two-way, even if in a roundabout way.

    the genral "nature" of androgens is pro-inflammatory which led me to believe ethey antagonize PPAR-alpha. again, pseudoscience.

    lastly, ancedotally and not ancedotally the nature of androgen realted obesity sort of counteracts PPAr-alpha activity. visceral adiposity.





    so after I hit submit here, I said, lets look at pubmed. and what do you know



    hints:





    Mol Endocrinol. 2007 Feb;21(2):388-400. Epub 2006 Dec 7. Links

    A novel peroxisome proliferator-activated receptor responsive element-luciferase reporter mouse reveals gender specificity of peroxisome proliferator-activated receptor activity in liver.Ciana P, Biserni A, Tatangelo L, Tiveron C, Sciarroni AF, Ottobrini L, Maggi A.

    Center of Excellence on Neurodegenerative Diseases, Department of Pharmacological Sciences, University of Milan, Via Balzaretti 9, 20133 Milan, Italy.



    There is a growing interest in peroxisome proliferator-activated receptors (PPARs) as major players in the regulation of lipid and carbohydrate metabolism. Drugs targeting PPARs were in fact shown to have major relevance for the treatment of diseases associated with aging, such as arteriosclerosis and diabetes. However, a variety of toxic effects associated with PPAR ligand administration has been documented, including hepatocarcinogenesis, which may severely limit its therapeutic use. A better comprehension of the multiplicity of PPAR physiological functions is therefore mandatory for the development of novel, safer drugs. We here describe the generation of a novel transgenic mouse for the detection of the generalized activities of PPARs, the PPAR responsive element-Luc reporter mouse. In this model luciferase expression is under the control of a PPAR-inducible promoter in all target organs. By optical imaging and ex vivo analysis, we were able to demonstrate the remarkable gender specificity of the PPAR transcriptional activity in liver. In fact, in the liver of female PPAR responsive element-Luc, the PPAR reporter transgene is more than one order of magnitude less expressed, thus leading to the conclusion that the signaling in females is much less activated than in males. Diet or hormonal manipulations as demonstrated here by treatments with high-fat diet or gonad removal and hormone replacement do not influence this low activation. The extent of the gender difference in PPAR transcriptional activity and the ineffectiveness of hormone treatments or diet to significantly elevate liver PPAR activity in females led us to hypothesize that gender-specific epigenetic events occurring during development may affect PPAR signaling in the liver. This study sets the ground for understanding the differential susceptibility of the two genders to metabolic disorders; furthermore, the model generated provides a novel opportunity for the molecular characterization of PPAR activity in pathophysiological conditions.



    PMID: 17158222


    and evidence:



    Clin Cancer Res. 2000 Aug;6(8):3241-8. Links

    Peroxisome proliferator-activated receptor alpha is an androgen-responsive gene in human prostate and is highly expressed in prostatic adenocarcinoma.Collett GP, Betts AM, Johnson MI, Pulimood AB, Cook S, Neal DE, Robson CN.

    School of Surgical and Reproductive Sciences, University of Newcastle upon Tyne, Newcastle, United Kingdom.



    Peroxisome proliferator-activated receptor (PPAR) alpha is a member of the nuclear receptor superfamily of ligand-activated transcription factors. PPARalpha is activated by peroxisome proliferators and fatty acids and has been shown to be involved in the transcriptional regulation of genes involved in fatty acid metabolism. In rodents, the PPARalpha-mediated change in such genes results in peroxisome proliferation and can lead to the induction of hepatocarcinogenesis. Using the mRNA differential display technique and Northern blot analysis, we have shown that chronic exposure of the prostate cancer epithelial cell line LNCaP to the synthetic androgen mibolerone results in the down-regulation of PPARalpha mRNA. Levels of PPARalpha mRNA are reduced to approximately 40% of control levels in LNCaP cells exposed to 10 nM mibolerone for 96 h. PPARalpha-responsive reporter plasmids derived from human ApoA-II and muscle carnitine palmitoyl-transferase I genes were stimulated by the PPARalpha-activating ligand Wy-14,643 in LNCaP cells. In situ hybridization and immunohistochemical analyses showed that PPARalpha expression in prostate is confined to epithelial cells. In benign prostatic tissue, PPARalpha mRNA was either absent or only weakly expressed in the basal epithelial cells. In 11 of 18 (61%) poorly differentiated (Gleason score, 8-10) prostatic carcinoma specimens, there was strong expression of PPARalpha compared with 4 of 12 Gleason score 7 tumors and 2 of 11 Gleason score 3-6 tumors (P < 0.01). These results suggest that PPARalpha is found and functional in human prostate and is down-regulated by androgens. The role of PPARalpha may be to integrate dietary fatty acid and steroid hormone signaling pathways, and its overexpression in advanced prostate cancer may indicate a role in tumor progression with the potential involvement of dietary factors.



