Essential Minerals And Metabolic Adaptation Of Immune Cells Part 2

3.2.3. Macrophages

In obese metabolic states, macrophages constitute up to 40% of the stromal vascular cells in the adipose tissue [68]. Adipose tissue macrophages encompass both resident and transitory cells recruited via MCP-1 and are sometimes designated as Me due to differences in surface markers [69]. In the resting state, macrophages use the energy produced from oxidative phosphorylation and abruptly switch to glycolysis when they enter the proinflammatory M1-activated state (CD11b+, F4/80+, and CD11c+) via IFN-γ or LPS signaling. 

Their activation is dependent on the same IKK-β implicated in the pathophysiology of insulin resistance, and results in PPAR-γ mediated secretion of IL-1β, TNF-α, IL-6, IL-12, and IL-23. On the biochemical level, M1 polarization results in the accumulation of succinate and malate [70] due to the Krebs cycle breaks at the level of isocitrate dehydrogenase and succinate dehydrogenase [71]. This allows for citrate shift towards fatty acid and prostaglandin synthesis, accumulation of succinate, and activation of the arginosuccinate shunt towards malate and nitric oxide production.

The alternatively activated M2 macrophages (CD206+ CD301+) participate in the resolution of inflammation via secretion of IL-10, IL-4, IL-13, and TGF-β that is heavily influenced by adipose tissue eosinophils and regulatory T cells. Both IL-4 and IL-10 are two suppressive cytokines that become more abundant in the gut mucosal tissue due to exposure to helminth and microbial products derived from the gut microflora, respectively [72].

There is a close relationship between stromal vascular cells and immunity. Stromal vascular cells play an important role in the vascular intima, including maintaining vascular structure and function, regulating vasoconstriction and dilation, regulating blood flow, and maintaining the endothelial barrier. In addition, stromal vascular cells are also involved in the modulation and regulation of immune responses.

Specifically, stromal vascular cells can regulate the degree of immune response by activating or inhibiting the function of immune cells. For example, stromal vascular cells can affect the activation and proliferation of T cells and B cells by secreting cytokines, antigen presentation, and expression of co-stimulatory molecules, thereby regulating the intensity and direction of immune responses. In addition, stromal vascular cells can also participate in the regulation of inflammatory responses and play a role in injury repair and tissue regeneration.

In conclusion, stromal vascular cells play an indispensable role in the immune response, affect the degree and effect of the immune response by regulating the function of immune cells, and also participate in important processes such as tissue repair and regeneration. Therefore, we must pay close attention to the improvement of our immunity. Cistanche has a significant effect on improving immunity. Meat ash contains a variety of biologically active ingredients, such as polysaccharides, two mushrooms, and Huangli, etc. These ingredients can stimulate the immune system. Various types of cells, increase their immune activity.

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3.2.4. Dendritic Cells

Dendritic cells link innate and adaptive immunity by presenting antigens to T-cell receptors. They induce a pro-inflammatory environment by producing IL-6 and macrophage recruitment signaling. Similar to other innate cells (dendritic cells differentiate from monocytes as do macrophages), activation of dendritic cells is critically dependent on glycolysis [73].

3.2.5. NK Natural Killer Cells CD56+

Activated NK cells maintain bioenergetic profiles that are similar to Th1 cells relying predominantly on glycolysis and glutaminolysis for energy supply. Like other innate immune cells described above, NK responses are rapid and nonspecific. The observed shifts to a higher metabolic level upon innate immune cell activation are required for the secretion of IFN-γ and direct cytotoxicity. The glycolysis is increased by regulating the expression of citric acid and malic acid reverse transporter SLC25A1 and ACLY15 via SREBP signaling [74].

3.2.6. B Cells CD19+

B cells are the lymphocyte component of adaptive immunity that produce immunoglobulins against familiar antigens. Their phenotypical activation in the adipose tissue promotes the chemotaxis of neutrophils, T cells, and monocytes. These cells are somewhat unique because they use glycolysis and glutaminolysis in all resting and maturation states [75]. B cell accumulation generally precedes T cell accumulation in metabolic disorders and promotes the pro-inflammatory activation of T cells [68].

3.2.7. T Cells CD3+ CD8+ (Cytotoxic)

These cells constitute a population of acquired immunity cells, and their abundance is increased in metabolically disadvantageous states. The energy requirements of these cells are maintained upon activation by glycolysis and glutaminolysis [70].

