Leptin & nutrients for mitigating stress/ANS/catecholamine elevation (SPED comment)

- useful info from a Guest of Walter M Chestnut. / Obesity and COVID19, or for maintaining a healthy weight – pomegranate and zinc may help as coregulators of leptin receptors.

Nutrients that may reduce catecholamine levels - Vitamin D, bioflavonoids, Zinc, Vitamin C, curcumin, (–)-Epigallocatechin-3-O-gallate (EGCG), Melatonin, and being obese increases risk of elevated catecholamine.

Guest of WMC Research SubStack, Nov 4, comment on: Ketogenic diet deplete epinephrine, by, Walter M Chestnut, (wmcresearch.substack.com)

FWIW... [For what it’s worth]

1. Vitamin D, effects on brain development, adult brain function and the links between low levels of vitamin D and neuropsychiatric disease - https://www.sciencedirect.com/science/article/abs/pii/S0091302212000295 - "...epidemiological associations have been made between low vitamin D and psychiatric disorders not typically associated with abnormalities in brain development such as depression and Alzheimer’s disease. Once again the preclinical findings revealing that vitamin D can regulate catecholamine levels and protect against specific Alzheimer-like pathology increase the plausibility of this link..."

2. Vitamin D Supplementation Improves Cardiovascular Response to Head Up Tilt in Adolescents Suffering from Syncope - https://www.ahajournals.org/doi/10.1161/hyp.72.suppl_1.P396 - "...Compared to baseline, vitamin D supplementation reduced the HR elevation post HUT and reduced NE/Epi baseline levels..."

3. Effects of bioflavonoids on catecholamine biosynthetic activity in the adrenal gland: In vitro studies using partially purified tyrosine hydroxylase and chromaffin cell cultures - https://pubmed.ncbi.nlm.nih.gov/20504598/ - "...The findings presented here suggest that quercetin may inhibit catecholamine biosynthesis..."

4. Zinc controls cell pores to regulate storage and release of catecholamine - https://cen.acs.org/articles/95/i13/Zinc-controls-cell-pores-regulate.html - "...They found that cultured adrenal cells treated with zinc store less catecholamine than untreated cells. Even though the treated cells store less, they actually release the same amount of catecholamine as the untreated cells because they’re releasing nearly all of what they have taken in. That release also occurs much more slowly than the release from untreated cells..."

5. Vitamin C prevents stress-induced damage on the heart caused by the death of cardiomyocytes, through down-regulation of the excessive production of catecholamine, TNF-α, and ROS production in Gulo(−/−)Vit C-Insufficient mice - https://www.sciencedirect.com/science/article/abs/pii/S0891584913003675

6. Curcumin suppresses gelatinase B mediated norepinephrine induced stress in H9c2 cardiomyocytes - https://pubmed.ncbi.nlm.nih.gov/24116115/

7. Neuromodulatory effect of curcumin on catecholamine systems and inflammatory cytokines in ovariectomized female rats - https://pubmed.ncbi.nlm.nih.gov/33098686/

8. (–)-Epigallocatechin-3-O-gallate (EGCG) attenuates the hemodynamics stimulated by caffeine through decrease of catecholamines release - https://link.springer.com/article/10.1007/s12272-016-0757-1

9. Melatonin regulates catecholamine biosynthesis by modulating bone morphogenetic protein and glucocorticoid actions - https://www.sciencedirect.com/science/article/abs/pii/S0960076016301728

10. Sympathetic Activity Increases With Obesity in Hypertensive Patients - https://www.ahajournals.org/doi/10.1161/hyp.70.suppl_1.114 - "...Increase in BMI is associated with increasing dopamine, catecholamines and metanephrines indicative of progressive SANS activation..."

10. is related to leptin - more adipose → more leptin. More leptin → more inflammatory signaling → more Th1 cell activation and inflammation. Pomegranate can help reduce leptin but adequate zinc might be needed for it to be able to help by activating medically functional bitter taste receptors that may be coregulators of the leptin receptor.

