Major clinical outcomes of the regulation of metainflammation in patients with obesity in the light of nutrology: a systematic review

Introduction: Obesity stands out as a multifactorial disease that can cause several public health problems. There are 2.0 billion overweight and obese people in the world, and Brazil is in fifth place in the world ranking. A healthy nutritional status promotes immune function and can prevent the onset of a serious inflammatory process and severe infections, especially in times of pandemics such as COVID-19. Objective: It was to highlight the main clinical outcomes of the regulation of meta-inflammation in patients with obesity in the light of nutrology. Methods: The systematic review rules of the PRISMA Platform were followed. The research was carried out from August to September 2023 in Scopus, PubMed, Science Direct, Scielo, and Google Scholar databases. The quality of the studies was based on the GRADE instrument and the risk of bias was analyzed according to the Cochrane instrument. Results and Conclusion: A total of 130 articles were found. A total of 42 articles were fully evaluated and 29 were included and developed in the present systematic review study. Considering the Cochrane tool for risk of bias, the overall assessment resulted in 29 studies at high risk of bias and 21 studies that did not meet the GRADE. Most studies showed homogeneity in their results, with X 2 =71.7%>50%. Research has shown that unbalanced eating patterns, such as the Western diet, rich in simple sugars, refined carbohydrates, and saturated and trans fatty acids, lead to chronic inflammatory responses, increased adipose deposition, and future comorbidities associated with overweight and obesity. Calorie restriction decreased CRP in obese patients and diet administration over 12 weeks had a beneficial effect. Furthermore, obese patients with antioxidant supplementation had lower values of BMI, waist circumference, fasting blood glucose level, and assessment of the homeostasis model of insulin resistance when compared to the placebo group, as well as having lower levels of total cholesterol, triglycerides, LDL, malondialdehyde and tumor necrosis factor-alpha. n-3 PUFA supplementation can significantly reduce serum C-reactive protein (CRP), tumor necrosis factor α (TNF α ), and interleukin 6 (IL-6) concentrations.


Major clinical outcomes of the regulation of metainflammation in patients with obesity in the light of nutrology: a systematic review
Renan Francisco Merloto1* , Bruna Rocha Soares 1

Introduction
Obesity stands out as a multifactorial disease that can cause several public health problems.Currently, more than 30% of the world's population is overweight or obese [1,2].By 2025, it is estimated that more than 60% of the world's population will be overweight or obese [3,4].In the current scenario, there are 2.0 billion overweight and obese people in the world, and Brazil is in fifth place in the world ranking, with an estimated 18.0 million people [5].In the United States, the prevalence of obesity is greater than 30.0%for both sexes, and obesity is the cause of death for 2.8 million people per year, affecting 26% of adults [4].In Europe, it is estimated that 10 to 20% of men and 15 to 25% of women are obese [2].
In this context, about the cause of obesity, there is a complex relationship between biological, psychosocial, and behavioral factors, including genetic composition, socioeconomic status, and cultural influences [6].Furthermore, obesity has been associated with microorganisms, epigenetics, increased maternal age, DOI: 10.54448/ijn24107 REVIEW ARTICLE greater fecundity, lack of sleep, endocrine disruptors, pharmaceutical iatrogenesis, and intrauterine and intergenerational effects [6][7][8].Comorbid conditions and their treatments may also be a factor in the development of obesity.
In this aspect, it has been postulated that a healthy nutritional status promotes immune function and can prevent the onset of a serious inflammatory process and severe infections, especially in times of pandemics such as COVID-19 [9-12].Thus, the optimal immune response depends on an adequate diet and nutrition to keep the infection under control.As an example, getting enough protein is crucial for optimal antibody production.Furthermore, low levels of micronutrients, such as vitamin A or zinc, are associated with an increased risk of infection, as this deficiency promotes inflammatory processes and oxidative stress.Furthermore, dietary constituents with antiinflammatory and antioxidant actions are highlighted by vitamin C, vitamin E, carotenoids, and polyphenols [13].
Therefore, several of these dietary elements can interact with transcription factors, such as NF-kB and Nrf-2.An important example is vitamin D, which protects tissue against viral cellular infection through angiotensin-converting enzyme 2 (ACE2).Dietary fiber and short-chain fatty acids have also shown antiinflammatory effects [13].
Therefore, the present systematic review study highlighted the main clinical outcomes of the regulation of meta-inflammation in patients with obesity in the light of nutrition.

