• Welcome to Phoenix Rising!

    Created in 2008, Phoenix Rising is the largest and oldest forum dedicated to furthering the understanding of and finding treatments for complex chronic illnesses such as chronic fatigue syndrome (ME/CFS), fibromyalgia (FM), long COVID, postural orthostatic tachycardia syndrome (POTS), mast cell activation syndrome (MCAS), and allied diseases.

    To become a member, simply click the Register button at the top right.

Lipopolysaccharide-induced leptin release is neurally controlled.

Ema

Senior Member
Messages
4,729
Location
Midwest USA
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC64748/

More decreased dopamine and increased prolactin...clearly an influence on metabolism.

That plasma leptin concentration declined gradually in anesthetized male rats during surgery led us to hypothesize that leptin secretion was under neural control (22). To assess the neural control of leptin, we used another type of stress, namely, the inflammatory stress induced by LPS that is known to increase leptin release (16). Furthermore, it was shown that LPS increased catecholamine levels in the CNS (9, 11) and in the periphery (10) and also activated the hypothalamic–pituitary–adrenal axis (5, 6). Therefore, we considered the present paradigm as a suitable model to assess the neural control of leptin.

Our previous results had shown that LPS evoked a rapid and long-lasting increase in plasma leptin concentrations, with the first increase obtained within 10 min and a plateau existing from 2 to 6 h. The current results show that at 6 h there was a highly significant increase in leptin mRNA in epididymal fat pads induced by LPS. The early release of leptin within 10 min could not have occurred by new synthesis of leptin and, instead, must be caused by release of stored leptin that has been found in pinocytotic vesicles in adipocytes (26). Therefore, presumably, LPS acts on its receptors within the brain or receptors on afferent neurons, such as vagal afferents, to activate neural or hormonal mechanisms that evoke exocytosis of leptin-containing vesicles, which accounts for the initial elevation of plasma leptin. This is followed by induction of leptin mRNA, which stimulates leptin synthesis, contributing to the release that occurs later along with that of preformed leptin.

As in our previous results with placement of jugular catheters in anesthetized rats (22), plasma leptin decreased in the current experiments. Moreover, anesthesia also decreased LPS-induced plasma leptin release in the same period, providing further support for our concept that leptin is under neural control. Surprisingly, ketamine anesthesia either alone or in the presence of LPS provoked a rebound in plasma leptin levels after 120 min that reached concentrations similar to or even greater than those present in the LPS-treated rats. We hypothesize that this rebound may be caused by decreased negative feedback of the depressed plasma leptin concentrations during anesthesia, which, at the termination of anesthesia, act centrally to stimulate leptin release.

To understand further the possible role of the sympathetic nervous system in LPS-induced leptin release, we studied the effects of α- and β-adrenergic agonists and antagonists on the response to LPS. Injection of the β-adrenergic agonist, isoproterenol, slightly but significantly decreased plasma leptin concentrations and, in the presence of LPS, largely blunted the LPS-induced increase in plasma leptin concentrations. Recently, it has been shown that there is noradrenergic innervation not only of brown but also of white fat (27). That propranolol increased baseline concentrations of plasma leptin is consistent with the hypothesis that there is β-adrenergic inhibitory tone depressing leptin release during resting conditions. However, in the presence of LPS, propranolol slightly but not significantly decreased LPS-induced leptin release, suggesting that the inhibitory β tone under resting conditions was not present after injection of LPS. Therefore, our data suggest that either circulating epinephrine and/or norepinephrine or norepinephrine released from noradrenergic terminals may inhibit leptin release by acting on β-adrenergic receptors present on cell membranes of the adipocytes (28).

Phentolamine, the α-adrenergic antagonist, induced a rapid and highly significant increase in plasma leptin either alone or in the presence of LPS, suggesting that there is a strong inhibitory tone acting through the α-adrenergic receptors to inhibit not only basal but LPS-stimulated leptin release.