    1. (Rahmouni, 2010) Rahmouni K. Leptin-Induced Sympathetic Nerve Activation: Signaling Mechanisms and Cardiovascular Consequences in Obesity. Curr Hypertens Rev. 2010 May 1;6(2):104-209. doi: 10.2174/157340210791170994. PMID: 21562617; PMCID: PMC3090157. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3090157/ Read on:

Obesity and COVID19, or for maintaining a healthy weight – pomegranate and zinc may help as coregulators of leptin receptors.

Bitter tasting phenolic compounds have been found to have weight loss/anti-obesity benefits including: resveratrol, caffeic acid, naringenin, proanthocyanidins, catechins, and cyanidin. (Sharma, et al., 2016) Proanthocyanidins, and catechins are present in pomegranate and chlorogenic and caffeic acid, both gallic acids. (Mahmoud and Ibrahim, 2013) Caffeic acid (Frank, et al, 2007) and many other pomegranate phytonutrients are bitter tasting. Adequate zinc is needed for transcription of taste and odor receptors (Sekine, et al, 2012) and adipocyte growth. (Wei, et al, 2013) Zinc also is needed for butyrate producing microbiome species to thrive. (Tako, IECN2020) 

Bitter taste receptors (Tas2rs) increase glucose tolerance, improve weight and dyslipidemia, and decrease insulin resistance, in part by stimulating production of the hormone glucagon-like peptide 1 (GLP-1); animal-based study on hops isohumulones. (Kok, et al, date) GLP-1 promotes satiety through interaction with ghrelin and leptin, resulting in inhibition of glucagon and increased insulin secretion. (Ronveaux, et al, 2015) Leptin also stimulates GLP-1 and GLP-1 is low in obesity, leptin resistance is suggested to be a factor. (Anini, et al, 2003) Leptin levels fall during fasting or weight loss, and then regain may occur. Maintaining leptin levels helped weight (animal study). (Ahima, 2008) Elevated leptin levels and leptin resistance are associated with obesity along with too few leptin receptors.

Leptin activates the Sympathetic Autonomic Nervous System and can increase cardiovascular disease risks and it can also be affected by ANS activity. (Rahmouni, 2010)

Leptin is cytokine like and structurally similar to interleukins IL-2 and IL-6. Deficiency has negative impacts on immune function and thymus T-cell growth. Leptin promotes thymus functions and CD+4 -T cells and Th1 cells and inhibits Th2 cells. “[41]” Lack of zinc led to less leptin and supplementation increased leptin levels and TNF-alpha and IL-2, but the reason why zinc and leptin are connected is not known. Zinc’s role in gene transcription was briefly considered. (Baltaci and Mogulkoc, 2012)

1. It likely is connected to the need for zinc to make zinc finger proteins which are involved in gene transcription and adipocyte growth for white and brown adipose tissue. (Wei, et al, 2013)

2. Lack of bitter taste receptors due to zinc deficiency might be a factor as they do use zinc finger proteins for transcription. (Sekine, et al, 2012)

   Bitter taste receptors may also be a involved as co-regulators of leptin receptor functions making zinc finger proteins needed for their transcription. The leptin receptor is co-regulated by a G protein coupled receptor in the pedunculopontine nucleus (PPN) of the reticular activating system (RAS) of the brain which regulates waking and rapid eye movement (REM) sleep. (Beck, et al, 2013)

3. Lack of bitter tasting phytonutrients in processed foods. Processed foods tend to have had the bitter tasting phytonutrients removed to increase consumer acceptance.

4. Lack of zinc negatively effects microbiome health and gut species epigenetically promote leptin expression when it is a normal fat diet. (Yao, et al, 2020) When low zinc is available less beneficial species that don't need zinc thrive instead. (Tako, IECN2020) 

It might be a combination of 2, 3, and 4 - bitter taste receptors as coregulators of the leptin receptor - creating a need for both adequate zinc for gene transcription of bitter taste receptors and adequate bitter phytonutrients in the diet. Pomegranate peel decreased leptin levels, improved bone density, and improved biomarkers for kidney and liver damage and for oxidative stress in overweight rats, (Soliman, et al, 2022), overweight lab rats probably had adequate zinc in their food.