    PMID: 10955810


    this is actually very intersting even if not really related- how PPAR ligands work with testosterone in skin cells to make more DHT.



    explains why fat+T=acne.



    1: Br J Dermatol. 2007 Mar;156(3):428-32. Links

    Testosterone metabolism to 5alpha-dihydrotestosterone and synthesis of sebaceous lipids is regulated by the peroxisome proliferator-activated receptor ligand linoleic acid in human sebocytes.Makrantonaki E, Zouboulis CC.

    Laboratory of Biogerontology, Dermatopharmacology and Dermatoendocrinology, Institute of Clinical Pharmacology and Toxicology, Charite University Medicine Berlin, Berlin, Germany.



    BACKGROUND: Despite the clinical evidence that androgens stimulate sebaceous lipids, androgens in vitro have shown no similar effects. This contradiction led to the assumption that cofactors may be required for lipid regulation and peroxisome proliferator-activated receptor (PPAR) ligands were suggested to be adequate candidates. OBJECTIVES: The influence of testosterone and linoleic acid, a PPAR ligand, as single agents and in combination with of LY191704, a 5alpha-reductase type I inhibitor, was examined on 5alpha-dihydrotestosterone (5alpha-DHT) synthesis and lipid content in human SZ95 sebocytes. METHODS: Cell proliferation and viability were measured by the 4-methylumbelliferyl heptanoate fluorescence assay and by the Boehringer Lactate Dehydrogenase Assay kit, respectively. 5alpha-DHT enzyme-linked immunosorbent assay was used for the detection of 5alpha-DHT synthesis in cell supernatants after treatment, whereas lipid production was documented by means of the Nile red lipid microassay and fluorescence microscopy. RESULTS:Testosterone promoted 5alpha-DHT synthesis (P < 0.001), whereas linoleic acid increased sebaceous lipids (P < 0.001). The combination of testosterone and linoleic acid exhibited a synergistic effect on the synthesis of 5alpha-DHT (P < 0.01 vs. testosterone) and sebaceous lipids (P < 0.01 vs. linoleic acid). Furthermore, LY191704 reduced 5alpha-DHT and sebaceous lipid levels (P < 0.01 and P < 0.001 in comparison with testosterone/linoleic acid, respectively). Cell proliferation and viability remained unchanged under treatment with all compounds tested. CONCLUSIONS: These data suggest a catalytic effect of PPAR ligands on cellular testosterone activation by 5alpha-reduction and the importance of the latter for the regulation of sebaceous lipids.



    PMID: 17300229


    there is also data hsowing PPARs affecting progesterone and estradiol - I didn't find anything going the other way, yet.



    Mr. Kite - working on that glutamine thing. started to gather my thoughts and intent
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  8. #8
    Senior Member Mr.Kite's Avatar
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    Liorrh, the studies you posted don't really show that androgens are PPAR antagonists, rather that they downregulate PPAR receptors. There is a critical difference here, in that down regulation of receptors happens all the time, as does the converse. However, antagonism of a receptor is a much different kind of effect, in that instead of down modulating the net response to a PPAR agonist, it will completely block any action from occurring at all at the receptors at which the antagonist is present. Although it appears that your original intent was to say that they sort of do the opposite of PPAR agonists, the differences between downregulation of receptors and antagonism of receptors are important.



    The study on the combined actions of PPAR ligands and Testosterone on acne is very interesting. It also gives a possible mechanism for the reported benefits of fish oil and sesamin on skin health -> they increase the lipid levels in the skin.