Recently, we found that prolactin stimulated leptin release and that α-bromoergocryptine, a dopaminergic-2 receptor agonist that inhibits prolactin release from the anterior pituitary gland, decreased plasma leptin concentrations (21), results that were obtained independently by Gualillo et al.(29). Moreover, we have shown previously that LPS increased prolactin release (5) in a similar experimental paradigm as that used here. Thus, it is likely that LPS-induced prolactin release increases leptin release by activation of prolactin receptors on adipocytes (30). Therefore, we studied the effect of α-bromoergocryptine, an inhibitor of prolactin release, alone or in the presence of LPS. As in the case of anesthesia, α-bromoergocryptine alone or in the presence of LPS decreased plasma leptin concentrations initially, but this decrease was followed by a later rebound of a lesser extent than that observed in the ketamine experiments. The rebound in both cases may be related to the initial lowering of plasma leptin, reducing its negative feedback. Then, as the drug or anesthesia dissipates, an increase in leptin release follows, leading to the rebound in plasma levels, which presumably is caused by increased prolactin release.

The decline in leptin in the bromocryptine-injected animals was much less than in the anesthetized animals, and the rebound was also less, perhaps because the lesser decrease in plasma leptin compared with that of anesthetized rats resulted in a lesser negative feedback of leptin in these animals.

We hypothesize that LPS acts on the CNS to inhibit the secretion of dopamine, removing the inhibition exerted by tuberoinfundibullar dopaminergic neurons on the secretion of prolactin (PRL) (see summary diagram, Fig. Fig.10).10). Therefore, the secretion of PRL is increased from the lactotropes. Thereafter, PRL circulates to the adipose tissue and, acting on its receptors (PRLr) on the adipocytes, increases the release of leptin that is stored in pinocytotic vesicles in the cytoplasma adjacent to the cell membrane. The sympathetic nervous system exerts a tonic inhibitory effect on leptin release—mediated predominantly by α-adrenergic and, to a lesser extent, by β-adrenergic receptors—that is still present and may be augmented by LPS.
 

heapsreal

iherb 10% discount code OPA989,
Messages
10,089
Location
australia (brisbane)
being a dam boy or a girl can always throw a spanner in the works when it comes to alot of research on hormones and neurotransmitters.

Probably 20yrs ago there was research on beta 3 receptor, prior to this only beta 1 and 2 receptors were thought to exist. What they found was some asthma medications could help people lose weight by speeding up their metabolisms, further research found a beta 3 receptor which is supposedly involved in fat metabolism. Just though i would mention this as it may fit into this interlocking web of hormones and neurotransmitters especially insulin/leptin sensitivity and maybe mito function, may play a role with carnitine??
 

Ema

Senior Member
Messages
4,729
Location
Midwest USA
Thought I would re-post this study here too:

J Transl Med. 2013 Apr 9;11:93. doi: 10.1186/1479-5876-11-93.
Daily cytokine fluctuations, driven by leptin, are associated with fatigue severity in chronic fatigue syndrome: evidence of inflammatory pathology.
Stringer EA1, Baker KS, Carroll IR, Montoya JG, Chu L, Maecker HT, Younger JW.
Author information
  • 1Department of Anesthesiology, Stanford University School of Medicine, Stanford, CA 94304, USA.
Abstract
BACKGROUND:
Chronic fatigue syndrome (CFS) is a debilitating disorder characterized by persistent fatigue that is not alleviated by rest. The lack of a clearly identified underlying mechanism has hindered the development of effective treatments. Studies have demonstrated elevated levels of inflammatory factors in patients with CFS, but findings are contradictory across studies and no biomarkers have been consistently supported. Single time-point approaches potentially overlook important features of CFS, such as fluctuations in fatigue severity. We have observed that individuals with CFS demonstrate significant day-to-day variability in their fatigue severity.

METHODS:
Therefore, to complement previous studies, we implemented a novel longitudinal study design to investigate the role of cytokines in CFS pathophysiology. Ten women meeting the Fukuda diagnostic criteria for CFS and ten healthy age- and body mass index (BMI)-matched women underwent 25 consecutive days of blood draws and self-reporting of symptom severity. A 51-plex cytokine panel via Luminex was performed for each of the 500 serum samples collected. Our primary hypothesis was that daily fatigue severity would be significantly correlated with the inflammatory adipokine leptin, in the women with CFS and not in the healthy control women. As a post-hoc analysis, a machine learning algorithm using all 51 cytokines was implemented to determine whether immune factors could distinguish high from low fatigue days.