The current nutrient guidelines do not reflect the increased need for zinc by the elderly for maintaining thymus function. About twice as much is needed after age 65 as in younger and middle age. (Kodama, et al, 2020) Extra zinc supplementation has been found to improve age related loss of thymus gland function in animal-based research. (Haase et al 2009) Zinc supplementation may help increase T-cell type of immune reaction and reduce NF-kappaB inflammatory activity. (McCarty et al, 2021)

"Fortuitously, for reasons that remain unclear, zinc supplementation tends to boost stimulated NF-kappaB activity in lymphocytes; this effect tends to aid the activation of T lymphocytes and support cell-mediated immunity [174,175]. This likely explains why zinc supplementation can reduce the incidence of infections in the elderly [171]. Zinc thus manages to accomplish the needed trick of supporting antigen-specific immunity while curbing inflammation." (McCarty et al, 2021)

Elevated leptin is seen in obesity, sepsis, and respiratory infections. Leptin is made by lymphoid tissues, bone marrow, brain, gastric mucosa, intestine, skeletal muscle, mammary gland and the placenta = leptin is a big deal.

Leptin regulates appetite but is in excess in obesity with resistance by the leptin receptors. It also has pro-inflammatory immune roles promoting Th1 cellular immunity and upregulates inflammatory cytokines TNF-α, IL-6, and IL-12, (Iikuni, et al, 2008), which may play a role in the increased mortality risk of COVID19 for obese patients. (Maurya, et al, 2021) Leptin is a pleiotropic adipocytokine, released by white adipose tissue in its endocrine gland capacity. (Tilg, Moschen, 2006) Elevated leptin levels are also seen in sepsis and respiratory infections. Elevated leptin may be involved in COVID19 severity. In addition to being produced by adipose tissue, “…leptin is produced by placenta, gastric mucosa, mammary gland, skeletal muscle, brain, intestine, bone marrow, and lymphoid tissues (Wolsk et al., 2012; Vernooy et al., 2013; Li et al., 2017; Pan et al., 2017; Pérez-Pérez et al., 2018).” (CC by Bruno, et al, 2021) Pomegranate has been found beneficial in all of those tissue types – improved endothelial function in the placenta, (El-Sayyad, et al, 2019), anti-microbial for bovine mastitis of the mammary gland. (Raheema, 2016), Table Pom Health has other studies.

Microbiome cross-talk may help promote leptin in a normal fat diet, but not in a high fat diet.

Microbiome health can be worsened towards an obesogenic profile by high fat diet and there is cross talk between the lungs and gut, a gut-lung axis in addition to the gut-brain axis. (Bruno, et al, 2021) The gut microbes promote leptin expression in a normal fat diet (10% of total calories, mice) by epigenetic methylation of the leptin promoter gene. The protective effect is lost with a high fat diet (60% of total calories) and increased weight leading to obesity seems to promote gut dysbiosis and reduced sensitivity to leptin. Leptin output increases with increasing adipose tissue. (Yao, et al, 2020) Hyperleptinemia itself leads to leptin resistance as opposed to a high fat diet with inhibited leptin levels, (animal study). (Knight, et al, 2010)

What is a high fat diet? and the PPAR/PDK switch is also a big deal.

In humans 20-30% calories from fat are typical, with a goal of 10% or less to be from saturated fats and zero from trans fats. Above 35-50% of the total calories from fats is considered high fat for human meal planning. Saturated fats in particular trigger PPAR inhibition of CoA production for Citric Acid Cycle use by mitochondria – they are switched to fermentation of fats instead – meant to be temporary for survival, becomes mitochondrial dysfunction with many modern diets. A high saturated fat diet is the normal cause for the PPAR beta/delta inhibition of PDK and the Citric Acid Cycle by limiting CoA production . . . which blocks the Citric Acid Cycle from functioning, and the mitochondria switch to using fat for energy. (Tyagi, et al, 2011) (Zhang S, et al, 2014, Fig. 2) This PDK switch is a standard part of metabolism and would be lifesaving when food was scarce - a rapid switch to using whatever type of energy was most available at the time. In modern life saturated fats can be a significant part of the diet. Using fermentation for energy production is more inefficient for energy needs though, and produces more waste and lactate build up from the accumulating pyruvate. Elevated pyruvate levels are seen in ME/CFS. (Anderson and Maes, 2020)

Lack of nutrients and cofactors needed in the Citric Acid Cycle can be involved and a high saturated fat diet may be adding to the shift in mitochondrial energy production to fermentation instead of using the more productive and less waste producing Citric Acid Cycle (pyruvate is a waste product of fermentation).

The curve ball is that Retinoid Toxicity may also be causing a chronic inhibition of PDK by PPAR activation by 9-cis-Retinoic Acid - leading to mitochondrial dysfunction - ongoing use of fermentation instead of the Citric Acid Cycle.

Mitochondrial dysfunction and failure to produce acetyl CoA is seen in ME/CFS. The reason why is not known but could be due to Retinoid Toxicity.  PPAR beta/delta receptors can activate fat burning in mitochondria by fermentation instead of Citric Acid Cycle oxidation and can be activated by 9-cis-Retinoic Acid. High saturated fat diets also cause the switch to fermentation of fat. This is meant to be temporary as the diet balance fluctuates, not a long-term change as seen in chronic conditions of modern life.

Retinol promotes the Citric Acid Cycle (Acin-Perez, et al, 2010) but Retinoic Acid could be blocking it. Retinoic acid excess could be a reason that CoA production is blocked. (Tyagi, et al, 2011) (Zhang S, et al, 2014, Fig. 2) Over-conversion of active Retinoic Acid in the liver leads to a deficiency of the inactive retinol form of vitamin A. (Mawson, Croft, 2020)

The ability to use the Citric Acid Cycle can be turned off by Retinoic acid activated PPAR beta/delta receptors, (Reay and Cairns, 2020), inhibiting PDK which then prevents production of Acetyl CoA, which is needed for the cycle to occur within mitochondria. (Tyagi, et al, 2011)

Nutrients and phytonutrients help inhibit the inflammatory signaling chemicals and promote healing Nrf2.

Plants can help and other nutrients like magnesium sulfate. Having adequate antioxidants from dietary sources or our own internal production of glutathione, promoted by Nrf2, helps reduce the oxidative damage that can result from normal or over-active metabolism and lead to neurodegenerative conditions. (Paladino, et al, 2018) Small molecules found to inhibit NF-kB includes phytonutrients (Gupta, et al, 2010) that also have been found to promote Nrf2 - the two pathways are linked. It makes sense that the same chemical would inhibit one and promote the other.

This might mean a diet balance of less than 35-50% of calories from fat with less than or equal to 10% of calories from saturated fats; and 10-30% from carbohydrates and resistant starches; and 20-55% calories from protein and/or ketones.

I personally lean towards recommending moderate carb, and more fats than protein to reduce nitrogen waste on the kidney’s ~ 45-50% fats, lower saturated fat sources, (nuts, seeds, olive oil, coconut as a vegan source of cholesterol precursors, sesame oil, avocado); 30% carbohydrates; 20-25% protein.

A high fat diet can increase glutamate activity at NMDA receptors and add to Alzheimer’s risk. (Valladolid-Acebes, et al, 2012), High fat or excess saturated or poly-unsaturated or trans-fats and lack of omega 3 fatty acids can increase inflammation and promote NF-kB pathways and may affect mitochondrial function.

Photo op

Point Reyes at sunrise. Photo by Stephen Leonardi on Unsplash

Good morning!

Disclaimer: This information is provided for educational purposes within the guidelines of fair use. While I am a Registered Dietitian this information is not intended to provide individual health guidance. Please see a health professional for individual health care purposes.