• Due to excessive bot signups along with nefarious actors we are limiting forum registration. Keep checking back for the register link to appear. Please do not send emails or have someone post to the forum asking for a signup link. Until the current climate changes we do not see a change of this policy. To join the forum you must have a compelling reason. Letting us know what skills/knowledge you will bring to the community along with the intent of your stay here will help in getting you approved.

Glucose Oxidation Prevents Obesity-associated Insulin Resistance And Inflammation

Hans

Member
Joined
Aug 24, 2017
Messages
4,691
I'm currently writing a big article on fixing fatty liver and came across this gem.
Just to give some background, endotoxins promote lipolysis, beta-oxidation and glycolysis, which creates a state of high ROS and subsequent immune response.
The immune response is driven by M1 polarization.

Pyruvate Dehydrogenase Kinase Is a Metabolic Checkpoint for Polarization of Macrophages to the M1 Phenotype
Here, we demonstrate that pyruvate dehydrogenase kinase (PDK), which inhibits the pyruvate dehydrogenase-mediated conversion of cytosolic pyruvate to mitochondrial acetyl-CoA, functions as a metabolic checkpoint in M1 macrophages. Polarization was not prevented by PDK2 or PDK4 deletion but was fully prevented by the combined deletion of PDK2 and PDK4; this lack of polarization was correlated with improved mitochondrial respiration and rewiring of metabolic breaks that are characterized by increased glycolytic intermediates and reduced metabolites in the TCA cycle. Genetic deletion or pharmacological inhibition of PDK2/4 prevents polarization of macrophages to the M1 phenotype in response to inflammatory stimuli (lipopolysaccharide plus IFN-γ). Transplantation of PDK2/4-deficient bone marrow into irradiated wild-type mice to produce mice with PDK2/4-deficient myeloid cells prevented M1 polarization, reduced obesity-associated insulin resistance, and ameliorated adipose tissue inflammation. A novel, pharmacological PDK inhibitor, KPLH1130, improved high-fat diet-induced insulin resistance; this was correlated with a reduction in the levels of pro-inflammatory markers and improved mitochondrial function. These studies identify PDK2/4 as a metabolic checkpoint for M1 phenotype polarization of macrophages, which could potentially be exploited as a novel therapeutic target for obesity-associated metabolic disorders and other inflammatory conditions.
 
Joined
Jun 16, 2017
Messages
1,790
Palmitic acid to the rescue.
 
Joined
Jun 16, 2017
Messages
1,790
I've been eating white chocolate for a while. I wonder what the results will be after like a month.
Cool. When you hit the 1-month mark, let us know how it went!

I'm not sure about the sugar content though.
You think it may cause problems when combined with fat?
 

Zigzag

Member
Joined
Aug 27, 2018
Messages
650
Cool. When you hit the 1-month mark, let us know how it went!


You think it may cause problems when combined with fat?

Well. I like it so much I can eat a whole bar at once :D. It's around 65g of carbs (still less than in 100g of white rice...) and around 28g of fat. Wouldn't those nutrients compete ?
 
Joined
Jun 16, 2017
Messages
1,790
Well. I like it so much I can eat a whole bar at once :D. It's around 65g of carbs (still less than in 100g of white rice...) and around 28g of fat. Wouldn't those nutrients compete ?
After reading many anecdotes of people on the forum regarding whether or not to consume carbs and fat together, I think the best advice I can give is to try it out and see what happens. If it makes you gain excessive weight, then it may mean you need to eat less fat or less carbs, or to space them out. If it doesn't cause fat gain, and you still feel good( no brain fog, no muscle loss, etc.), then I don't see why you shouldn't combine that amount of carbs and fat.

Fat and carbs, when eaten at the same time, do compete with each other to be burned as fuel, but that isn't necessarily bad. Peat mentioned a study in pilots where the ones who received high fat diets( with also a significant amount of carbs) did better than the pilots who received low fat diets. Because there was fat available for the muscles to burn, the brain could have a bigger portion of the sugar from the blood for itself, therefore functioning better. The pilots who didn't eat much fat experienced a situation where both the brain and the muscles were absorbing a lot of glucose from the bloodstream, causing cognition to suffer. There is also the distinction between safe fats and PUFAs. The safe fats will cause temporary insulin resistance( sparing sugar for the tissues that need it, like the brain), which will subside once the fats in the blood are burned( by the muscles, for example), but the PUFAs not only will cause insulin resistance, but also will lower the PDH enzyme( essential for burning sugar), as well as cause organ damage, likely through peroxidation, as well as through energy depletion, not to mention they will increase estrogen.

Also, make sure to get enough vitamin B1 to balance the white sugar in the chocolate bar.
 