RESULTS:
Self-reported fatigue severity was significantly correlated with leptin levels in six of the participants with CFS and one healthy control, supporting our primary hypothesis. The machine learning algorithm distinguished high from low fatigue days in the CFS group with 78.3% accuracy.

CONCLUSIONS:
Our results support the role of cytokines in the pathophysiology of CFS.

PMID:

23570606

[PubMed - indexed for MEDLINE]
PMCID:

PMC3637529

Free PMC Article

Images from this publication.See all images (3)Free text




Publication Types, MeSH Terms, Substances, Grant Support

LinkOut - more resources

PubMed Commons home
PubMed Commons
0 comments
How to join PubMed Commons
 

Ema

Senior Member
Messages
4,729
Location
Midwest USA
What they found was some asthma medications could help people lose weight by speeding up their metabolisms, further research found a beta 3 receptor which is supposedly involved in fat metabolism. Just though i would mention this as it may fit into this interlocking web of hormones and neurotransmitters especially insulin/leptin sensitivity and maybe mito function, may play a role with carnitine??

I know theophylline works for this by blocking adenosine. And I guess these beta receptors too?

Am J Physiol Cell Physiol. 2002 Jul;283(1):C244-50.
Mechanisms of leptin secretion from white adipocytes.
Cammisotto PG1, Bukowiecki LJ.
Author information

Abstract
The mechanisms regulating leptin secretion were investigated in isolated rat white adipocytes. Insulin (1-100 nM) linearly stimulated leptin secretion from incubated adipocytes for at least 2 h. The adrenergic agonists norepinephrine, isoproterenol (two nonselective beta-agonists), or CL-316243 (potent beta3) all inhibited insulin (10 nM)-stimulated leptin release. The inhibitory effects of norepinephrine and isoproterenol could be reversed not only by the nonselective antagonist propranolol but also by the selective antagonists ICI-89406 (beta1) or ICI-118551 (beta2), the beta2-antagonist being less effective than the beta1. Insulin-stimulated leptin secretion could also be inhibited by a series of agents increasing intracellular cAMP levels, such as lipolytic hormones (ACTH and thyrotropin-stimulating hormone), various nonhydrolyzable cAMP analogs, pertussis toxin, forskolin, methylxanthines (caffeine, theophylline, IBMX), and specific inhibitors of phosphodiesterase III (imazodan, milrinone, and amrinone). Significantly, antilipolytic agents other than insulin (adenosine, nicotinic acid, acipimox, and orthovanadate) did not mimic the acute stimulatory effects of insulin on leptin secretion under these conditions. We conclude that norepinephrine specifically inhibits insulin-stimulated leptin secretion not only via the low-affinity beta3-adrenoceptors but also via the high-affinity beta1/beta2-adrenoceptors. Moreover, it is suggested that 1) activation of phosphodiesterase III by insulin represents an important metabolic step in stimulation of leptin secretion, and 2) lipolytic hormones competitively counterregulate the stimulatory effects of insulin by activating the adenylate cyclase system.
 

Ema

Senior Member
Messages
4,729
Location
Midwest USA
This increasing cellular cAMP always comes up too in terms of mitochondria and energy generation.

I think I posted a study under Hormones showing how glucocorticoids do this, and I know we've talked about forskolin before as increasing cAMP.

That's also how that PQQ supp from Life Ext is supposed to work as well, I think, at least in part.

I'm currently working under the assumption (from other studies) that part of the problem is interferon gamma not turning "off" properly and thus allowing the infection to turn chronic (by not producing antibodies properly) so this is kind of interesting as well.

Buhner says something similar...that the Th1 response never properly converts to the Th2 response which is what perpetuates chronic disease in some and interferon gamma may be one reason why that happens.

http://onlinelibrary.wiley.com/doi/10.1002/glia.440140204/abstract

Abstract
The aim of the present study was to determine whether two classical macrophage activators, bacterial lipopolysaccharide (LPS) and interferon-γ (IFN-γ) could affect the accumulation of the second messenger cAMP in cultured rat microglia and astrocytes.

...