    Quote Originally Posted by ATB
    Yeah, but its in brain health that PPAR delta looks really interesting too.
    Thank you for leading me to look into PPAR and its relation to the brain. I have a very close friend who has Multiple Sclerosis, and it seems that PPARα and PPARγ agonists are in the early stages of testing for treatment of MS. I may recommend that she try an OTC PPAR agonist after further research, but the initial reports look promising.

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    Mr. Kite, you are right. down-regulating is not the same as antagonizing.



    reagarding sesamin and fish oil I think they do their magic more by lowering T/DHT than by raising lipid levels... as the study noted its is not a good thing... or did I mesread it... on another note don't PPAR a agonsits lower lipids in the cell anyway
    Man on a mission

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    Quote Originally Posted by liorrh' post='396421' date='Apr 8 2007, 04:08 PM
    HA!



    I was right, I think.



    here's the deal.



    feedback loops in the body... and general "nature" of action of comounds... hear me out.

    there must be some kind of action by T on the PPAR because the other way we allready know exists. and usually that's how it works in the body - things are always two-way, even if in a roundabout way.

    the genral "nature" of androgens is pro-inflammatory which led me to believe ethey antagonize PPAR-alpha. again, pseudoscience.

    lastly, ancedotally and not ancedotally the nature of androgen realted obesity sort of counteracts PPAr-alpha activity. visceral adiposity.

    so after I hit submit here, I said, lets look at pubmed. and what do you know



    hints:

    and evidence:

    this is actually very intersting even if not really related- how PPAR ligands work with testosterone in skin cells to make more DHT.



    explains why fat+T=acne.



    1: Br J Dermatol. 2007 Mar;156(3):428-32. Links

    Testosterone metabolism to 5alpha-dihydrotestosterone and synthesis of sebaceous lipids is regulated by the peroxisome proliferator-activated receptor ligand linoleic acid in human sebocytes.Makrantonaki E, Zouboulis CC.

    Laboratory of Biogerontology, Dermatopharmacology and Dermatoendocrinology, Institute of Clinical Pharmacology and Toxicology, Charite University Medicine Berlin, Berlin, Germany.




    BACKGROUND: Despite the clinical evidence that androgens stimulate sebaceous lipids, androgens in vitro have shown no similar effects. This contradiction led to the assumption that cofactors may be required for lipid regulation and peroxisome proliferator-activated receptor (PPAR) ligands were suggested to be adequate candidates. OBJECTIVES: The influence of testosterone and linoleic acid, a PPAR ligand, as single agents and in combination with of LY191704, a 5alpha-reductase type I inhibitor, was examined on 5alpha-dihydrotestosterone (5alpha-DHT) synthesis and lipid content in human SZ95 sebocytes. METHODS: Cell proliferation and viability were measured by the 4-methylumbelliferyl heptanoate fluorescence assay and by the Boehringer Lactate Dehydrogenase Assay kit, respectively. 5alpha-DHT enzyme-linked immunosorbent assay was used for the detection of 5alpha-DHT synthesis in cell supernatants after treatment, whereas lipid production was documented by means of the Nile red lipid microassay and fluorescence microscopy. RESULTS:Testosterone promoted 5alpha-DHT synthesis (P < 0.001), whereas linoleic acid increased sebaceous lipids (P < 0.001). The combination of testosterone and linoleic acid exhibited a synergistic effect on the synthesis of 5alpha-DHT (P < 0.01 vs. testosterone) and sebaceous lipids (P < 0.01 vs. linoleic acid). Furthermore, LY191704 reduced 5alpha-DHT and sebaceous lipid levels (P < 0.01 and P < 0.001 in comparison with testosterone/linoleic acid, respectively). Cell proliferation and viability remained unchanged under treatment with all compounds tested. CONCLUSIONS: These data suggest a catalytic effect of PPAR ligands on cellular testosterone activation by 5alpha-reduction and the importance of the latter for the regulation of sebaceous lipids.



    PMID: 17300229





    there is also data hsowing PPARs affecting progesterone and estradiol - I didn't find anything going the other way, yet.




    great find.

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