3.2.8. T Cells CD3+ CD4+ (Helper)

T helper cells interact with antigen-presenting cells like dendritic cells, macrophages, and B cells to modulate the inflammatory status of the target tissue. The maturation of these cells occurs in the thymus and leads to the amplification of several different subclasses of T cells that differ in their surface markers and cytokine profiles as summarized below [76].

Th1 cells are differentiated via pro-inflammatory IL-12 and IFN-γ signaling to release pro-inflammatory IFN-γ and TNF-α. Their bioenergetic profile depends on glycolysis and glutaminolysis upon activation.

Th2 cells are differentiated via IL-4 signaling to further secrete IL-4 (critical for the survival of the B-type lymphocytes), IL-5, IL-10, and IL-13. Th2 and the majority of T helper cells described below maintain energy supply via glycolysis and partial preservation of oxidative phosphorylation.

Th9 cells are differentiated via IL-4 and TGF-β signaling to release IL-9.

Th17 cells are differentiated via IL-1β, IL-6, IL-23, and TGF-β signaling to release IL-17 in control of pathogenic infections and autoimmunity, as well as a series of IL-21/26 cytokines. Interestingly, high levels of glucose lead to the excessive differentiation and stimulation of Th17 cells and provoke inflammation in the host [77].

Th22 cells are differentiated via IL-6 and TNF-α signaling to release IL-22.

Treg (CD3+ CD4+ FOXP3+) regulatory cells are differentiated via IL-2 and TGF-β signaling to release IL-10 and TGF-β. The former maintains the immunosuppressive function of Tregs. The bioenergetic profile of T regs is similar to naïve T cells and is primarily supported by fatty acid oxidation and oxidative phosphorylation [76].

4. Influence of Essential Minerals on Immunological Outcomes

Nutrients exert their role in innate immunity and inflammation at two major checkpoints: (i) gut-associated lymphoid tissue in the intestinal tract, and (ii) immune cell crosstalk and signaling in the different host tissues. Inadequate nutritional status caused by malnutrition, unhealthy diet, and disorders associated with loss, or inability, of essential nutrients leads to nutritional deficiencies that can directly affect the immune and inflammatory status of the body. The interactions among nutrients within foods and diets add a level of complexity to the expected immune outcomes. This is especially evident at the level of macronutrients through the existence of nutrient-specific appetite systems for proteins, carbohydrates, and fats [78]. In many animals, the appetite prioritizes proteins for reproductive success and carbohydrates for longevity [79], and the overall food intake increases as nutrient concentrations fall in the food due to compensatory feeding for these macronutrients [80]. As such, total energy intakes are highest on diets with low protein and/or low carbohydrate content [81], and this obvious discrepancy may form the basis for many lifestyle metabolic disorders.

While a similar seeking behavior may exist for at least two macronutrients, sodium, and calcium, the remaining micronutrients are maintained within healthy limits by continuous intake from the available variety of foods. Essential minerals form a subgroup of these micronutrients with high implications for immune health. These include major—calcium (Ca), phosphorus (P), sodium (Na), potassium (K), magnesium (Mg), chloride (Cl), sulfur (S), and trace minerals—iron (Fe), zinc (Zn), copper (Cu), manganese (Mn), selenium (Se), iodine (I), molybdenum (Mo), and possibly trivalent chromium (Cr) and fluorine (F). Minerals play a vital role in maintaining the integrity of various physiological and metabolic processes occurring within living tissues. Their regulatory effects on immune function have been defined to a certain extent, and inadequate levels of minerals have been reported to alter immune competence in humans [82].

A balanced and diverse diet can commonly support all essential minerals for the body [83], whether it is based on natural or fortified foods, yet modern lifestyles, dietary patterns, and agricultural production system has changed this equilibrium towards common inadequacies in some minerals (Table 1). The US data based on the National Health and Nutrition Examination Surveys (NHANES) supported prominent micronutrient inadequacies in the US population, with a particular focus on calcium, potassium, magnesium, and iron [84,85]. In Western diets, severe deficiencies occur only when minerals are not obtained in sufficient amounts or are not absorbed from the diet due to the inaccessible chemical formulation or malabsorption disorders of the gastrointestinal tract, especially in patients on parenteral nutrition, elderly, and children with inborn errors of metabolism who require very specialized diets. This is in contrast to many developing countries where a variety of food choices is limited, the risk of economically driven malnutrition is high, and vegan diets are more widespread [86]. Individuals sustaining a vegetarian diet may require up to 50% more dietary minerals due to the plant phytates consumed. Inadequacies, however, are rather common all over the world, and the critical shortfall minerals with immune effects are described in more detail below.