Our observations indicate that two potent activators of microglia acting at different receptors, LPS and IFN-γ, can diminish the accumulation of cAMP through a common mechanism, the stimulation of a specific form of cAMP phosphodiesterase.

The fact that IFN-γ, but not LPS, was effective in astrocytes suggests that LPS receptors are scarcely, if at all, expressed in these cells, or that they are differently coupled to second messengers. Selective inhibitors of type IV phosphodiesterase might prevent some of the obnoxious actions of LPS or IFN-γ in the living organism. © 1995 Wiley-Liss, Inc.

Maybe I just like that they called IFN-g "obnoxious" in a scientific journal. :)
 
Last edited:

Ema

Senior Member
Messages
4,729
Location
Midwest USA
And that appears to possibly be why some go on to develop chronic Lyme, while others can more rapidly clear an infection.

HLA-DR alleles determine responsiveness to Borrelia burgdoferi antigens
Bettina Panagiota Iliopoulou, Mireia Guerau-de-Arellano, and Brigitte T. Huber. Arthritis Rheum. 2009 December; 60(12): 3831–3840.

Source:http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2828865

The authors of this particular paper wrote up their own informative article, Sometimes It's All In Your Genes with descriptions of their project for the layperson. I highly recommend reading it, as it is an educational and easily readable description of their research in greater detail from the perspective of the researchers themselves.

In the above study, researchers experimented with mice who have the genetic profiles of HLA-DR4 (which is related to developing arthritis) and HLA-DR11 (which is predicted to clear spirochetes quickly).They infected both groups of mice with Borrelia burgdorferi and monitored their ability to clear spirochetes and develop signs of arthritis.

According to the researchers, mice with HLA-DR4 alleles produced lots of interferon gamma and very few antibodies to the spirochete - whereas those with HLA-DR11 alleles produced lots of antibodies but no interferon gamma.

To translate:

Interferon gamma = Produces LOTS of inflammation, which hurts and sucks.
Very few antibodies = Nothing much to fight off the infection.
Lots of antibodies + No Interferon gamma = Fight off infection while having little or no inflammation.

When you look at the paper itself, this is of particular note:
"We found that DR11 tg mice mount a vigorous Ab response, but are defective in IFN-γ production. In addition, Bb-infected DR11 tg mice had decreased spirochete burden compared to DR4 tg mice, measured by qPCR of Bb DNA. This is in contrast to DR4 tg mice, which produce an inflammatory response characterized by high level of IFN-γ production, in accordance with our published results (10). Furthermore, the Ab response to Bb-antigens was significantly lower than that of DR11 tg mice, which is consistent with the higher spirochete burden observed in DR4 tg mice after Bb-infection. Thus, our data provide a possible explanation for the differential regulation of the immune response in DR4+ and DR11+ patients upon Bb-infection; namely, HLA-DR4 would predispose individuals to chronic Lyme arthritis by generating an inflammatory milieu to Bb-infection, while HLA-DR11 would exert a protective role through the production of anti-spirochetal Abs." So, to review, in this study:

HLA-DR4 mice have a significantly lower antibody response to Bb antigens compared to HLA-DR11 mice.

HLA-DR4 mice have a significantly higher inflammatory response (measured as Interferon gamma or IFN-γ ). (It sounds as if HLA-DR11 has no real inflammatory response.)

HLA-DR4 mice have a significantly higher spirochetal load compared to HLA-DR11 mice.

If you look at figure 5b & c (if I'm to read the caption properly based on the full text) the amount of spirochetal DNA present in an ear punch sample was twice as high in the HLA-DR4 mice compared to the HLA-DR11 mice, and the amount of spirochetal DNA present in the joints appears to be about 6 times higher in HLA-DR4 mice compared to the HLA-DR11 mice.

That's a huge difference.

To add to this, the study also immunized two groups of mice with these alleles with rOspA and found out that:

HLA-DR4 mice mount a poor response to rOspA.

HLA-DR11 mice mount a strong antibody response to rOspA. They have a good humoral response.
 
Last edited:

rosie26

Senior Member
Messages
2,446
Location
NZ
@Ema if you come across any more research about Bacterial Lipopolysaccharide. I would be most grateful. I don't know good research from not so good. Many thanks.
 
Last edited: