Leptin, POMC, Iodine and Pomegranate

Hidden inside of my pomegranate paper was a paper on leptin and bitter taste receptors.

I have wondered if pomegranate is rich in iodine and if that was part of the benefit of pomegranate products. But iodine doesn’t stand out in the research on the chemical composition of pomegranate/peel. In my own study of pomegranate, I learned of bitter taste receptors as a possible regulatory or co-control of leptin receptors - which would then explain how the bitter polyphenols in pomegranate could be helping in iodine like ways - the bitter taste receptors in collaboration with leptin receptors may be affecting leptin’s functions that intersect with iodine and internal light generation. I’m still learning.

• Leptin is part of the discussion in a video shared by Timothy Winey. The video is a talk by Dr. Jack Kruse being interviewed by, or meeting with Andrew Huberman and the guest Rick Rubin was invited by Dr. Kruse, in part as a health success story of Dr. Kruse’s health recommendations, (~4 hours), and there was mention of a second part to be filmed some other time. https://podcastnotes.org/tetragrammaton-rick-rubin/dr-jack-kruse-and-andrew-huberman-ph-d-tetragrammaton-with-rick-rubin/

I will have to have a part two to this post, the leptin story I already had discovered, as I look into what Dr. Kruse is discussing regarding POMC and leptin and our internal light producing capabilities - iodine is involved - and sunshine helps, and melanin is involved. But not our skin’s tan, but internal melanin.

POMC and leptin are involved in appetite and weight, which is what much of my lengthy post is about. Dr. Kruse is discussing a role in energy production through UV light I think. I need a couple more listens yet and some time with a search engine.

• This research dissertation seems to be related to the topic described by Jack Kruse. (Melanopsin-and-Leptin-Dissertation)

Dr Jack Kruse

Dr. Kruse and I both wouldn’t have learned about leptin in college because it was discovered in 1994 he mentioned. It is involved in appetite and research has been focused on weight and obesity more than leptin’s roles in immune function. It has signaling power similar to inflammatory cytokines and it can degranulate allergy mast cells.

What I had learned about leptin while writing my pomegranate paper…. and forgot much of - good thing I can reread it…a few summary points:

1. 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)

2. Leptin and thymus function need zinc, and leptin metabolism seems to need bitter phytonutrients for normal function.

3. Elevated leptin levels may be due to a high fat diet that lacks bitter phytonutrients; negative effects on the microbiome from lack of zinc and bitter phytonutrients may be an additive factor.

4. My impression: Bitter taste receptors may have some co-regulatory function with leptin receptors.

5. Leptin is produced in so many tissue types that it may be an underlying link to the kidney, liver, and brain damage that is often seen with histamine and Retinoid excess as leptin degranulates mast cells.

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 increased leptin expression stops with a high fat diet (60% of total calories) and increased weight followed and seemed to promote gut dysbiosis and reduced sensitivity to leptin, (animal based study). Leptin output increases with increasing adipose tissue. (Yao, et al, 2020)

Pomegranate/peel decreases leptin

Leptin can degranulate mast cells and increase inflammation; zinc may be needed and a moderate to low fat diet.

Elevated leptin levels are seen in sepsis and respiratory infections. Elevated leptin may be involved in COVID19 severity. (Bruno, et al, 2021) 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)

Leptin is a pleiotropic adipocytokine, cytokine-like but released by white adipose tissue in its endocrine gland capacity, (Tilg, Moschen, 2006), and it is produced by lymphoid tissues, bone marrow, brain, gastric mucosa, intestine, skeletal muscle, mammary gland and the placenta. “(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 – including improved endothelial function in the placenta, (El-Sayyad, El-Ghawet, El-Sayed, 2019), anti-microbial for bovine mastitis of the mammary gland, (Raheema, 2016), and Table 3. Pom Health has other studies.

• Leptin caused degranulation of rat mast cells, release of histamine, and increased intracellular calcium. (Żelechowska, et al, 2018) Which suggests that leptin adds to the hyperinflammation positive feedback loop shown in Figure 1. Graphical Abstract. Niacin treatment reduced leptin levels in a hypercholesterolemia animal model by promoting PPAR gamma. (Yang, J. et al, 2008)

• 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 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 regulates appetite and helps maintain weight, but elevated levels and leptin resistance are associated with obesity along with too few leptin receptors. (Iikuni, et al, 2008)

• Leptin activates TRPV1 channels which blocks Leptin-CCK regulation, (Table 1, Kumar, Goswami, Goswami, 2013) which could increase appetite, as leptin and cholecystokinin (CCK) interact to produce satiety in lean mice. (Barrachina, et al, 1997). Antagonists of the CCK receptor led to an increase in plasma leptin and seemed to increase uptake to the cerebrospinal fluid. (Cano, et l, 2003)

• Leptin activates TRPC1, 4-7 channels (Table 1, Kumar, Goswami, Goswami, 2013) which generate an action potential in T-type calcium channels which causes calcium influx and activation of Proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus. (Perissinotti, Martínez-Hernández, Piedras-Rentería, 2021) In normal health POMC neurons are activated during energy abundance leading to satiety signals and weight loss and are inhibited by lack of food energy. Reduced POMC activity is associated with increased appetite and obesity. (Rau, Hentges, 2019) POMC neurons may be regulated by signaling from leptin, insulin, and glucose. (Pinto et al., 2004; Parton et al., 2007; Belgardt et al., 2009; Dodd et al., 2018, as cited by Rau, Hentges, 2019)

  • The T-type calcium channels can be inhibited by 6-phenylnaringenin, from hops, and it reduced visceral and neuropathic pain in mice, but naringenin was not an inhibitor. (Sekiguchi, et al, 2018)

  • Naringenin is a bitter tasting bioflavonoid found in tangerine peel with anti-cancer (El-Kersh, et al, 2021) and weight control benefits. (Ke, et al, 2015) It may promote conversion of white adipose tissue to brown adipose which releases energy as heat. (Rebello, et al, 2019)

  • Inhibiting the POMC neurons, as 6-phenylnaringenin might, would lead to increased appetite and weight gain. (Rau, Hentges, 2019)

  • In the TRPC4 and -5 section we learn that TRPC4 and TRPC5 channels also require PLC for activation. TRPC4 required coincident activation by a G coupled receptor and PLC. (Thakur, et al, 2016) Taste receptors are G-coupled protein receptors. (Sanematsu, et al, 2014)

Flavonoids, like those found in pomegranate/peel are ROS scavengers … and removal of Reactive oxidative stress chemicals might help to inhibit TRPC channels from being activated by the ROS chemicals and prevent calcium from entering a cell.

Pomegranate or other ROS scavengers might not help against mechanical stress - pressure change activation of TRPC channels though.

Mechanical stress and oxidative stress are activators of TRPC channels and activation by mechanical stress persisted even in the presence of PLC and G protein coupled receptor inhibitors. (Hall, Wang, Spurney, 2020)

TRPC channels are activated by oxidative stress (ROS) - hydrogen peroxide is an example.

“A third mechanism of TRPC activation is oxidative stress, which is reported to activate TRPC5 and TRPC6 [38,39,40]. In podocytes, TRPC6 activation by angiotensin II and cell permeable DAG analogs is inhibited by both scavengers of reactive oxygen species (ROS) and by pharmacologic inhibition of NADPH oxidase 2 (NOX2) [41,42]. Similarly, ROS quenchers inhibit TRPC6 activation by ATP [43]. In addition, TRPC6 coimmunoprecipitates with the catalytic subunit of NOX2, and the TRPC6–NOX2 interaction appears to require podocin because knockdown of the scaffolding protein podocin eliminates the TRPC6–NOX2 protein–protein interaction [42]. Taken together, these data suggest that localized production of ROS plays a key role in GPCR-induced TRPC6 activation.” (CC BY Hall, Wang, Spurney, 2020)

TRPC channels and phospholipase C (PLC):

“All TRPC ion channels are calcium permeable, but the channels are poorly selective, with permeability ratios (PCa/PNa) that vary significantly between family members [26]. The calcium influx is stimulated following receptor-induced phospholipase C (PLC) activation in response to both tyrosine kinase receptors (TKRs) and G protein coupled receptors (GPCRs) [27]. PLC catalyzes hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) and generates the second messengers diacylglycerol (DAG) and inositol 1,4,5 trisphosphate (IP3) [28] that differentially affect TRPC activation, as reviewed elsewhere [27].” (CC BY Hall, Wang, Spurney, 2020)

Our endogenous antioxidants such as superoxide dismutase (SOD), peroxidase, glutathione (GSH) and nutrients like vitamin C and E or minerals like selenium can help reduce oxidative chemicals - neutralizing risk of damage to other tissues. Oxidative chemicals are a similar risk to the rust on our iron garden gate.

Photo by Scott Ymker on Unsplash

Glutathione production is promoted by Nrf2 and that anti-inflammatory protein is promoted by pomegranate and other functional foods. Oxidative chemicals, can cause damage by taking electrons from healthy cells, and that can damage them. Over-acidity accumulation would be an added risk.

Adding Nrf2 promoting phytonutrients or foods like pomegranate can help prevent degranulation of mast cells and reduce inflammation that may lead to degranulation because Nrf2 inhibits NF-κB. Produce rich diets can help and other nutrients like magnesium. Magnesium supplementation increased Nrf2 in a HIV-1 animal-based study. (ElZohary, et al, 2019)

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-κB 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.

Flavonoids including luteolin, quercetin and apigenin, help prevent breakdown of NAD+ and help reduce symptoms of histamine excess. (Rajman, Chwalek, Sinclair, 2018) They are also Nrf2 promoting phytonutrients. Olives or olive oil are also Nrf2 promoting and contain phenols, hydroxytyrosol and oleuropein, found to inhibit mast cells. (Persia, et al, 2014)

Histamine excess causes symptoms of seasonal allergies, but can also cause severe mental symptoms including paranoia, mania, and self harm or violent urges. Leptin degranulates mast cells so an excess of leptin seen with obesity, might also be causing symptoms of histamine excess.

Mitochondrial melatonin is also an antioxidant

Healthy Circadian Cycle, good sleep and light/dark habits also promote Nrf2 and mitochondrial health.

NF-κB inhibiting phytonutrients are also Nrf2 promoting phytonutrients as the two pathways share a circadian cycle Clock protein. Restoring a healthy circadian cycle with sleep/wake, dark/full spectrum light strategies is also a need as Nrf2 activity reduces inflammation and pain and is involved in DNA damage repair. Reducing inflammation is needed to reduce breakdown of endocannabinoids as that leads to activation of TRP channels, increased calcium entry into cells, edematous changes, and increased expression of TRP channels on cell surfaces may result – which would lead to increased sensitivity to TRP activators into the future.

Our mitochondria also have periodic activity and may need us to have a daily blackout/full spectrum light cycle in order for their optimal health and melatonin production.

Mitochondria have been found to produce melatonin in quantity and to actively maintain a high concentration. Their oscillatory cycles are periodic like the circadian cycle. Melatonin within mitochondria acts as an antioxidant against ROS, promotes mitochondrial fission instead of fusion, inhibits the mitochondrial permeability transition pore (MPTP), and can activate Uncoupling Proteins. These functions help preserve the mitochondrial membrane potential at optimal levels. (Tan, Manchester, Qin, Reiter, 2016)

“In addition, melatonin acts on the mitochondrial specific proteins such as uncoupling proteins (UCPs) to dissipate the proton gradient across the inner membrane of the mitochondria to moderately reduce the inner membrane potential [57,58,59,60]. The relative lowering of the inner membrane potential significantly increases the activities of complex I and III, and accelerates electron transport through the ETC. These changes decrease electron leak from the ETC and reduce free radical formation. This is referred to as the free radical avoidance reaction of melatonin [61].” (CC-BY the authors: Tan, Manchester, Qin, Reiter, 2016)

What is a high fat diet? 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.

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 a undiagnosed cause of chronic inhibition of PDK by PPAR activation by the activate form of vitamin A that is called 9-cis-Retinoic Acid - leading to mitochondrial dysfunction with an ongoing use of fermentation instead of the Citric Acid Cycle.

Diet with moderate to low saturated fats. Added complexity, 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)

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Zinc is needed to promote Leptin which has roles in immunity & growth of T-cells in the thymus gland

Leptin is structurally similar to interleukins IL-2 and IL-6. Deficiency has negative impacts on immune function and thymus T-cell growth. It promoted thymus function, CD+4 and Th1 cells and inhibited Th2 cells. » Lack of zinc led to less leptin and supplementation increased leptin levels and TNF-alpha and IL-2 in a review of research, but the reason why zinc seems to have a regulatory role over leptin is not known. Zinc’s role in gene transcription was briefly considered in the review by Baltaci and Mogulkoc, 2012.

Zinc may be needed for Gene expression of leptin:

The link between zinc deficiency and leptin levels may be connected to a need for zinc finger proteins for the expression of leptin or leptin receptors, as they are involved in gene transcription and adipocyte growth for white and brown adipose tissue. (Wei, et al, 2013)

Zinc may promote gut species that promote production of leptin:

An indirect effect may be changes in microbiome species with zinc deficiency. Lack of zinc negatively effects microbiome health and beneficial gut species epigenetically promote leptin expression when there is a normal fat diet. (Yao, et al, 2020) When low zinc is available less beneficial species that don't need zinc thrive instead of beneficial butyrate producing species. (Tako, Koren, 2020) 

Pomegranate and other bitter phytonutrient foods might help by promoting beneficial microbiome species:

Pomegranate promotes balanced growth of species that produce butyrate and other short chain fatty acids (SCFA), improving the ratio of Bacteroidetes to Firmicutes. Rosaburia and Blauta were increased and also are SCFA producing species. (George, et al, 2019) Pomegranate does not provide zinc however, unless in a combined supplement or food that was considering the advantages of prebiotic nutrients that work together synergistically.

Bitter taste receptors do need Zinc finger protein for gene expression:

Lack of bitter taste receptors due to zinc deficiency might be a factor in the benefits of zinc and pomegranate on leptin levels as bitter taste receptors need zinc finger proteins for transcription, (Sekine, et al, 2012), and pomegranate could be helping leptin by way of the bitter taste receptor function in a possible co-regulatory function.

Bitter taste receptors may be coregulators of the leptin receptor:

Example: 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. Leptin also promoted NMDA receptor-mediated responses in the PPN and single neurons, (Beck, et al, 2013), which may add to Alzheimer’s risk with chronic leptin elevation.

Processed foods have little bitter tasting phytonutrients:

Lack of bitter tasting phytonutrients in processed foods may be a factor if bitter taste receptors have regulatory control. Processed foods tend to have had the bitter tasting phytonutrients removed to increase consumer acceptance.

Bitter tasting polyphenols and phospholipids (precursors for endocannabinoids) are found in the pomegranate peel, arils or seeds.

Leptin and thymus function need zinc, and leptin metabolism seems to need bitter phytonutrients for normal function.

It might be a combination - bitter taste receptors as coregulators of the leptin receptor would create a need for both adequate zinc for gene transcription of bitter taste receptors and adequate bitter phytonutrients in the diet

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Zinc

• Zinc is needed for gene transcription of taste and odor receptors.

• The recommended intake guidelines may be significantly low for elderly people.

• Zinc is needed by butyrate producing and other beneficial microbiome species.

Zinc deficiency effects gene transcription of taste receptors and other genes. Zinc deficiency would cause a lack of bitter taste receptors as Zinc finger proteins are needed for gene transcription of odor and taste receptors, (Sekine, et al, 2012), and many other proteins including genes transcribed by other nuclear transcription factors. (Mackeh, et al, 2018) Zinc deficiency can impact gene transcription by retinoid X receptors (RXR) and 27 other types of gene transcription factors, so deficiency of zinc can negatively impact stem cell differentiation in neonatal or adult neurogenesis. (Morris and Levenson, 2013) The elderly and chronically ill may have zinc deficiency as an underlying causal factor, as bitter taste receptors on immune cells and within the kidney and elsewhere in the body affect health. Supplementation at higher than standard recommendation may be needed for at least three months to see improvement in taste and odor sensation, (Kodama, et al, 2020), and other chronic symptoms may improve also due to the functional nature of bitter taste receptors.

Beneficial species of the microbiome need adequate zinc, up to 30% of our daily intake may be used by beneficial species. Unhealthy species can survive without.

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Leptin and weight

• Healthy weight and microbiome need good zinc levels and bitter tasting phytonutrients.

• Bitter taste receptors in the gut promote satiety and better blood sugar regulation and improve weight and dyslipidemia.

• Processed foods tend to lack bitter phytonutrients.

• Leptin helps regulate weight and satiety in normal function but is elevated in obesity and the receptors are unresponsive.

• Coregulation by bitter taste receptors or modulation by bitter phytonutrients may be involved. « My theory.

Maintaining a healthy weight – pomegranate and zinc can help. Bitter tasting phenolic compounds have been found to have weight loss/anti-obesity benefits including: resveratrol, caffeic acid, naringenin, proanthocyanidins, catechins, and cyanidin. (Sharma, S.P., et al., 2016) Proanthocyanidins, and catechins are present in pomegranate and chlorogenic and caffeic acid, both gallic acids.(Mahmoud, Ibrahim, 2013) Caffeic acid (Frank, et al, 2007)  and many other pomegranate phytonutrients are bitter tasting. Bitter taste receptors in the gut promote satiety and stable blood sugar. Pomegranate juice was more effective compared to an extract for improving glycemic response with a high-glycemic index food. (Kerimi, et al, 2017) There is synergy in the whole fruit products.

Taste 2 receptors, TAS2Rs, are a type of bitter taste receptor in the gut which stimulate Nrf2 mediated immune responses. (Liszt, et al, 2021) 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)

Bitter taste receptors seem to be co-regulatory with weight and appetite. Processed foods tend to have had the bitter tasting phytonutrients removed to increase consumer acceptance.

Leptin regulates appetite and helps maintain weight, but elevated levels and leptin resistance are associated with obesity along with too few leptin receptors. (Iikuni, et al, 2008) 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 the decrease signals to eat, and then regain may occur. Maintaining leptin levels helped weight (animal study). (Ahima, 2008)

»Hyperleptinemia itself leads to leptin resistance as opposed to a high fat diet with inhibited leptin levels, (animal study). (Knight, et al, 2010)

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)

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, Koren, 2020)

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)

Reduce weight and inflammation to reduce leptin. It can activate TRPV1 and TRPC1, 4-7 channels.