4.1. Calcium

Calcium is critically important for healthy bones and teeth, muscle contraction and relaxation, nerve functioning, blood clotting, blood pressure regulation, and the health of the immune system. Calcium is tightly regulated and rarely varies from physiologic levels of 8.8–10.4 mg/dL serum (4.7–5.2 mg/dL if ionized) [87]. Calcium binds to bile acids and fatty acids to form insoluble complexes that protect the intestinal cells of the gut and maintain the immunological integrity of the intestine, in part by suppressing cell proliferation by promoting differentiation or apoptosis [88]. Calcium not only facilitates T-cell activation but also modulates the distinctive metabolic changes that arise in different T-cell subsets and developmental stages. The calcium influx is defective and the calcium efflux is increased in autophagy-deficient T cells, which leads to a decreased level of lymphocyte activation [89].

4.2. Potassium

Potassium is a systemic electrolyte that supports nerve transmission, muscle contraction, water balance, and energy production. Historically, potassium was used to treat symptoms of chronic cough as a mucus expectorant and is expected to have similar effects on other mucosal surfaces, including gastric secretion and gastrointestinal tissue synthesis [90]. Normal serum potassium values are in the 3.5–5 mmol/L range. Potassium balances sodium's effects on the innate immune system in part by inhibiting the NLRC4 inflammasome [91]. In the instances of insulin resistance, the body enters the catabolic state that suppresses the T lymphocyte-dependent adaptive immune system and drives inflammation in a continuous attempt to repair the damaged tissues, while unable to complete the immune sequence. The sodium/potassium pump is critical to the ionic integrity of the lymphocyte under the conditions of insulin resistance and depleted potassium stores, thus preventing the lymphocyte to proceed in its cycle [92].

4.3. Magnesium

Magnesium is found in healthy bone tissue, this element also supports muscle contraction, nerve transmission, the health of the immune system, as well as cellular energy production and protein synthesis. Normal serum magnesium levels are between 1.8 and 2.2 mg/dL [93]. Magnesium acts as a cofactor for enzymatic activation in multiple biochemical pathways such as glycolysis and the Krebs cycle. It is a co-factor for immunoglobulin synthesis, C 03 convertase, antibody-dependent cytolysis, immune cell adherence, IgM lymphocyte binding, macrophage response to lymphokines, and T or B cell adherence [94].

4.4. Iron

Iron is a critical part of red blood cell hemoglobin that ensures oxygen transfer and contributes to energy metabolism in all tissues as an electron transfer medium. Iron is also an integrated part of many enzyme systems that regulate cell regulation/proliferation, DNA synthesis, and electron transport in the mitochondria. Iron differs from other body minerals due to the absence of any physiological process of excretion. The normal value range is 60–170 µg/dL [95]. Iron is somewhat unique that it participates in nutritional immunity, an active withdrawal of iron from circulation in response to the infection [96]. 

Iron is pro-inflammatory both in macrophages and neutrophils when present in excess and not properly stored within ferritin, thus strengthening the elimination of pathogens at the expense of higher levels of tissue inflammation [97]. Iron also selectively promotes Th2 over Th1 cells differentiation and activity via INF-γ signaling, as well as contributes to the modulation of Treg due to the imbalance at the transferrin receptor CD71, an iron uptake protein [98]. The opposing effect is observed in B cells where iron promotes proliferation [99]. Downstream of the immune cell signaling, however, iron deficiency led to the downregulation of the antibody responses [100].

4.5. Other Major Minerals (Phosphorus, Sodium, Chloride, Sulfur)

Currently, there are no critical shortcomings in this group of minerals as long as a balanced diet is maintained in the target population. Other than obvious participation in cell signaling and energy metabolism, the interactions between phosphorus and the immune system are inconsistent. Similarly, even though sodium can amplify inflammatory macrophage and T-cell responses, translational evidence for the effects of dietary salt on human immunity is scarce [101]. Chloride, the most abundant anion in humans, is actively accumulated in the intracellular space of the myeloid cells such as neutrophils and macrophages and reacts with hydrogen peroxide via phagolysosome hypochlorous acid to produce the defensive hypochlorous acid [102].

Sulfur is obtained from a diet mostly in the form of sulfur amino acids and contributes to the regulation of immune health via the metabolites such as glutathione, homocysteine, and taurine. Glutathione is the major storage form of sulfur in the body, as neither cysteine nor methionine is stored, and any excess is readily oxidized to sulfate and excreted in the urine, often in the form of phase II metabolites of dietary pharmacophores [103]. Sulfur also contributes to immune health with the production of tissue and colonic (microbiota) hydrogen sulfide that decreases the severity of various immune-mediated diseases [104], but can be detrimental in the pathogenesis of infectious diseases such as tuberculosis [105].

4.6. Other Trace Minerals (Zinc, Copper, Selenium, Manganese)

Trace mineral deficiency is not commonly seen in developed regions unless associated with aging and chronic disorders. Patients with an acquired form of deficiency usually are unable to maintain intake, absorb, metabolize, or excrete the mineral efficiently. Precise assessment of the mineral status, however, is challenging because commonly used measurements in the clinic do not directly reflect mineral status in the target tissues where minerals tend to accumulate [106]. Even though healthy diets tend to cost more, it becomes increasingly evident that many nutritional inadequacies are driven by the consumer preference of low nutrient, high-energy density diets at the same price point [107]. Paired with a dramatic decrease in consumption of organ meats that historically served as a good source of minerals for an omnivore population [108], selected trace mineral inadequacies may still be expected. Nutritional risks for trace mineral inadequacies include lack of meat intake, excess dietary phytates (legumes, seeds, whole grains), or oxalates (sorrel, spinach, okra, nuts, and tea). Impaired gastrointestinal absorption due to chronic gastrointestinal and metabolic diseases usually manifests itself by redistribution of body mineral stores away from the epithelium in the gut and skin, thus allowing for an increase of autoimmune disorders associated with these tissues [109].

Among the trace minerals discussed, zinc stands out in its requirement for several classes of catalytic enzymes such as matrix metalloproteinases, liver alcohol dehydrogenase, carbonic anhydrase, and transcriptional zinc finger proteins. Zinc is critical in reproductive health [110] and the immune system, where it has a significant effect on the normal functioning of macrophages, neutrophils, natural killer cells, and complement activity, yet it cannot be stored in the body and must be replenished continuously [109]. Zinc inadequacy is a risk factor for the epithelial barrier integrity, both in the skin, gut (diarrhea), and lungs (viral infections). The immune effects are mediated in part by incorrect activation and maturation of T and B cells, and an unbalanced ratio skewed in the direction of Th1 and Th17 pro-inflammatory phenotypes [111]. Increased recruitment of zinc into the activated immune cells and away from blood circulation and epithelial tissues may be essential to ensure transcription and translation of the acute phase proteins, but further depletes the available stores [112].

Copper is a cofactor for cytochrome c oxidase, the terminal enzyme in the electron transport chain that is critical for oxidative phosphorylation. This determines copper applicability to the proper functioning of organs and metabolic processes, stimulation of the immune system to fight infections, and repair of injured tissues [113]. Its relevance to the immune system is mediated by iron and protein metabolism, as copper-containing ceruloplasmin is an important antioxidant component of ferroxidase, erythrocyte superoxide dismutase, and diamine oxidase [114]. Copper deficiencies are associated with impaired proliferation of T lymphocytes, decreased IL-2 production, and decreased activity of phagocytes, B-lymphocytes, and natural killer cells [115]. In the presence of inflammation, plasma copper and ceruloplasmin concentrations are increased, resulting in increased protection against pathogens and oxygen radicals.