Study Design
The present study followed the international systematic review model, following the rules of PRISMA (preferred reporting items for systematic reviews and meta-analysis).Available at: http://www.prismastatement.org/?AspxAutoDetectCookieSupport=1.

Data sources and research strategy
The search strategies for this systematic review were based on the keywords (MeSH Terms): "Obesity.Inflammatory processes.Meta-inflammation.Diet therapy.Nutritional regulation".The search was carried out from August to September 2023 in the Scopus, PubMed, Science Direct, Scielo, and Google Scholar databases.Furthermore, a combination of keywords with the Boolean operators "OR", "AND" and "NOT" was used to target scientific articles of interest.

Study Quality and Risk of Bias
The quality of the studies was based on the GRADE instrument.The methodological quality of AMSTAR-2 and the risk of bias were analyzed according to the Cochrane instrument.

Summary of Findings
A total of 130 articles were found.Initially, duplications of articles were excluded.After this process, the abstracts were evaluated and a new exclusion was carried out, removing articles that did not cover the topic of this article, resulting in 71 articles.A total of 42 articles were evaluated in full and 29 were included and developed in the present systematic review study (Figure 1).Considering the Cochrane tool for risk of bias, the global assessment resulted in 29 studies with a high risk of bias and 21 studies that did not meet GRADE and AMSTAR-2.Most studies showed homogeneity in their results, with X 2 =71.7%>50%.

Main Outcomes
In the setting of obesity, the circulating level of cytokines and acute phase proteins associated with inflammation is elevated.Adipocytes secrete several cytokines and acute-phase proteins that increase the production and circulation of factors related to inflammation.The inflammatory process may be due to resistance to insulin action and other disorders associated with obesity, such as hyperlipidemia and metabolic syndrome [14,15].
There are three possibilities, the first reflects production and release from organs other than adipose, mainly the liver and immune cells.The second explanation is that white adipose tissue secretes factors that stimulate the production of inflammatory markers by the liver and other organs.The third possibility is that adipocytes themselves are a ready source of some, or several, of these inflammatory markers [16-18].
In this context, it can be highlighted that the adipokines related to inflammatory processes are interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), leptin, and adiponectin [17].Some studies have shown low concentrations of the anti-inflammatory adipokine (adiponectin) associated with the occurrence of various types of cancer and high concentrations with the inhibition of tumor growth.There are also others such as TNF-α, IL-6, IL-1, CC-chemokine ligand 2 (CCL2), a visceral adipose-tissue-derived serine protease inhibitor (vaspin), and retinol-binding protein 4 (RBP4) [17].
In this aspect, adipokines have a great impact on various bodily functions.In this case, the control of food intake and energy balance, immune system, insulin sensitivity, angiogenesis, blood pressure, lipid metabolism, and body homeostasis stand out, as situations strongly correlated with cardiovascular disease [15].Furthermore, high plasma concentrations of adiponectin are associated with a reduced risk of myocardial infarction in men [15].
In this context, obesity induces a change in the macrophage profile, with an increase in the M1 (proinflammatory) phenotype.This effect corresponds to an upregulation in inflammatory genes, and a downregulation in anti-inflammatory genes [19,20].Furthermore, the primary increase in the inflammatory response in obese patients works as a predictor for the hyperinflammatory state observed in COVID-19.Therefore, this primary increase can be amplified by SARS-CoV-2 infection, increasing the production of cytokines such as TNF-α, IL-1, and IL-6 As a corollary of this, meta-inflammation describes the combination of inflammation and metabolic changes that occur in the body of obese patients [5].Several toxic mediators that contribute to the inflammatory state and tissue damage are present in obesity, such as free fatty acids (FFA), toxic lipid derivatives, such as diacylglycerol, toxic nitric oxide metabolites, and inflammatory mediators, such as protein C reactive, cytokines, chemokines, macrophages, and TNF-α.
The imbalance in inflammatory mediators induced by excess nutrients is the basis of meta-inflammation in obesity.Obesity can cause multiple organ dysfunction and metainflammation leads to myocardial dysfunction through direct damage to inflammatory mediators, as well as through dysfunction in other organs [7].
In this scenario, obese patients stand out among the young population that progresses to the severe form of COVID-19.The unfavorable evolution is possible because these patients have a more inflamed and hyperreactive endothelium, which, under the stimulus of SARS-CoV-2, presents an excessive response, responsible for the hyperinflammation with cytokine storm.As a corollary to the exacerbated inflammatory process, the coagulation cascade is deregulated, causing hypercoagulability.
Therefore, the endothelial dysfunction caused by SARS-CoV-2 explains why patients with comorbidities related to blood vessels such as cardiovascular disease, hypertension, diabetes, and obesity are more likely to develop severe COVID-19, even death Still, other authors observed the relationship between obesity and the development of severe respiratory manifestations when analyzing 103 patients hospitalized with COVID-19.They reported that 47% of these patients were obese.In this study, patients who had a BMI above 30 kg/m 2 were among those most in need of ICU admission and mechanical ventilation [23].

