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  1. Irisin -- Is it a myth?

    It still has some interesting data stuff, though also some conflicting. Brain Plast. 2015;1(1):55-61. doi: 10.3233/BPL-150019. FNDC5/irisin - their role in the nervous system and as a mediator for beneficial effects of exercise on the brain. Wrann CD(1). Author information: (1)Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA. Exercise can improve cognitive function and the outcome of neurodegenerative diseases, like Alzheimer's disease. This effect has been linked to the increased expression of brain-derived neurotrophic factor (BDNF). However, the underlying molecular mechanisms driving the elevation of this neurotrophin remain unknown. Recently, we have reported a PGC-1α-FNDC5/irisin pathway, which is activated by exercise in the hippocampus in mice and induces a neuroprotective gene program, including Bdnf. This review will focus on FNDC5 and its secreted form "irisin", a newly discovered myokine, and their role in the nervous system and its therapeutic potential. In addition, we will briefly discuss the role of other exercise-induced myokines on positive brain effects. DOI: 10.3233/BPL-150019 PMCID: PMC5419585 PMID: 28480165 Med Hypotheses. 2016 May;90:23-8. doi: 10.1016/j.mehy.2016.02.020. Epub 2016 Mar 2. FNDC5/irisin, a molecular target for boosting reward-related learning and motivation. Zsuga J(1), Tajti G(2), Papp C(2), Juhasz B(3), Gesztelyi R(4). Interventions focusing on the prevention and treatment of chronic non-communicable diseases are on rise. In the current article, we propose that dysfunction of the mesocortico-limbic reward system contributes to the emergence of the WHO-identified risk behaviors (tobacco use, unhealthy diet, physical inactivity and harmful use of alcohol), behaviors that underlie the evolution of major non-communicable diseases (e.g. cardiovascular diseases, cancer, diabetes and chronic respiratory diseases). Given that dopaminergic neurons of the mesocortico-limbic system are tightly associated with reward-related processes and motivation, their dysfunction may fundamentally influence behavior. While nicotine and alcohol alter dopamine neuron function by influencing some receptors, mesocortico-limbic system dysfunction was associated with elevation of metabolic set-point leading to hedonic over-eating. Although there is some empirical evidence, precise molecular mechanism for linking physical inactivity and mesocortico-limbic dysfunction per se seems to be missing; identification of which may contribute to higher success rates for interventions targeting lifestyle changes pertaining to physical activity. In the current article, we compile evidence in support of a link between exercise and the mesocortico-limbic system by elucidating interactions on the axis of muscle - irisin - brain derived neurotrophic factor (BDNF) - and dopaminergic function of the midbrain. Irisin is a contraction-regulated myokine formed primarily in skeletal muscle but also in the brain. Irisin stirred considerable interest, when its ability to induce browning of white adipose tissue parallel to increasing thermogenesis was discovered. Furthermore, it may also play a role in the regulation of behavior given it readily enters the central nervous system, where it induces BDNF expression in several brain areas linked to reward processing, e.g. the ventral tegmental area and the hippocampus. BDNF is a neurotropic factor that increases neuronal dopamine content, modulates dopamine release relevant for neuronal plasticity and increased neuronal survival as well as learning and memory. Further linking BDNF to dopaminergic function is BDNF's ability to activate tropomyosin-related kinase B receptor that shares signalization with presynaptic dopamine-3 receptors in the ventral tegmental area. Summarizing, we propose that the skeletal muscle derived irisin may be the link between physical activity and reward-related processes and motivation. Moreover alteration of this axis may contribute to sedentary lifestyle and subsequent non-communicable diseases. Preclinical and clinical experimental models to test this hypothesis are also proposed. Copyright © 2016 Elsevier Ltd. All rights reserved. DOI: 10.1016/j.mehy.2016.02.020 PMID: 27063080 [Indexed for MEDLINE]
  2. In addition to the archives themselves, the chinese Baidu bot guests in the "Online Users" tab lead to some great threads.
  3. Pretty interesting shit. Am J Med Genet B Neuropsychiatr Genet. 2018 Mar;177(2):181-198. doi: 10.1002/ajmg.b.32599. Epub 2017 Sep 13. The role of CLOCK gene in psychiatric disorders: Evidence from human and animal research. Schuch JB(1), Genro JP(2), Bastos CR(3), Ghisleni G(3), Tovo-Rodrigues L(4). The circadian clock system drives daily rhythms in physiology, metabolism, and behavior in mammals. Molecular mechanisms of this system consist of multiple clock genes, with Circadian Locomotor Output Cycles Kaput (CLOCK) as a core member that plays an important role in a wide range of behaviors. Alterations in the CLOCK gene are associated with common psychiatric disorders as well as with circadian disturbances comorbidities. This review addresses animal, molecular, and genetic studies evaluating the role of the CLOCK gene on many psychiatric conditions, namely autism spectrum disorder, schizophrenia, attention-deficit/hyperactivity disorder, major depressive disorder, bipolar disorder, anxiety disorder, and substance use disorder. Many animal experiments focusing on the effects of the Clock gene in behavior related to psychiatric conditions have shown consistent biological plausibility and promising findings. In humans, genetic and gene expression studies regarding disorder susceptibility, sleep disturbances related comorbidities, and response to pharmacological treatment, in general, are in agreement with animal studies. However, the number of controversial results is high. Literature suggests that the CLOCK gene exerts important influence on these conditions, and influences the susceptibility to phenotypes of psychiatric disorders. © 2017 Wiley Periodicals, Inc. DOI: 10.1002/ajmg.b.32599 PMID: 28902457 Neurosci Bull. 2015 Feb;31(1):141-59. doi: 10.1007/s12264-014-1495-3. Epub 2015 Feb 6. Genetics and epigenetics of circadian rhythms and their potential roles in neuropsychiatric disorders. Liu C(1), Chung M. Author information: (1)State Key Laboratory of Medical Genetics of China, Changsha, 410078, China, liucy@uic.edu. Circadian rhythm alterations have been implicated in multiple neuropsychiatric disorders, particularly those of sleep, addiction, anxiety, and mood. Circadian rhythms are known