The relationship between the remaining trace minerals and immune function is less well documented in humans. Selenium is a part of the glutathione peroxidase and iodothyronine deiodinase enzyme systems, and plasma selenium levels correlate with the CD4+ counts and differentiation of CD4+ T-cells into Th1 cells [116]. Manganese is a co-factor of several proteins including superoxide dismutase [117]. Iodine (synthesis of thyroid hormones), molybdenum (mitochondrial bioenergetics), chromium (glucose and lipid metabolism), and fluorine (bone health) may have effects on immune health, but these are not well-defined. Of critical interest, both zinc and copper are classical examples of micronutrients that undergo spatiotemporal alterations in tissues during the onset and resolution of the inflammatory process [118]. Increased recruitment of zinc and copper into the immune cells at the time of infection or immune activation strengthens host defenses against pathogens by direct toxicity, as well as indirect increases in free radical formation and activation of the central enzymes in cellular metabolism [119]. The recently emerging evidence suggests that other trace elements such as selenium, manganese, or molybdenum may participate in similar processes and express similar transient increases in the activated immune cells [120].

5. Changes in the Mineral Content of Foods

Domestication of crops resulted in significant losses in biodiversity (crop package), complex carbohydrates, micronutrients, and dietary fiber in modern diets [20]. Limited ability to absorb, store, and metabolize these nutrients due to environmental or soil impacts, socioeconomic conditions, and health status may further lead to the development of multiple mineral inadequacies in the susceptible populations [121]. While food fortification strategies certainly help with the most commonly identified deficiencies (iron, zinc, iodine), important opportunities for tackling multiple mineral malnutrition are missed by targeting single foods for single nutrients [21].

5.1. Agrociltural Food Production

Nutritional values of plant and animal foods changed during the selective domestication and breeding events all over the world. The energy density of everyday foods in the form of increased calorie retention has increased dramatically both in plants (accumulation of carbohydrates at the expense of protein and mineral content [122]) and animals (accumulation of saturated fat and cholesterol at the expense of unsaturated fat and minerals [123]).

Technological advances that allow for the production of refined sugars and oils also increased the high energy density of processed foods yet contributed negligible amounts of micronutrients to human diets. This transition formed a modern energy-dense diet in which the total food energy is derived from 51.8% carbohydrate, 32.8% fat, and 15.4% protein [124]. Finally, nutritionary dense organ meats (offal) such as liver, heart, kidney, brain, tripe, intestine, and sweetbreads (thymus and pancreas) have fallen out of many modern diets [108]. These tissues usually contain higher amounts of minerals than skeletal muscles, as shown both for beef [125] and lamb [126].

Limited information is available to estimate the contribution of different food groups to mineral intake at the populational level. For a few selected minerals such as phosphorus, potassium, magnesium, zinc, copper, and manganese, the older data from British households suggested that total plant foods and fruits & vegetables contributed to daily diets 37% and 14% phosphorus, 60%, and 45% potassium, 65% and 28% magnesium, 36%, and 11% zinc, 61% and 24% copper, and 93% and 27% manganese, respectively [127]. These numbers, however, are significantly affected by systematic declines in the mineral content of fruits and vegetables as shown for the UK (sodium, calcium, magnesium, copper, and iron between 1940 and 2019), USA (calcium, phosphorus, copper, and iron between 1950–2009), Finland (potassium, manganese, zinc and copper between 1970–2000s), Australia (iron and zinc between 1980–2000s) as summarized recently [21] (Table 2).

5.2. Bioavailability, Fortification, and Dietary Guidelines

A recent significant rise in alternative plant and cellular culture protein-based foods is another unknown in the mineral health status of the populations that consume significant amounts of these products since most minerals present in whole animal and plant foods exist in biological complexes consisting of coenzymes and trace element activators.

This places additional constraints on absorption, fortification, and direct supplementation with micronutrients, especially among rapidly developing infants and children [121]. For these reasons, fortification of foods with micronutrients is often performed for iodine, iron, as well as vitamins A and D, and several B vitamins (thiamine B1, riboflavin B2, and niacin B3). Furthermore, increased access to nutritious foods, including products fortified with micronutrients (especially for iron, calcium, zinc, and folate), supports dietary adequacy for most individuals in developing populations [128]. However beneficial, micronutrient supplementation also comes with an increased health risk or no added health benefits for certain populations, as shown in clinical settings for countries with a high endemic burden of infectious diseases [129,130], or in several recent meta-analyses performed in industrialized countries [131,132].