Joined
Aug 21, 2018
Messages
1,153

rob

Member
Joined
Aug 31, 2019
Messages
146
Location
UK
I'm currently writing a big article on fixing fatty liver and came across this gem.
Just to give some background, endotoxins promote lipolysis, beta-oxidation and glycolysis, which creates a state of high ROS and subsequent immune response.
The immune response is driven by M1 polarization.

Pyruvate Dehydrogenase Kinase Is a Metabolic Checkpoint for Polarization of Macrophages to the M1 Phenotype
Here, we demonstrate that pyruvate dehydrogenase kinase (PDK), which inhibits the pyruvate dehydrogenase-mediated conversion of cytosolic pyruvate to mitochondrial acetyl-CoA, functions as a metabolic checkpoint in M1 macrophages. Polarization was not prevented by PDK2 or PDK4 deletion but was fully prevented by the combined deletion of PDK2 and PDK4; this lack of polarization was correlated with improved mitochondrial respiration and rewiring of metabolic breaks that are characterized by increased glycolytic intermediates and reduced metabolites in the TCA cycle. Genetic deletion or pharmacological inhibition of PDK2/4 prevents polarization of macrophages to the M1 phenotype in response to inflammatory stimuli (lipopolysaccharide plus IFN-γ). Transplantation of PDK2/4-deficient bone marrow into irradiated wild-type mice to produce mice with PDK2/4-deficient myeloid cells prevented M1 polarization, reduced obesity-associated insulin resistance, and ameliorated adipose tissue inflammation. A novel, pharmacological PDK inhibitor, KPLH1130, improved high-fat diet-induced insulin resistance; this was correlated with a reduction in the levels of pro-inflammatory markers and improved mitochondrial function. These studies identify PDK2/4 as a metabolic checkpoint for M1 phenotype polarization of macrophages, which could potentially be exploited as a novel therapeutic target for obesity-associated metabolic disorders and other inflammatory conditions.

Thought you might be interested to read Human and murine macrophages exhibit differential metabolic responses to lipopolysaccharide - A divergent role for glycolysis - ScienceDirect. Suggests we might want to proceed with caution in applying animal immunometabolic studies to humans until a lot more dots are connected on this stuff.

Unlike in mice, the study observed that human macrophages didn't exhibit any metabolic reprogramming from OXPHOS to glycolysis upon LPS stimulation. Indeed, OXPHOS remained the predominant ATP source regardless of polarisation. Moreover, intriguingly, the study indicated that glycolysis, not OXPHOS, was essential to the expression of the anti-inflammatory cytokine IL-10 in human macrophages, which presumably adds emphasis upstream of the PDC.
 

Hans

Member
Thread starter
Joined
Aug 24, 2017
Messages
4,691
Thought you might be interested to read Human and murine macrophages exhibit differential metabolic responses to lipopolysaccharide - A divergent role for glycolysis - ScienceDirect. Suggests we might want to proceed with caution in applying animal immunometabolic studies to humans until a lot more dots are connected on this stuff.

Unlike in mice, the study observed that human macrophages didn't exhibit any metabolic reprogramming from OXPHOS to glycolysis upon LPS stimulation. Indeed, OXPHOS remained the predominant ATP source regardless of polarisation. Moreover, intriguingly, the study indicated that glycolysis, not OXPHOS, was essential to the expression of the anti-inflammatory cytokine IL-10 in human macrophages, which presumably adds emphasis upstream of the PDC.
Thanks for sharing.

"M1-like macrophages are typically characterized by their antibacterial and antitumor functions, along with the high production of various pro-inflammatory cytokines as well as reactive nitrogen and oxygen species (RNS, ROS). On the other hand, cytokines such as IL-4/IL-13, IL-10 and TGF-β (transforming growth factor beta) will contribute to M2 (or M2-like), anti-inflammatory phenotypes which are broadly involved in immunosuppression, angiogenesis, and tissue repair [1, 13]."

"direct transcriptional activation and subsequent protein production of canonical M1 markers including iNOS, TNFα, IL-12, CXCL9 (C-X-C motif chemokine ligand 9) and CXCL10 [11]."
Endotoxins are a very potent inducer of iNOS, which would cause M1 polarization."

The Metabolic Signature of Macrophage Responses
"In particular, M1 macrophages rely mainly on glycolysis and present two breaks on the TCA cycle that result in accumulation of itaconate (a microbicide compound) and succinate. Excess of succinate leads to Hypoxia Inducible Factor 1α (HIF1α) stabilization that, in turn, activates the transcription of glycolytic genes, thus sustaining the glycolytic metabolism of M1 macrophages. On the contrary, M2 cells are more dependent on oxidative phosphorylation (OXPHOS), their TCA cycle is intact and provides the substrates for the complexes of the electron transport chain (ETC)."