to be maintained by a set of classic clock genes that form complex mutual and self-regulatory loops. While many other genes showing rhythmic expression have been identified by genome-wide studies, their roles in circadian regulation remain largely unknown. In attempts to directly connect circadian rhythms with neuropsychiatric disorders, genetic studies have identified gene mutations associated with several rare sleep disorders or sleep-related traits. Other than that, genetic studies of circadian genes in psychiatric disorders have had limited success. As an important mediator of environmental factors and regulators of circadian rhythms, the epigenetic system may hold the key to the etiology or pathology of psychiatric disorders, their subtypes or endophenotypes. Epigenomic regulation of the circadian system and the related changes have not been thoroughly explored in the context of neuropsychiatric disorders. We argue for systematic investigation of the circadian system, particularly epigenetic regulation, and its involvement in neuropsychiatric disorders to improve our understanding of human behavior and disease etiology. DOI: 10.1007/s12264-014-1495-3 PMCID: PMC4821655 PMID: 25652815
  4. Elife. 2016 Jun 2;5. pii: e15092. doi: 10.7554/eLife.15092. Exercise promotes the expression of brain derived neurotrophic factor (BDNF) through the action of the ketone body β-hydroxybutyrate. Sleiman SF(1), Henry J(2)(3)(4)(5), Al-Haddad R(1), El Hayek L(1), Abou Haidar E(1), Stringer T(2)(3)(4)(5), Ulja D(2)(3)(4)(5), Karuppagounder SS(6)(7), Holson EB(8)(9), Ratan RR(6)(7), Ninan I(2)(3)(4)(5), Chao MV(2)(3)(4)(5). Exercise induces beneficial responses in the brain, which is accompanied by an increase in BDNF, a trophic factor associated with cognitive improvement and the alleviation of depression and anxiety. However, the exact mechanisms whereby physical exercise produces an induction in brain Bdnf gene expression are not well understood. While pharmacological doses of HDAC inhibitors exert positive effects on Bdnf gene transcription, the inhibitors represent small molecules that do not occur in vivo. Here, we report that an endogenous molecule released after exercise is capable of inducing key promoters of the Mus musculus Bdnf gene. The metabolite β-hydroxybutyrate, which increases after prolonged exercise, induces the activities of Bdnf promoters, particularly promoter I, which is activity-dependent. We have discovered that the action of β-hydroxybutyrate is specifically upon HDAC2 and HDAC3, which act upon selective Bdnf promoters. Moreover, the effects upon hippocampal Bdnf expression were observed after direct ventricular application of β-hydroxybutyrate. Electrophysiological measurements indicate that β-hydroxybutyrate causes an increase in neurotransmitter release, which is dependent upon the TrkB receptor. These results reveal an endogenous mechanism to explain how physical exercise leads to the induction of BDNF. DOI: 10.7554/eLife.15092 PMCID: PMC4915811 PMID: 27253067 J Neurochem. 2016 Dec;139(5):769-781. doi: 10.1111/jnc.13868. Epub 2016 Nov 14. 3-Hydroxybutyrate regulates energy metabolism and induces BDNF expression in cerebral cortical neurons. Marosi K(1), Kim SW(1), Moehl K(1), Scheibye-Knudsen M(2), Cheng A(1), Cutler R(1), Camandola S(1), Mattson MP(1)(3). Author information: (1)Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, Maryland, USA. (2)Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark. (3)Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. During fasting and vigorous exercise, a shift of brain cell energy substrate utilization from glucose to the ketone 3-hydroxybutyrate (3OHB) occurs. Studies have shown that 3OHB can protect neurons against excitotoxicity and oxidative stress, but the underlying mechanisms remain unclear. Neurons maintained in the presence of 3OHB exhibited increased oxygen consumption and ATP production, and an elevated NAD+ /NADH ratio. We found that 3OHB metabolism increases mitochondrial respiration which drives changes in expression of brain-derived neurotrophic factor (BDNF) in cultured cerebral cortical neurons. The mechanism by which 3OHB induces Bdnf gene expression involves generation of reactive oxygen species, activation of the transcription factor NF-κB, and activity of the histone acetyltransferase p300/EP300. Because BDNF plays important roles in synaptic plasticity and neuronal stress resistance, our findings suggest cellular signaling mechanisms by which 3OHB may mediate adaptive responses of neurons to fasting, exercise, and ketogenic diets. Published 2016. This article is a U.S. Government work and is in the public domain in the USA. DOI: 10.1111/jnc.13868 PMCID: PMC5123937 PMID: 27739595
  5. Anyone ever tried huffing vodka? The gut microbiota includes a community of bacteria that play an integral part in host health and biological processes. Pronounced and repeated findings have linked gut microbiome to stress, anxiety, and depression. Currently, however, there remains only a limited set of studies focusing on microbiota change in substance abuse, including alcohol use disorder. To date, no studies have investigated the impact of vapour alcohol administration on the gut microbiome. For research on gut microbiota and addiction to proceed, an understanding of how route of drug administration affects gut microbiota must first be established. Animal models of alcohol abuse have proven valuable for elucidating the biological processes involved in addiction and alcohol-related diseases. This is the first study to investigate the effect of vapour route of ethanol administration on gut microbiota in mice. Adult male C57BL/6J mice were exposed to 4 weeks of chronic intermittent vapourized ethanol (CIE, N=10) or air (Control, N=9). Faecal samples were collected at the end of exposure followed by 16S sequencing and bioinformatic analysis. Robust separation between CIE and Control was seen in the microbiome, as assessed by alpha (p<0.05) and beta (p<0.001) diversity, with a notable decrease in alpha diversity in CIE. These results demonstrate that CIE exposure markedly alters the gut microbiota in mice. Significant increases in genus Alistipes (p<0.001) and significant reductions in genra Clostridium IV and XIVb (p<0.001), Dorea (p<0.01), and Coprococcus (p<0.01) were seen between CIE mice and Control. These findings support the viability of the CIE method for studies investigating the microbiota-gut-brain axis and align with previous research showing similar microbiota alterations in inflammatory states during alcoholic hepatitis and psychological stress. https://www.ncbi.nlm.nih.gov/pubmed/?term=25803049
  6. After all of that, it was just a few dudes shitposting on facebook and twitter.
  7. In the last episode of The CKD Files, Derf and Dan Jr. had just returned home from the gym following their two hour glycogen depletion workout and had subsequently commenced preparations for the ensuing carb-up. Setting: Daytime in a living room DERF: Typical musclehead, 240+ lbs, sub 6% bodyfat, head shaved to hide the consequences of years of 5-alpha reductase activity, rummages through a tackle box full of pills, vials, and syringes. DAN JR: who couldn't grow on a gram of tren a day, sits, rolling a joint. DERF Dude, I'm low on gear. DAN JR. Yeah, me too. We should go back by the gym and see BigWill after we smoke this. He takes a puff and hands it to Derf, who does the same. DERF I'm gonna need to eat first. DAN JR. (annoyed) Did you take your shot already?? He nods, a bit woozy. Dan just shakes his head, grabsa syringe, and stands up. Derf passes out. Dan heads to the kitchen and returns with a bottle of glucose. He draws some into the syringe and injects it into one of the giant veins on Derf's arm. He comes to. DERF Thanks, dude. Let's hit McDonald's. DAN JR. (shakes his head) That's far too high in fat. Glycogen storage and amino acid uptake are optimal right now -- We need high Glycemic Index carbohydrates. A post workout drink of dextrose and whey is ideal. DERF Bullshit. I haven't had anything except whey and flaxfor the last two weeks. I want some food. DAN JR. Fine. But, we're not eating McDonald's -- we'll go toan all you can eat place. Dan takes out a syringe and injects himself in thethigh. DERF Nubain? DAN JR. Insulin. Derf nods. Dan pulls out another. DERF Nubain? DAN JR. GH. He injects it and pulls out another. DERF Nubain? DAN JR. Yep. Setting: Daytime at all All-You-Can-Eat Restaurant They walk into the restaurant, anxious to begin refilling of glycogen stores and raising leptin levels. There are a couple of people in line in front of them, so they step back. They stand there for a moment, already impatient, when an OBESE WOMAN waddles up and cuts in front of them in line. They give each other a "What the fuck?!" look, then stare at her back, in a rage fueled by low blood sugar, serotonin depletion, and supraphysiological androgen levels. DAN JR. Did that chubby bitch just cut in front of us? DERF Yeah. DAN JR. Does she think we're just standing here to greet people as they walk in the door? Derf shrugs. DAN JR. She doesn't need to be getting seconds anyway. DERF Nope. DAN JR. How much do you think she weighs? DERF Three hundred? DAN JR. I'm thinking maybe as much as four bills. But it's pretty hard to tell when they get that big... I'd say she's definitely pushing at least three and somechange... You'd think they'd have some kind of width limit to eat at all-you-can-eatrestaurants. You know? DERF (laughs) Like the height requirements for rollercoasters? DAN JR. Yeah. They should have a sign when you first walk in the door with a guy holding his arms out that says: Dan holds his arms out really wide. DAN JR. "You must not be this wide to eat at this restaurant." -- 'Cause if you are, you damn sure don't need to be eating at an all-you-can-eat restaurant. DERF She needs some EC. DAN JR. Fuck EC, she needs DNP and some meth. DERF Maybe she just has low leptin levels. DAN JR. Yeah, and maybe she swallowed a guy who swallowed a fly, but I fucking seriously doubt it. It takes a concerted effort to get that fat. You don't go to sleep one night looking like a normal human being and wake up the next day with 54% bodyfat. That doesn't happen. It takes years of determination and willpower. To look like that, there can be no skipping meals, no going to bed hungry, no exercise. Shit, just walking from the couch to the kitchen must burn more than a hundred calories when you weigh that much... I bet she keeps a crate of Krispy Kremes, in her fucking living room, so she can grab a box whenever the urge should strike... Low leptin levels my ass. I guarantee you that bitch gets three tiers of food on her tray. DERF (smiles) She's just got more to love, that's all. Derf walks up closer to her back. He pretends to spank her. DERF Big is beautiful. Ain't it baby. DAN JR. (shaking his head) Fat is not beautiful unless you're a sick, deviant motherfucker with a fetish for that shit. It just isn't aesthetically pleasing. The Obese Woman continues piling food on her tray. DAN JR. I mean, granted, culture and normal personal preferences play a role incertain aspects of what is considered beautiful at different times. For example: Hairstyles and fashion change -- certain trends are hip for a while, but fiveyears later are atrocious -- the 1980's come to mind. But some things are universally beautiful. And certain things are universally not beautiful in any way, shape, or form. DERF Like what? DAN JR. Things like Nicole Bass, and pimples, and warts, and melted flesh from third degree burns... And well-fed bitches like her. DERF You make a good argument. DAN JR. Don't kid yourself, Derf. I'm not finished. I haven't yet begun to ridicule. DERF Oh. DAN JR. You know it's gotta be unsanitary. I mean, can you imagine what kind ofbacteria and yeast and STD's and shit are spawning and fermenting betweeneach and every fucking chub roll on that immense body? DERF It's a sick thought. DAN JR. Of course, it is. And the other day I heard on Oprah something about "foodaholism". Like it's a fucking disease, like cancer. Like they can't help. Like it's not their fault. DERF I did read on MFW about a study linking obesity to a virus. DAN JR. Well, then the CDC needs to come out here and quarantine this bitch. DERF (laughing) If it was a virus, what do you think they'd call it. DAN JR. There's already a name for what she has. It's called "gluttony". The Obese Woman turns around with two trays full of food, each with plates piled one on top of the other like a pyramid. DAN JR . (as she walks by) How now, brown cow. She doesn't respond. Derf laughs, and they finally approach the windowto order their long-awaited food. The End. The following was a fictional skit. Any resemblance to actual people, be they from your local gym or alt.support.fat-acceptance, is purely coincidental.