Minerals in the food matrices are further bound to various organic and inorganic compounds (multiforms) which directly affect their solubility, absorption, and bioavailability. Food processing can have a substantial influence on mineral bioavailability, both in the direction of irreversible loss or reduction, and more rarely in the direction of increased uptake [133]. Localization and activity of ion channels, transport proteins, and epithelial integrity in the target areas of the gastrointestinal tract can also significantly modulate mineral uptake by the host. In instances when mineral chelation to phytates, polyphenols, tannins, lectins, dietary fibers, and proteins prevents their absorption in the upper intestine and enhances the delivery of these minerals to the colonic lumen, the gut microbiome may provide additional benefits through the generation of short-chain fatty acids, reduced luminal pH (acidification), and increased mineral solubility [134]. Their assessment in human tissues other than biological liquids is challenging, as serum and urine mineral levels do not precisely reflect tissue micronutrient content [82] (Table 3).

Obtaining higher levels of minerals from diverse and whole-food diets for a healthy individual without chronic gastrointestinal disorders is rather straightforward. The preferred dietary choices generally overlap with foods proposed to prevent and promote the recovery from depressive disorders [135], including bivalves (oysters, clams, or mussels), organ meats (liver, spleen, kidneys, or heart), and leafy greens (watercress, spinach, mustard, turnip, or Swiss chard). As a part of a healthy dietary pattern, this selection aligns well with the current guidelines on using nutrient-dense foods to meet daily nutrient requirements without consuming excessive calories [136].

6. Conclusions

The crucial function of minerals in application to metabolic and immune health cannot be overlooked. This is especially applicable to chronic metabolic and pro-inflammatory states that take time to develop and resolve. Recent developments in our understanding of absorption and bioavailability specific to each mineral, their abundance in circulation, and target tissues represent a series of major advances in uncovering the nutritional basis of mineral intake and their application to human health. However, our understanding of the metabolically restrictive environments of the inflamed tissues, the critical dependence on aerobic glycolysis to supply immune cells with energy to perform immune functions, and mineral fluxes into the target tissues and back into circulation in support of these changes remain very fragmented.

The connection between the transitory and permanent states of insulin resistance associated with most metabolic and immune disorders is largely not explored, even though knowledge about the connection between type I diabetes and an impaired immune response exists [137]. Redistribution of metabolic fluxes during the prolonged immune activation from pyruvate to lactate (outside of the TCA cycle towards NADH production and biosynthesis), glutamine to pyruvate (to compensate for the former), and citrate (for the added synthesis of fatty acids and lipid species) lead to dysfunctional regulation of developmental metabolic programs of the immune cells. Future studies may discover that these metabolic states define a broader spectrum of cell subpopulations exemplified by M1 and M2 macrophage extremes, and mediated both by the inflammasome (IL-1β) and non-inflammasome (TNF-α) pathways, as well as a balance between pro-inflammatory palmitate (C16:0) and anti-inflammatory palmitoleate (C16:1n7) signaling [138]. It is interesting to note that inhibition of the aspartate-aminotransferase AST enzyme that shunts the fragmented TCA cycle is sufficient to promote mitochondrial respiration, inhibits nitric oxide and IL-6 production, and decrease M1 macrophage polarization [139].

Successful nutritional care of metabolic and immune outcomes with essential minerals is an important goal, as many mineral deficiencies and inadequacies are difficult to diagnose and quantify. Recent studies conducted with several minerals in the context of insulin resistance, systemic inflammation, and vaccination highlighted the need to further investigate these interventions in clinical settings [140] and emphasized the use of more effective multiforms for enhanced mineral delivery to the target tissues [106]. In the future, precise targeting of human mineral status and its contribution to overall health with interventions selected for desired physiological outcomes may be used to personalize nutrition strategies that help to manage chronic health disorders and promote optimal health.

Author Contributions:

M.A. and S.K. conceived the study and outlined the scope of work. M.A. and S.K. performed literature searches and wrote the manuscript. J.G. researched and organized table and figure data. All authors have read and agreed to the published version of the manuscript.

Funding:

This work was supported in part by the USDA National Institute of Food and Agriculture Hatch projects #1023927 (S.K.). M.A. was supported in part by the Kingdom of Saudi Arabia scholarship from the Cultural Mission of the Royal Embassy of Saudi Arabia (grant number 21032019).

Institutional Review Board Statement:

Not applicable.

Informed Consent Statement:

Not applicable.

Data Availability Statement:

Not applicable.

Conflicts of Interest:

The authors declare no conflict of interest.

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