Nutrological Regulation of Meta-Inflammation
Nutritional status can have a significant impact on an individual's overall health, reducing comorbidities and reducing susceptibility to developing infections such as COVID-19.However, according to the WHO, there is still no single food or natural medicine with proven scientific evidence that prevents COVID-19 infections [24].Despite this, based on previous studies, it is known that nutritional status plays a significant role in patient outcomes [25].Therefore, it is necessary to follow a diet characterized by anti-inflammatory properties to benefit from or prevent COVID-19 [26][27][28][29].
In this sense, evidence suggests that dietary patterns and individual nutrients can influence systemic markers of immune functions.Therefore, maintaining nutritional status at this time is significant, given that the fight against COVID-19 can last a long time.Furthermore, to maintain a healthy immune system, special attention must be paid to maintaining a healthy diet, lifestyle, and exercise regimen [30].
Still in this scenario, there are nutritional deficiencies of calcium, vitamin C, vitamin D, folate, and zinc among elderly populations [31], making them immunocompromised [32].Thus, a healthy and balanced diet can provide the necessary macro-and micronutrients, prebiotics, probiotics, and synbiotics in elderly people that can restore and maintain immune cell function [33].
In this context, a review study analyzed the usefulness of early micronutrient intervention, focusing on zinc, selenium, and vitamin D, to alleviate the rise of COVID-19.The results revealed that there is direct evidence of the associations between zinc, selenium, and vitamin D and COVID-19.Adequate supplies of zinc, selenium, and vitamin D are essential for resistance to other viral infections, immune function, and reduced inflammation [34].
In this scenario of nutritional triggers to promote immune strengthening responses, as well as improving the performance of mitoses, meiosis, and all cellular functioning, all of this functioning is directly integrated with the energy balance and nutritional status of the organism.Metabolic byproducts and substrates that regulate epigenetic and signaling pathways are considered to have instructive, rather than bystander, roles in regulating cell fate decisions.Metabolism encompasses the interactions between diet, the microbiome, and cellular enzymatic processes that generate the chemical pathways necessary to sustain life.Furthermore, endogenous metabolites and dietary nutrients can directly influence epigenetic enzymes.Epigenetic modifications to DNA and histone proteins alter cell fate by controlling chromatin accessibility and downstream gene expression patterns.Thus, most substrates and cofactors for chromatin-modifying enzymes are derived from metabolic pathways such as the tricarboxylic acid cycle, methionine cycle, folate cycle, glycolysis, β-oxidation and the hexosamine pathway [35].
In addition to the connection between metabolism and epigenetic pathways, nutrients can impact cellular state by modulating signaling pathway activity.A clear example is through the mechanistic target of rapamycin (mTOR) signaling pathway and in particular the mTOR complex 1 (mTORC1), which regulates cell growth only when nutrients and growth factors are present.Depletion of specific nutrients including arginine, leucine, and S-adenosyl methionine prevents growth factor-induced mTORC1 activation by blocking Rag GTPase-mediated mTORC1 recruitment to the lysosome where it can be activated by Rheb GTPase [36].
Another way that nutrients are sensed to impact cellular state is through AMP-activated protein kinase (AMPK), which at low levels of cellular ATP phosphorylates substrates to restore the cell's energy balance and in the process regulates cell growth.and autophagy.Furthermore, transcription factors can be directly regulated by metabolites.Tryptophan kynurenine is an endogenous agonist for the aryl hydrocarbon receptor and alpha-ketoglutarate (α-KG) that binds and activates IKKβ and initiates NF-κβ signaling [35].
Thus, nutritional health acts directly on the human intestinal microbiota, impacting metabolism and the immune system for tissue regeneration.Recent discoveries on the role of the "nutritional microbiota" in mechanisms involved in tissue regeneration, in particular skin, liver, bone, and nervous system regeneration [36].
In this aspect, in the inflammatory phase, vitamin A increases the release of cytokines, bromelain, and amino acids to prevent prolonged inflammatory events, and vitamin C increases neutrophil migration and lymphocyte activation.In the proliferative phase, vitamin C is necessary for collagen synthesis, glucosamine increases the production of hyaluronic acid.Vitamin A promotes the differentiation of epithelial cells.