Metabolic influence on macrophage polarization and pathogenesis
"Even with the increased glycolytic rate, OXPHOS in M1 macrophages is largely impaired (Fig. 2), which is in sharp contrast to the induction of OXPHOS in the M2 macrophages (59). As described above, NO is not only an antimicrobial agent but also plays a role in the metabolic modulation of M1 macrophages. NO modifies ETC complex I with S-nitrosylation and inhibits mitochondrial respiration (60). Intriguingly, Van den Bossche et al. recently showed that inhibition of iNOS using a chemical inhibitor or genetic ablation markedly improved mitochondrial function in M1 macrophages, which promoted IL-4-induced repolarization of M1 into M2 (49)."
 

rob

Member
Joined
Aug 31, 2019
Messages
146
Location
UK
Thanks for sharing.

"M1-like macrophages are typically characterized by their antibacterial and antitumor functions, along with the high production of various pro-inflammatory cytokines as well as reactive nitrogen and oxygen species (RNS, ROS). On the other hand, cytokines such as IL-4/IL-13, IL-10 and TGF-β (transforming growth factor beta) will contribute to M2 (or M2-like), anti-inflammatory phenotypes which are broadly involved in immunosuppression, angiogenesis, and tissue repair [1, 13]."

"direct transcriptional activation and subsequent protein production of canonical M1 markers including iNOS, TNFα, IL-12, CXCL9 (C-X-C motif chemokine ligand 9) and CXCL10 [11]."
Endotoxins are a very potent inducer of iNOS, which would cause M1 polarization."

The Metabolic Signature of Macrophage Responses
"In particular, M1 macrophages rely mainly on glycolysis and present two breaks on the TCA cycle that result in accumulation of itaconate (a microbicide compound) and succinate. Excess of succinate leads to Hypoxia Inducible Factor 1α (HIF1α) stabilization that, in turn, activates the transcription of glycolytic genes, thus sustaining the glycolytic metabolism of M1 macrophages. On the contrary, M2 cells are more dependent on oxidative phosphorylation (OXPHOS), their TCA cycle is intact and provides the substrates for the complexes of the electron transport chain (ETC)."

Metabolic influence on macrophage polarization and pathogenesis
"Even with the increased glycolytic rate, OXPHOS in M1 macrophages is largely impaired (Fig. 2), which is in sharp contrast to the induction of OXPHOS in the M2 macrophages (59). As described above, NO is not only an antimicrobial agent but also plays a role in the metabolic modulation of M1 macrophages. NO modifies ETC complex I with S-nitrosylation and inhibits mitochondrial respiration (60). Intriguingly, Van den Bossche et al. recently showed that inhibition of iNOS using a chemical inhibitor or genetic ablation markedly improved mitochondrial function in M1 macrophages, which promoted IL-4-induced repolarization of M1 into M2 (49)."

Yeah, a lot of these immunometabolic studies, even some of the 2019 stuff, cite findings from murine studies, which is problematic.

Other very recent studies using human macrophages, such as https://www.spiedigitallibrary.org/...in-response-to/10.1117/1.JBO.25.1.014512.full, also seem to point to divergent metabolitic reprogramming in face of LPS stimulation, thus, challenging current immunometabolic models.

"Our optical redox ratio and mitochondrial clustering results are inconsistent for M[LPS] in studies of murine macrophages, but consistent with studies performed with human M[LPS]. In murine macrophages, it is established that in response to pro-inflammatory stimuli glycolysis is enhanced while oxidative phosphorylation (oxphos) is limited due to a dysfunctional tricarboxylic acid (TCA) cycle.45,46 A significant decrease in the NAD(P)H bound fraction as assessed by corresponding lifetime measurements has been reported in LPS activation of murine macrophages and is consistent with enhanced glycolysis.47 However, recent studies suggest that proinflammatory human peripheral blood-derived macrophages rely on oxidative phosphorylation for energy production10 and do not produce nitric oxide or regulate reactive oxygen species production, thus contradicting the assumed reprogramming of the TCA cycle for glycolytic metabolism as is seen in their murine counterparts.7,10 In addition, human macrophage responses to β-glucan (an immunostimulant glucose polymer that induces some similar effects in macrophages as LPS)48 have been found to be contingent upon the glutaminolysis pathway,49 supporting a potential role for enhanced glutaminolysis under pro-inflammatory conditions, consistent with our findings."

As also noted in this study, FAO and glutaminolysis changes in human macrophages when faced with LPS challenge haven't been elucidated and might help shed light on what's going on.
 
Last edited:

Light

Member
Joined
Oct 5, 2018
Messages
304
Peat mentioned a study in pilots where the ones who received high fat diets( with also a significant amount of carbs) did better than the pilots who received low fat diets.
Hi @Rafael Lao Wai ,
I've been scanning the forums looking for this study that Ray mentions in one of his interview,
Do you have the actual study?
Thanks
 

Similar threads

Top