  8. The following is an interview with TC Luoma. TC is the editor of TestosteroneMagazine, former editor of Muscle Media 2000, bodybuilding pioneer, and badass. THE LESBIAN PIMP How are you doing today, TC? TC LUOMA Man, I accidentally used too much Androsol this morning -- it's got me almost homicidal. I had to stop by a biker bar and kick some ass o­n my way out here. THE LESBIAN PIMP Really? TC LUOMA Oh yeah. This is powerful stuff. I can literally feel the increased protein synthesis - in fact, I've gained 29 grams of rock solid mass in the last 2 hours. THE LESBIAN PIMP Very impressive. Actually, you've made a number of impressive claims as far as results from different supplements over the years - it seems as though you should be vying for the Mr. O by now, yet looking at you, I can't really tell you work out. TC LUOMA Yeah, a lot of people say that. But, I'm 173 lbs at less than 13% bodyfat, so I just don't get it. And frankly, it pisses a T-dude off. In fact, if this Androsol wasn't wearing off, you'd be dead right now... just for bringing it up. THE LESBIAN PIMP I see. Why did Charles leave T-Mag? TC LUOMA I can't go into that too much, for legal reasons. THE LESBIAN PIMP Most of us assume that all of the hype and bullshit left him with a Biotest stank that he could no longer wash off of himself each night, even with Lava. And that has pumice, so it must have been really bad. TC LUOMA No. That's not it at all. It didn't have anything to do with Biotest. He-- (TC stops) Let's just say he saw something that made our business relationship uncomfortable. THE LESBIAN PIMP Like pissing in the Methoxy-7 or what?? TC LUOMA Like I said, I can't really say too much - so I'll just leave it at this: "Me, Tim, full body latex, and a tub of vanilla Grow." THE LESBIAN PIMP Fascinating. What was your relationship with Bill Phillips like? TC LUOMA (Getting teary eyed) I loved that man. Bill Phillips was a great man in the early years - when he still cared about the sport. But, then came the fame, then the drugs and the fitness bimbos... And after he started those physique transformation contests... he just turned into a completely different person. (TC breaks out crying) THE LESBIAN PIMP There. There. It's gonna be okay. TC LUOMA He made me eat out of a dog bowl. THE LESBIAN PIMP I see... Wait, he what?... Nevermind. (TC calms down a bit) So what does the "T" in "TC Luoma" stand for, TC? I assume it must be something pretty bad if it made you go through life just using your initials - 'cause "TC" really sounds pretty stupid itself. I bet it's a hermaphroditic name- that would explain a lot of the machismo - you know, like a coping mechanism for sharing your name with a girl. Is it Terry?... Tracey? (He bursts out crying again) TC LUOMA Bill used to call me that... Are you clean, Tracey? Are you wearing my favorite dress??... Who's ass is this, Tracey?! (he continues crying) It's your ass Bill -- It's your ass! (He's hysterical) Okay, I'll call you daddy -- please, just don't hit me again! THE LESBIAN PIMP Okay. I think that will just about do it. Thank you for coming by today, TC. We look forward to talking with you again soon. Obviously, this has been a fictional skit -- it is parody, co-written by The Lesbian Pimp and Par Deus, and is not intended to be taken at all seriously, nor is it intended to imply anything about the sexual inclinations of the real TC Luoma, Tim Patterson, or Bill Phillips.
  9. Okay, there is not going to be a true one master signal, as the body has a bunch of redundant systems, but BDNF may be the closest thing to it. It is increased by proper leptin and insulin signalling, decreased by cortisol, modulates the the positive neurotransmitter response and neurogenesis from exercise and anti-depressants, and it controls feeding and metabolic behavior.... Behav Neurosci. 2012 Aug;126(4):505-14. doi: 10.1037/a0028600. Epub 2012 Jun 11. A putative model of overeating and obesity based on brain-derived neurotrophic factor: direct and indirect effects. Ooi CL(1), Kennedy JL, Levitan RD. Author information: (1)Department of Psychiatry, University of Toronto, Ontario, Canada. Increased food intake is a major contributor to the obesity epidemic in all age groups. Elucidating brain systems that drive overeating and that might serve as targets for novel prevention and treatment interventions is thus a high priority for obesity research. The authors consider 2 major pathways by which decreased activity of brain-derived neurotrophic factor (BDNF) may confer vulnerability to overeating and weight gain in an obesogenic environment. The first "direct" pathway focuses on the specific role of BDNF as a mediator of food intake control at brain areas rich in BDNF receptors, including the hypothalamus and hindbrain. It is proposed that low BDNF activity limited to this direct pathway may best explain overeating and obesity outside the context of major neuropsychiatric disturbance. A second "indirect" pathway considers the broad neurotrophic effects of BDNF on key monoamine systems that mediate mood dysregulation, impulsivity, and executive dysfunction as well as feeding behavior per se. Disruption in this pathway may best explain overeating and obesity in the context of various neuropsychiatric disturbances including mood disorders, attention-deficit disorder, and/or binge eating disorders. An integrative model that considers these potential roles of BDNF in promoting obesity is presented. The implications of this model for the early prevention and treatment of obesity are also considered. DOI: 10.1037/a0028600 PMID: 22687148 [Indexed for MEDLINE] Trends Neurosci. 2013 Feb;36(2):83-90. doi: 10.1016/j.tins.2012.12.009. Epub 2013 Jan 18. BDNF and the central control of feeding: accidental bystander or essential player? Rios M(1). Author information: (1)Tufts University School of Medicine, Department of Neuroscience, Boston, MA 02111, USA. maribel.rios@tufts.edu A considerable body of evidence links diminished brain-derived neurotrophic factor (BDNF) signaling to energy balance dysregulation and severe obesity in humans and rodents. Because BDNF exhibits broad neurotrophic properties, the underpinnings of these effects and its true role in the central regulation of food intake remain topics of debate in the field. Here, I discuss recent evidence supporting a critical role for this neurotrophin in physiological mechanisms regulating nutrient intake and body weight in the mature brain. They include reports of functional interactions of BDNF with central anorexigenic and orexigenic signaling pathways and evidence of recognized appetite hormones exerting neurotrophic effects similar to those of BDNF. Copyright © 2013 Elsevier Ltd. All rights reserved. DOI: 10.1016/j.tins.2012.12.009 PMCID: PMC3568936 PMID: 23333344 [Indexed for MEDLINE] Psychiatry Clin Neurosci. 2010 Oct;64(5):447-59. doi: 10.1111/j.1440-1819.2010.02135.x. Interface between hypothalamic-pituitary-adrenal axis and brain-derived neurotrophic factor in depression. Kunugi H(1), Hori H, Adachi N, Numakawa T. Author information: (1)Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan. hkunugi@ncnp.go.jp Although the pathophysiology of depressive disorder remains elusive, two hypothetical frameworks seem to be promising: the involvement of hypothalamic pituitary-adrenal (HPA) axis abnormalities and brain-derived neurotrophic factor (BDNF) in the pathogenesis and in the mechanism of action of antidepressant treatments. In this review, we focused on research based on these two frameworks in relation to depression and related conditions and tried to formulate an integrated theory of the disorder. Hormonal challenge tests, such as the dexamethasone/corticotropin-releasing hormone test, have revealed elevated HPA activity (hypercortisolism) in at least a portion of patients with depression, although growing evidence has suggested that abnormally low HPA axis (hypocortisolism) has also been implicated in a variety of stress-related conditions. Several lines of evidence from postmortem studies, animal studies, blood levels, and genetic studies have suggested that BDNF is involved in the pathogenesis of depression and in the mechanism of action of biological treatments for depression. Considerable evidence has suggested that stress reduces the expression of BDNF and that antidepressant treatments increase it. Moreover, the glucocorticoid receptor interacts with the specific receptor of BDNF, TrkB, and excessive glucocorticoid interferes with BDNF signaling. Altered BDNF function is involved in the structural changes and possibly impaired neurogenesis in the brain of depressed patients. Based on these findings, an integrated schema of the pathological and recovery processes of depression is illustrated. © 2010 The Authors. Psychiatry and Clinical Neurosciences © 2010 Japanese Society of Psychiatry and Neurology. DOI: 10.1111/j.1440-1819.2010.02135.x PMID: 20923424 [Indexed for MEDLINE] Med Hypotheses. 2016 May;90:23-8. doi: 10.1016/j.mehy.2016.02.020. Epub 2016 Mar 2. FNDC5/irisin, a molecular target for boosting reward-related learning and motivation. Zsuga J(1), Tajti G(2), Papp C(2), Juhasz B(3), Gesztelyi R(4). Author information: (1)Department of Health Systems Management and Quality Management for Health Care, Faculty of Public Health, University of Debrecen, Nagyerdei krt 98, 4032 Debrecen, Hungary. Electronic address: zsuga.judit@med.unideb.hu. (2)Department of Health Systems Management and Quality Management for Health Care, Faculty of Public Health, University of Debrecen, Nagyerdei krt 98, 4032 Debrecen, Hungary. (3)Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Debrecen, Nagyerdei krt 98, 4032 Debrecen, Hungary. (4)Department of Pharmacology, Faculty of Pharmacy, University of Debrecen, Nagyerdei krt 98, 4032 Debrecen, Hungary. Interventions focusing on the prevention and treatment of chronic non-communicable diseases are on rise. In the current article, we propose that dysfunction of the mesocortico-limbic reward system contributes to the emergence of the WHO-identified risk behaviors (tobacco use, unhealthy diet, physical inactivity and harmful use of alcohol), behaviors that underlie the evolution of major non-communicable diseases (e.g. cardiovascular diseases, cancer, diabetes and chronic respiratory diseases). Given that dopaminergic neurons of the mesocortico-limbic system are tightly associated with reward-related processes and motivation, their dysfunction may fundamentally influence behavior. While nicotine and alcohol alter dopamine neuron function by influencing some receptors, mesocortico-limbic system dysfunction was associated with elevation of metabolic set-point leading to hedonic over-eating. Although there is some empirical evidence, precise molecular mechanism for linking physical inactivity and mesocortico-limbic dysfunction per se seems to be missing; identification of which may contribute to higher success rates for interventions targeting lifestyle changes pertaining to physical activity. In the current article, we compile evidence in support of a link between exercise and the mesocortico-limbic system by elucidating interactions on the axis of muscle - irisin - brain derived neurotrophic factor (BDNF) - and dopaminergic function of the midbrain. Irisin is a contraction-regulated myokine formed primarily in skeletal muscle but also in the brain. Irisin stirred considerable interest, when its ability to induce browning of white adipose tissue parallel to increasing thermogenesis was discovered. Furthermore, it may also play a role in the regulation of behavior given it readily enters the central nervous system, where it induces BDNF expression in several brain areas linked to reward processing, e.g. the ventral tegmental area and the hippocampus. BDNF is a neurotropic factor that increases neuronal dopamine content, modulates dopamine release relevant for neuronal plasticity and increased neuronal survival as well as learning and memory. Further linking BDNF to dopaminergic function is BDNF's ability to activate tropomyosin-related kinase B receptor that shares signalization with presynaptic dopamine-3 receptors in the ventral tegmental area. Summarizing, we propose that the skeletal muscle derived irisin may be the link between physical activity and reward-related processes and motivation. Moreover alteration of this axis may contribute to sedentary lifestyle and subsequent non-communicable diseases. Preclinical and clinical experimental models to test this hypothesis are also proposed. Copyright © 2016 Elsevier Ltd. All rights reserved. DOI: 10.1016/j.mehy.2016.02.020 PMID: 27063080 [Indexed for MEDLINE]
  10. Proper signalling of both leptin and insulin are necessary for proper brain function much like they are for metabolism and anabolism (and, through largely the same molecular signalling pathways. Endocrinology. 2011 Jul;152(7):2634-43. doi: 10.1210/en.2011-0004. Epub 2011 Apr 26. Impaired CNS leptin action is implicated in depression associated with obesity. Yamada N(1), Katsuura G, Ochi Y, Ebihara K, Kusakabe T, Hosoda K, Nakao K. Author information: (1)Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, 54 Shougoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan. Comment in Endocrinology. 2011 Jul;152(7):2539-41. Recent epidemiological studies indicate that obesity increases the incidence of depression. We examined the implication of leptin for obesity-associated depression. Leptin induced antidepressive behavior in normal mice in a forced swimming test (FST), and leptin-overexpressing transgenic mice with hyperleptinemia exhibited more antidepressive behavior in the FST than nontransgenic mice. In contrast, leptin-deficient ob/ob mice showed more severe depressive behavior in the FST than normal mice, and leptin administration substantially ameliorated this depressive behavior. Diet-induced obese (DIO) mice fed a high-fat diet showed more depressive behavior in the FST and in a sucrose preference test compared with mice fed a control diet (CD). In DIO mice, leptin induced neither antidepressive action nor increment of the number of c-Fos immunoreactive cells in the hippocampus. Diet substitution from high-fat diet to CD in DIO mice ameliorated the depressive behavior and restored leptin-induced antidepressive action. Brain-derived neurotrophic factor concentrations in the hippocampus were significantly lower in DIO mice than in CD mice. Leptin administration significantly increased hippocampal brain-derived neurotrophic factor concentrations in CD mice but not in DIO mice. The antidepressant activity of leptin in CD mice was significantly attenuated by treatment with K252a. These findings demonstrated that leptin induces an antidepressive state, and DIO mice, which exhibit severe depressive behavior, did not respond to leptin in both the FST and the biochemical changes in the hippocampus. Thus, depression associated with obesity is due, at least in part, to impaired leptin activity in the hippocampus. DOI: 10.1210/en.2011-0004 PMID: 21521746 [Indexed for MEDLINE] Exp Gerontol. 2018 Feb 5;104:66-71. doi: 10.1016/j.exger.2018.02.005. [Epub ahead of print] Impaired insulin signaling and spatial learning in middle-aged rats: The role of PTP1B. Kuga GK(1), Muñoz VR(2), Gaspar RC(2), Nakandakari SCBR(3), da Silva ASR(4), Botezelli JD(2), Leme JACA(5), Gomes RJ(6), de Moura LP(7), Cintra DE(8), Ropelle ER(9), Pauli JR(10). The insulin and Brain-Derived Neurotrophic Factor (BDNF) signaling in the hippocampus promotes synaptic plasticity and memory formation. On the other hand, aging is related to the cognitive decline and is the main risk factor for Alzheimer's Disease (AD). The Protein-Tyrosine Phosphatase 1B (PTP1B) is related to several deleterious processes in neurons and emerges as a promising target for new therapies. In this context, our study aims to investigate the age-related changes in PTP1B content, insulin signaling, β-amyloid content, and Tau phosphorylation in the hippocampus of middle-aged rats. Young (3 months) and middle-aged (17 months) Wistar rats were submitted to Morris-water maze (MWM) test, insulin tolerance test, and molecular analysis in the hippocampus. Aging resulted in increased body weight, and insulin resistance and decreases learning process in MWM. Interestingly, the middle-aged rats have higher levels of PTP-1B, lower phosphorylation of IRS-1, Akt, GSK3β, mTOR, and TrkB. Also, the aging process increased Tau phosphorylation and β-amyloid content in the hippocampus region. In summary, this study provides new evidence that aging-related PTP1B increasing, contributing to insulin resistance and the onset of the AD. Copyright © 2018 Elsevier Inc. All rights reserved. DOI: 10.1016/j.exger.2018.02.005 PMID: 29421605 Mol Neurobiol. 2016 Nov;53(9):5807-5817. doi: 10.1007/s12035-015-9494-6. Epub 2015 Oct 26. Brain Insulin Administration Triggers Distinct Cognitive and Neurotrophic Responses in Young and Aged Rats. Haas CB(1), Kalinine E(1), Zimmer ER(1)(2), Hansel G(1), Brochier AW(1), Oses JP(3), Portela LV(1), Muller AP(4). Aging is a major risk factor for cognitive deficits and neurodegenerative disorders, and impaired brain insulin receptor (IR) signaling is mechanistically linked to these abnormalities. The main goal of this study was to investigate whether brain insulin infusions improve spatial memory in aged and young rats. Aged (24 months) and young (4 months) male Wistar rats were intracerebroventricularly injected with insulin (20 mU) or vehicle for five consecutive days. The animals were then assessed for spatial memory using a Morris water maze. Insulin increased memory performance in young rats, but not in aged rats. Thus, we searched for cellular and molecular mechanisms that might account for this distinct memory response. In contrast with our expectation, insulin treatment increased the proliferative activity in aged rats, but not in young rats, implying that neurogenesis-related effects do not explain the lack of insulin effects on memory in aged rats. Furthermore, the expression levels of the IR and downstream signaling proteins such as GSK3-β, mTOR, and presynaptic protein synaptophysin were increased in aged rats in response to insulin. Interestingly, insulin treatment increased the expression of the brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB) receptors in the hippocampus of young rats, but not of aged rats. Our data therefore indicate that aged rats can have normal IR downstream protein expression but failed to mount a BDNF response after challenge in a spatial memory test. In contrast, young rats showed insulin-mediated TrkB/BDNF response, which paralleled with improved memory performance. DOI: 10.1007/s12035-015-9494-6 PMID: 26497034 [Indexed for MEDLINE]
  11. IBS

    Some interesting stuff on the comorbidity and bi-directional dysfunction of IBS with with the brain/mood. In other words, the microbiota-gut-brain axis... World J Gastroenterol. 2014 Oct 21;20(39):14126-31. doi: 10.3748/wjg.v20.i39.14126. Impact of psychological stress on irritable bowel syndrome. Qin HY(1), Cheng CW(1), Tang XD(1), Bian ZX(1). Author information: (1)Hong-Yan Qin, Department of Pharmacy, First Hospital of Lanzhou University, Lanzhou 730000, China. Psychological stress is an important factor for the development of irritable bowel syndrome (IBS). More and more clinical and experimental evidence showed that IBS is a combination of irritable bowel and irritable brain. In the present review we discuss the potential role of psychological stress in the pathogenesis of IBS and provide comprehensive approaches in clinical treatment. Evidence from clinical and experimental studies showed that psychological stresses have marked impact on intestinal sensitivity, motility, secretion and permeability, and the underlying mechanism has a close correlation with mucosal immune activation, alterations in central nervous system, peripheral neurons and gastrointestinal microbiota. Stress-induced alterations in neuro-endocrine-immune pathways acts on the gut-brain axis and microbiota-gut-brain axis, and cause symptom flare-ups or exaggeration in IBS. IBS is a stress-sensitive disorder, therefore, the treatment of IBS should focus on managing stress and stress-induced responses. Now, non-pharmacological approaches and pharmacological strategies that target on stress-related alterations, such as antidepressants, antipsychotics, miscellaneous agents, 5-HT synthesis inhibitors, selective 5-HT reuptake inhibitors, and specific 5-HT receptor antagonists or agonists have shown a critical role in IBS management. A integrative approach for IBS management is a necessary. DOI: 10.3748/wjg.v20.i39.14126 PMCID: PMC4202343 PMID: 25339801 [Indexed for MEDLINE] World J Gastroenterol. 2014 Jun 28;20(24):7570-86. doi: 10.3748/wjg.v20.i24.7570. Role of negative affects in pathophysiology and clinical expression of irritable bowel syndrome. Muscatello MR(1), Bruno A(1), Scimeca G(1), Pandolfo G(1), Zoccali RA(1). Author information: (1)Maria Rosaria A Muscatello, Antonio Bruno, Giuseppe Scimeca, Gianluca Pandolfo, Rocco A Zoccali, Psychiatry Unit, Department of Neurosciences, University of Messina, 98125 Messina, Italy. Irritable bowel syndrome (IBS) is regarded as a multifactorial disease in which alterations in the brain-gut axis signaling play a major role. The biopsychosocial model applied to the understanding of IBS pathophysiology assumes that psychosocial factors, interacting with peripheral/central neuroendocrine and immune changes, may induce symptoms of IBS, modulate symptom severity, influence illness experience and quality of life, and affect outcome. The present review focuses on the role of negative affects, including depression, anxiety, and anger, on pathogenesis and clinical expression of IBS. The potential role of the autonomic nervous system, stress-hormone system, and immune system in the pathophysiology of both negative affects and IBS are taken into account. Psychiatric comorbidity and subclinical variations in levels of depression, anxiety, and anger are further discussed in relation to the main pathophysiological and symptomatic correlates of IBS, such as sensorimotor functions, gut microbiota, inflammation/immunity, and symptom reporting. DOI: 10.3748/wjg.v20.i24.7570 PMCID: PMC4069288 PMID: 24976697 [Indexed for MEDLINE] Psychother Psychosom. 2017;86(1):31-46. Epub 2016 Nov 25. Gut Microbiota, Bacterial Translocation, and Interactions with Diet: Pathophysiological Links between Major Depressive Disorder and Non-Communicable Medical Comorbidities. Slyepchenko A(1), Maes M, Jacka FN, Köhler CA, Barichello T, McIntyre RS, Berk M, Grande I, Foster JA, Vieta E, Carvalho AF. Author information: (1)McMaster Integrative Neuroscience Discovery and Study (MiNDS), McMaster University, Hamilton, Ont., Canada. BACKGROUND: Persistent low-grade immune-inflammatory processes, oxidative and nitrosative stress (O&NS), and hypothalamic-pituitary-adrenal axis activation are integral to the pathophysiology of major depressive disorder (MDD). The microbiome, intestinal compositional changes, and resultant bacterial translocation add a new element to the bidirectional interactions of the gut-brain axis; new evidence implicates these pathways in the patho-aetiology of MDD. In addition, abnormalities in the gut-brain axis are associated with several chronic non-communicable disorders, which frequently co-occur in individuals with MDD, including but not limited to irritable bowel syndrome (IBS), chronic fatigue syndrome (CFS), obesity, and type 2 diabetes mellitus (T2DM). METHODS: We searched the PubMed/MEDLINE database up until May 1, 2016 for studies which investigated intestinal dysbiosis and bacterial translocation (the 'leaky gut') in the pathophysiology of MDD and co-occurring somatic comorbidities with an emphasis on IBS, CFS, obesity, and T2DM. RESULTS: The composition of the gut microbiota is influenced by several genetic and environmental factors (e.g. diet). Several lines of evidence indicate that gut-microbiota-diet interactions play a significant pathophysiological role in MDD and related medical comorbidities. Gut dysbiosis and the leaky gut may influence several pathways implicated in the biology of MDD, including but not limited to immune activation, O&NS, and neuroplasticity cascades. However, methodological inconsistencies and limitations limit comparisons across studies. CONCLUSIONS: Intestinal dysbiosis and the leaky gut may constitute a key pathophysiological link between MDD and its medical comorbidities. This emerging literature opens relevant preventative and therapeutic perspectives. © 2016 S. Karger AG, Basel. DOI: 10.1159/000448957 PMID: 27884012 [Indexed for MEDLINE]
  12. I think epigenetics are going to be the next big thing that we can readily influence, after the gut microbiota (and, to a fair extent the gut microbiota influences epigenetics). MicroRNA research is still too new and complex to do much with, right now, but there is a great deal of stuff on acetylation and methylation. Anyway, a few interesting reviews... Genet Epigenet. 2016 Sep 25;8:43-51. eCollection 2016. Epigenetics and Cellular Metabolism. Xu W(1), Wang F(1), Yu Z(2), Xin F(1). Author information: (1)Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences (CAAS), Beijing, China. (2)Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA. Living eukaryotic systems evolve delicate cellular mechanisms for responding to various environmental signals. Among them, epigenetic machinery (DNA methylation, histone modifications, microRNAs, etc.) is the hub in transducing external stimuli into transcriptional response. Emerging evidence reveals the concept that epigenetic signatures are essential for the proper maintenance of cellular metabolism. On the other hand, the metabolite, a main environmental input, can also influence the processing of epigenetic memory. Here, we summarize the recent research progress in the epigenetic regulation of cellular metabolism and discuss how the dysfunction of epigenetic machineries influences the development of metabolic disorders such as diabetes and obesity; then, we focus on discussing the notion that manipulating metabolites, the fuel of cell metabolism, can function as a strategy for interfering epigenetic machinery and its related disease progression as well. DOI: 10.4137/GEG.S32160 PMCID: PMC5038610 PMID: 27695375 Curr Genomics. 2017 Oct;18(5):385-407. doi: 10.2174/1389202918666170412112130. Aging as an Epigenetic Phenomenon. Ashapkin VV(1), Kutueva LI(1), Vanyushin BF(1). Author information: (1)Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russia. INTRODUCTION: Hypermethylation of genes associated with promoter CpG islands, and hypomethylation of CpG poor genes, repeat sequences, transposable elements and intergenic genome sections occur during aging in mammals. Methylation levels of certain CpG sites display strict correlation to age and could be used as "epigenetic clock" to predict biological age. Multi-substrate deacetylases SIRT1 and SIRT6 affect aging via locus-specific modulations of chromatin structure and activity of multiple regulatory proteins involved in aging. Random errors in DNA methylation and other epigenetic marks during aging increase the transcriptional noise, and thus lead to enhanced phenotypic variation between cells of the same tissue. Such variation could cause progressive organ dysfunction observed in aged individuals. Multiple experimental data show that induction of NF-κB regulated gene sets occurs in various tissues of aged mammals. Upregulation of multiple miRNAs occurs at mid age leading to downregulation of enzymes and regulatory proteins involved in basic cellular functions, such as DNA repair, oxidative phosphorylation, intermediate metabolism, and others. CONCLUSION: Strong evidence shows that all epigenetic systems contribute to the lifespan control in various organisms. Similar to other cell systems, epigenome is prone to gradual degradation due to the genome damage, stressful agents, and other aging factors. But unlike mutations and other kinds of the genome damage, age-related epigenetic changes could be fully or partially reversed to a "young" state. DOI: 10.2174/1389202918666170412112130 PMCID: PMC5635645 [Available on 2018-04-01] PMID: 29081695 Biochim Biophys Acta. 2015 Mar;1849(3):309-16. doi: 10.1016/j.bbagrm.2015.01.002. Epub 2015 Jan 15. Regulation of skeletal muscle development and homeostasis by gene imprinting, histone acetylation and microRNA. Moresi V(1), Marroncelli N(2), Coletti D(2), Adamo S(2). Author information: (1)Dept. of Anat., Histol., Forens. & Orthop. Sciences, Section of Histology and Medical Embryology, Sapienza University of Rome, Via Scarpa, 14, 00161 Rome, Italy. Electronic address: viviana.moresi@uniroma1.it. (2)Dept. of Anat., Histol., Forens. & Orthop. Sciences, Section of Histology and Medical Embryology, Sapienza University of Rome, Via Scarpa, 14, 00161 Rome, Italy. Epigenetics is defined as heritable information other than the DNA sequence itself. The concept implies that the regulation of gene expression is a highly complex process in which epigenetics plays a major role that ranges from fine-tuning to permanent gene activation/deactivation. Skeletal muscle is the main tissue involved in locomotion and energy metabolism in the body, accounting for at least 40% of the body mass. Body mass and function vary according to age but also quickly adapt to both physiological and pathological cues. Besides transcriptional mechanisms that control muscle differentiation, postnatal growth and remodeling, there are numerous epigenetic mechanisms of regulation that modulate muscle gene expression. In this review, we describe and discuss only some of the mechanisms underlying epigenetic regulation, such as DNA methylation, histone modifications and microRNAs, which we believe are crucial to skeletal muscle development and disease. Copyright © 2015. Published by Elsevier B.V. DOI: 10.1016/j.bbagrm.2015.01.002 PMID: 25598319 [Indexed for MEDLINE]
  13. For those who do not know about it, you can get most full papers for free through Sci-Hub Because it is controversial, the working links tend to change. Here are a bunch of different ones: https://sci-hub.la https://tree.sci-hub.la https://sci-hub.mn https://sci-hub.name https://sci-hub.tw https://sci-hub.tv https://sci-hub.hk https://sci-hub.is https://sci-hub.ws https://80.82.77.83 https://80.82.77.84 (Tor Browser) https://scihub22266oqcxt.onion.link https://scihub22266oqcxt.onion
  14. This is highly speculative but really interesting (It also has a couple of reviewer comments at the end of the paper, plus the authors' responses) Biol Direct. 2014 Jul 2;9:14. doi: 10.1186/1745-6150-9-14. Midichlorians--the biomeme hypothesis: is there a microbial component to religious rituals? Panchin AY(1), Tuzhikov AI, Panchin YV. Author information: (1)Institute for Information Transmission Problems, Moscow, Russian Federation. alexpanchin@yahoo.com. BACKGROUND: Cutting edge research of human microbiome diversity has led to the development of the microbiome-gut-brain axis concept, based on the idea that gut microbes may have an impact on the behavior of their human hosts. Many examples of behavior-altering parasites are known to affect members of the animal kingdom. Some prominent examples include Ophiocordyceps unilateralis (fungi), Toxoplasma gondii (protista), Wolbachia (bacteria), Glyptapanteles sp. (arthropoda), Spinochordodes tellinii (nematomorpha) and Dicrocoelium dendriticum (flat worm). These organisms belong to a very diverse set of taxonomic groups suggesting that the phenomena of parasitic host control might be more common in nature than currently established and possibly overlooked in humans. PRESENTATION OF THE HYPOTHESIS: Some microorganisms would gain an evolutionary advantage by encouraging human hosts to perform certain rituals that favor microbial transmission. We hypothesize that certain aspects of religious behavior observed in the human society could be influenced by microbial host control and that the transmission of some religious rituals could be regarded as the simultaneous transmission of both ideas (memes) and parasitic organisms. TESTING THE HYPOTHESIS: We predict that next-generation microbiome sequencing of samples obtained from gut or brain tissues of control subjects and subjects with a history of voluntary active participation in certain religious rituals that promote microbial transmission will lead to the discovery of microbes, whose presence has a consistent and positive association with religious behavior. Our hypothesis also predicts a decline of participation in religious rituals in societies with improved sanitation. IMPLICATIONS OF THE HYPOTHESIS: If proven true, our hypothesis may provide insights on the origin and pervasiveness of certain religious practices and provide an alternative explanation for recently published positive associations between parasite-stress and religiosity. The discovery of novel microorganisms that affect host behavior may improve our understanding of neurobiology and neurochemistry, while the diversity of such organisms may be of interest to evolutionary biologists and religious scholars. REVIEWERS: This article was reviewed by Prof. Dan Graur, Dr. Rob Knight and Dr. Eugene Koonin. DOI: 10.1186/1745-6150-9-14 PMCID: PMC4094439 PMID: 24990702 [Indexed for MEDLINE]
  15. What a blast from the past

    You take Shock Therapy first, for 10 days, to clear out the bad bacteria, so the good ones you are about to take don't have to compete with them. Then, you switch to Suprabiotic (probiotic) and Primer (prebiotic), together.
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