Leptin activates TRPV1 channels which blocks Leptin-CCK regulation, (Table 1, (Kumar, Goswami, Goswami, 2013) which could increase appetite, as leptin and cholecystokinin (CCK) interact to produce satiety in lean mice. (Barrachina, et al, 1997). Antagonists of the CCK receptor led to an increase in plasma leptin and seemed to increase uptake to the cerebrospinal fluid. (Cano, et l, 2003)

Leptin activates TRPC1, 4-7 channels (Table 1, (Kumar, Goswami, Goswami, 2013) which generate an action potential in T-type calcium channels which causes calcium influx and activation of Proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus. (Perissinotti, Martínez-Hernández, Piedras-Rentería, 2021)

In normal health POMC neurons are activated during energy abundance leading to satiety signals and weight loss and are inhibited by lack of food energy. Reduced POMC activity is associated with increased appetite and obesity. (Rau, Hengtes, 2019) POMC neurons may be regulated by signaling from leptin, insulin, and glucose. (Pinto et al., 2004; Parton et al., 2007; Belgardt et al., 2009; Dodd et al., 2018, as cited by (Rau, Hengtes, 2019)

The T-type calcium channels can be inhibited by 6-phenylnaringenin, from hops, and it reduced visceral and neuropathic pain in mice, but naringenin was not an inhibitor. (Sekiguchi, et al, 2018)

Bitter citrus bioflavonoids like naringenin found in tangerine peel have anti-cancer (El-Kersh, et al, 2021) and weight control benefits. (Ke, et al, 2015) It may promote conversion of white adipose tissue to brown adipose which releases energy as heat instead of storing it as more fat. (Rebello, et al, 2019) Inhibiting the POMC neurons, as 6-phenylnaringenin might, would lead to increased appetite and weight gain. (Rau, Henges, 2019)

Leptin summary points.

• A high fat diet and lack of bitter phytonutrients may be involved in elevated leptin levels;

• Negative effects on the microbiome from lack of zinc and bitter phytonutrients may be an additive factor.

• Mast cell degranulation by elevated levels of leptin, and leptin is produced in so many tissue types that it may be an underlying factor to the risk for kidney, liver, and brain damage that is seen with both histamine excess and Retinoid excess.

A high fat diet can cause inflammatory problems by disrupting microbiome support of leptin production and high saturated fats can cause mitochondria to switch to fermentation instead of using the Citric Acid Cycle. Leptin resistance in obesity involves the elevated leptin levels but may also involve a lack of zinc and bitter tasting phytonutrients in the diet. Elevated leptin can increase appetite by activating TRPV1 channels that block CCK co-regulation with leptin of satiety - that satisfied feeling after eating a normal meal.

Inflammation would increase leptin production in non-adipose tissues which impact many areas of the body: lymphoid tissues, bone marrow, brain, gastric mucosa, intestine, skeletal muscle, mammary gland and the placenta. “(Wolsk et al., 2012; Vernooy et al., 2013; Li et al., 2017; Pan et al., 2017; Pérez-Pérez et al., 2018).” (CC-BY the authors Bruno, et al, 2021)

Over exertion may increase myokines and the leptin; bowel troubles may include excess leptin output; bone marrow affects blood cell production and lymphoid tissue also affects cardiovascular health; the brain affects everything; and leptin is elevated in early breast milk suggesting an essential role for it in early life. (Ilcol, Hizli, Ozkan, 2006) It would provide immune support to an infant with an underdeveloped system. Leptin excess may be key to the kidney, liver and brain risks seen with histamine and Retinoid Toxicity as leptin degranulates mast cells.

Lactation factoid: More leptin is in the early colostrum and declining levels as the baby is older. Weight of the woman and other hormone levels affect the leptin concentration - insulin and thyroxin for mature milk and insulin and cortisol for the first milk, colostrum. Breast fed infant’s leptin levels are correlated with their mother’s leptin level. (Ilcol, Hizli, Ozkan, 2006)

Disclaimer: Like much of my work, this is incomplete to my level of curiosity and perfectionism, but it is interesting and is being provided for educational purposes within the guidelines of Fair Use. It is not intended to provide individual health care guidance, however, pomegranate is pretty awesome.

References - see: ‘Pomegranate Products for the Pain of Histamine Excess.’ copyright Jennifer Depew, RD (Pom pdf in my sync file)