Leptin resistance increased by ultra-processed food diet...experts probably puzzled...it is lack of bitter phytonutrients and/or zinc deficiency.

*Info I learned writing the pomegranate paper. Pomegranate would help leptin resistance. Leptin is also an adipocytokine - inflammatory.

‘Women who eat more ultraprocessed foods more likely to have leptin resistance’, (healio.com). **Leptin Resistance Protocol, pdf, updated, 1/21/2023.

Lack of bitter tasting phytonutrients may be involved in leptin resistance because bitter taste receptors can have a co-regulatory control over leptin receptors. Zinc deficiency could be causal because zinc finger proteins are needed for transcription of bitter taste receptors.

Pomegranate polyphenols help with leptin resistance and are bitter tasting. Gut dysbiosis may also be involved as a healthy microbiome promotes normal leptin response (satiety) and better weight control, or a high fat diet disrupts this effect. Pomegranate also promotes a healthy microbiome and butyrate producing species in the colon.

That is the nutshell version - there are ~50,000 other words - here are a few:

A high fat diet (above 60% total calories) shifted microbiome species away from promoting leptin expression and weight increased, leptin resistance seemed to occur along with gut dysbiosis.

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)

Leptin is an inflammatory cytokine produced by adipose and other tissue types.

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)

Figure 1. Graphical Abstract - The hyperinflammation positive feed-back loop. Inflammatory triggers from modern life, stress, (Baldwin, 2006; Carabotti, et al, 2015; Kempurai, et al, 2017; Martin, et al, 2018; Wang, S., et al, 2022), leptin, (Żelechowska, et al, 2018), EMF, (Kivrak, et al, 2017), diet, (Table 11. Potentially Inflammatory Foods), glyphosate (Barnett, Bandy, Gibson, 2022; Winstone, et al., 2022), and other environmental toxins, (Pardo, et al, 2020), degranulates mast cells and activates TRP channels. (1) Activated mast cells release histamine and cytokines including TNF-alpha which increases inflammatory Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB), a group of inducible transcription factors. (Nizamutdinova, et al, 2016, Schütze, et al, 1995) NF-κB inhibits anti-inflammatory nuclear factor erythroid 2–related factor 2 (Nrf2) pathways; the two are linked via a shared CBP-CREB binding protein (Ambrozova, et al, 2017, Figure 4) and Circadian Cycle proteins. Nrf2 can inhibit CLOCK/BMAL1 protein complex (Wible, et al, 2018) and NF-κB transcription of genes can be upregulated by the Circadian cycle CLOCK protein and blocked by the BMAL1 proteins. (Spengler, et al, 2012);; Niacin (Si, et al, 2014, Wei, et al, 2014) and butyrate (Chen G, 2018) can down-regulate the inflammatory NF-κB signaling pathway, by activation of the GP109 receptor in mitochondria or coincident to TRP channels. (Zhou and Greka, 2016) Niacin treatment reduced leptin levels in a hypercholesterolemia animal model. (Yang, J. et al, 2008)  NF-κB can inhibit mast cell degranulation, a self-controlling feedback mechanism. NF-κB increase inhibits Nrf2 which would have helped reduce inflammation by promoting glutathione production. Ongoing mast cell degranulation promotes more NF-κB and ongoing lack of Nrf2 - a positive feedback loop if inflammation is not inhibited. Pomegranate wine extract containing phytonutrients gallic acid, ellagic acid, and punicalagin, (Li, X., Liu, Pischetsrieder, 2017), and other phytonutrients promote Nrf2 and inhibit NF-κB reducing effects of mast cell degranulation. (Rasheed, et al, 2009);; (1) Mast cell degranulation leads to (2) histamine excess and H1 receptor activation and increased sensitivity to inflammatory triggers. (Thangam, 2018) If the excess continues to (3) histamine hyperexcitability and H1 over-activation it causes (4) NMDAR over-activation and results in damage to the hippocampus and can result in cell death. (Langlais, et al, 1994, cited by Hough, 1999) Excess dietary glutamate would increase this risk and/or a high fat diet. (Valladolid-Acebes, et al, 2012) (5) Retinoic Acid degranulates mast cells. The retinoic X receptor alpha (RXRα) and peroxisome proliferator-activated receptor-γ (PPAR γ) are endogenous inhibitors of Nrf2 actions within the cell nucleus, (Kim, J.Y., et al, 2016), they are activated by retinoids and would increase inflammation if there are excess active retinoids as Nrf2 inhibits NF-κB. Excess activated retinoids may be a result of liver injury (Mawson et al, 2021) and may be a long-term change due to liver enzyme genetic changes following a viral infection or immune challenge. (Jones, et al, 2007, Bonilla, et al, 2022) Gene changes affecting retinoid activation also may occur in Fetal Alcohol Syndrome (FAS) and Attention Deficit Hyperactivity Disorder (ADHD) from alcohol exposure to the sperm from the father of the child. It takes 74 days to grow a sperm. (Luan, et al, 2022) Other toxins may also affect sperm DNA. (Carrell, 2013; Pourmasumi, et al, 2017);; The hyperinflammation and histamine excess also increases risk of misfolded proteins or prions, post-translational modification of protein, (Laedermann, Abriel, Decosterd, 2015), and increased risk for more pain and neurological conditions. (Sharma, H.S., 2004, viewable at: (Histamine H1 Receptor; Waller, Sampson, 2018) Leaky gut membranes and microbiome dysbiosis also can result from stress effects on the Autonomic Nervous System, (Carabotti, et al, 2015, Martin, et al, 2018) and increased risk for autoimmune and allergy risks, inflammatory bowel conditions, and eczema or other skin conditions and neuropathy may be a later risk. (Kumar, Goswami, Goswami, 2013) Microbiome dysbiosis is seen in ME/CFS. (Varesi, et al, 2021) Taste 2 receptors, TAS2Rs, are a type of bitter taste receptor in the gut which stimulate Nrf2 mediated immune responses. (Liszt, et al, 2021) Mitochondrial dysfunction from oxidative stress and lack of Nrf2 to promote glutathione adds to fatigue and risk of mitochondrial genetic conditions. (Guo, et al, 2013, Chen, Y., et al, 2018) Migraines, fibrotic conditions and cancer may also be risks. Emotional dysregulation and mood imbalance, mania, reckless behavior, anger, paranoia, and schizoaffective symptoms may occur with chronic histamine excess or Retinoid Toxicity. (See: Table 1. Symptoms of Histamine Excess and of Retinoid Toxicity.)

What else does leptin do?

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 of leptin and resistance to it by the leptin receptors are associated with obesity along with having 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)

Zinc deficiency leads to less leptin. Supplementing zinc increased leptin levels.

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.

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

An indirect effect may be changes in microbiome species with zinc deficiency. In health, gut species epigenetically promote leptin expression when there is a normal fat diet. (Yao, et al, 2020) Less beneficial species thrive that don't need zinc instead of butyrate producing when zinc deficient diets are used. (Tako, Koren, 2020) Pomegranate promotes balanced growth of butyrate species, (George, et al, 2019), but it does not provide zinc unless in a combined supplement or food.

Lack of bitter taste receptors due to zinc deficiency might be a factor as they need zinc finger proteins for transcription. (Sekine, et al, 2012) Bitter taste receptors may be coregulators of the leptin receptor. 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.

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.

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