Zinc is necessary for DNA and protein synthesis and cell division.In the remodeling phase, amino acids and proteins play a key role in stabilizing the wound scar [37].
Finally, age-related reduction in muscle repair efficiency contributes to the development of sarcopenia.Nutrients such as amino acids, polyunsaturated fatty acids, polyphenols, and vitamin D can improve skeletal muscle regeneration by targeting key functions of immune cells, muscle cells, or both [38].
In this sense, epigenetic signaling pathways and transcription are affected by changing nutrient levels.Furthermore, the focus of the literature on stem cell metabolism is centered on central carbon metabolism and the balance between glycolysis and oxidative phosphorylation in the regulation of cell fate [28].
As literary support, a double-blind randomized placebo-controlled clinical study evaluated the effects of propolis supplementation for 8 weeks (510 mg per day) on glucose homeostasis, lipid profile, liver function, anthropometric and meta-inflammation in patients with non-alcoholic fatty liver disease (NAFLD).In this trial, 44 patients with NAFLD confirmed by ultrasound findings were randomly allocated to the "propolis" (n=23) or "placebo" (n=21) group along with a calorie-restricted diet group (-500 kcal d -1 ) for 8 weeks.Fasting serum levels of metabolic factors, liver enzymes, and inflammatory factors, as well as anthropometric indices, food intake, and appetite status, were assessed pre-and postintervention.The liver fibrosis score, homeostasis model assessment of insulin resistance (HOMA-IR), and quantitative insulin sensitivity verification index (QUICKI) were also calculated.Weight, body mass index (BMI), waist and hip circumferences, and waist-to-height ratio decreased significantly in both groups (p<0.001), while waist-tohip ratio (p= 0.006) and serum cholesterol level total (p=0.038)decreased only in the propolis arm.Fasting blood glucose (p = 0.037), serum insulin level (p = 0.040), HOMA-IR (p = 007), desire for sweets (p = 0.005), and NAFLD fibrosis score (p = 0.013 ) decreased significantly in the propolis group compared to the placebo group, post-intervention after adjusting for baseline values and potential confounding factors.However, QUICKI showed a significant increase (p = 0.015) in the propolis arm compared to the placebo in the study endpoint.Although there were significant reductions in serum levels of inflammatory factors, including tumor necrosis factor-α (TNF-α), toll-like receptor-4 (TLR-4), and monocyte chemoattractant protein-1 (MCP-1), as well such as liver enzymes and fatty liver severity, differences between groups were not statistically significant after adjusting for potential confounders [39].
Furthermore, chronic inflammation in obese patients can be controlled through a calorie-restricted diet, characterized by a reduction in C-reactive protein (CRP).A review study based on randomized clinical trials evaluated the role of this diet in CRP.The results showed that calorie restriction decreased CRP in obese patients and diet administration over 12 weeks had a beneficial effect [40].
Added to this, a meta-analysis study showed heterogeneity in the beneficial effects of antioxidant supplementation in obese adults, exploring the differential effects of antioxidant supplementation on basic indicators of obesity, lipid metabolism, systemic antioxidant capacity, inflammatory biomarkers, and liver function.A total of 30 studies were included in this study with a sample of 845 obese patients from the antioxidant supplementation group and 766 obese patients from the placebo control group.The meta-analysis showed that obese patients with antioxidant supplementation had lower values of BMI, waist circumference, fasting blood glucose level, and assessment of the homeostasis model of insulin resistance when compared to the placebo group.Furthermore, obese patients on antioxidant supplementation had lower levels of total cholesterol, triglycerides, LDL, malondialdehyde, and tumor necrosis factoralpha when compared to the placebo group.Furthermore, obese patients with antioxidant supplementation had higher levels of HDL and superoxide dismutase when compared to the placebo group.Antioxidant supplementation had no effects on other parameters analyzed, including waist-to-hip ratio, leptin, fat mass, interleukin-6, C-reactive protein, alanine transaminase, and aspartate transaminase in obese patients [41].

Conclusion
It was concluded that unbalanced eating patterns, such as the Western diet, rich in simple sugars, refined carbohydrates, and saturated and trans fatty acids, lead to chronic inflammatory responses, increased adipose deposition, and future comorbidities associated with overweight and obesity.Calorie restriction decreased CRP in obese patients and diet administration over 12 weeks had a beneficial effect.Furthermore, obese patients with antioxidant supplementation had lower values of BMI, waist circumference, fasting blood glucose level, and assessment of the homeostasis model of insulin resistance when compared to the placebo group, as well as having lower levels of total cholesterol, triglycerides, LDL, malondialdehyde and tumor necrosis factor-alpha.

Figure 1 .
Figure 1.Flowchart of the article selection process.

Figure 2
Figure 2 presents the results of the risk of bias of the studies using the Funnel Plot, showing the calculation of the Effect Size (Magnitude of the difference) using the Cohen Test (d).The sample size was determined indirectly by the inverse of the standard error (1/Standard Error).This graph showed symmetrical behavior, suggesting no significant risk of bias, both among studies with small sample sizes (lower precision) that are shown at the bottom of the graph, and in studies with large sample sizes that are presented at the top.

Figure 2 .
Figure 2. The symmetrical funnel plot suggests no risk of bias among the small sample size studies shown at the bottom of the graph.High confidence and high [21].This was also reported in a multicenter study involving 5,700 hospitalized patients in the New York metropolitan area.Obesity has been described as the second most common comorbidity, present in around 40% of patients with COVID-19.During the hospitalization of the 2634 patients, 14.2% were treated in the ICU and 12.2% received invasive mechanical ventilation.Mortality for those who required mechanical ventilation was 88.1%[22].