The silent flame of obesity: inflammation and risk for diabetes

ABSTRACT

Introduction:  It is important to understand in depth the inflammatory processes that participate in obesity and type 2 diabetes mellitus, aiming to contribute to the development of new therapeutic and control strategies capable of modulating the inflammatory response associated with them.

Objective:  To understand in a more in-depth way the inflammatory processes that participate in obesity and type 2 diabetes mellitus.

Method:  Integrative literature review was carried out by collecting information published on virtual platforms in Portuguese and English. The material for reading and analysis was selected from the SciELO, Google Scholar, Pubmed and Scopus platforms. Initially, a search was carried out for the descriptors “obesity. type 2 diabetes mellitus, TNF-α, IL-6” with AND or OR search, considering the title and/or abstract. Afterwards, considering only those that had a greater relationship with the theme, the full texts were read.

Results:  35 articles that met the inclusion criteria were evaluated.

Conclusion:  The integrative review demonstrates that low-grade inflammation plays a central role in the connection between obesity and type 2 diabetes mellitus, highlighting TNF-α as the main pro-inflammatory marker associated with insulin resistance. Although relevant, IL-6 presents results that are still inconsistent, indicating the need for further studies. These findings reinforce the importance of modulation of the inflammatory response as a potential therapeutic strategy in the prevention and management of these metabolic diseases.

KEYWORDS:
Obesity; Type 2 diabetes mellitus; TNF-α; IL-6

VISUAL ABSTRACT

RESUMO

Introdução:  É importante compreender de modo aprofundado os processos inflamatórios que participam da obesidade e do diabete melito tipo 2, objetivando contribuir para o desenvolvimento de novas estratégias terapêuticas e de controle capazes de modular a resposta inflamatória associada a eles.

Objetivo:  Compreender de modo mais aprofundado os processos inflamatórios que participam da obesidade e do diabete melito tipo 2.

Método:  A revisão integrativa da literatura foi feita colhendo informações publicadas em plataformas virtuais em português e inglês. O material para leitura e análise foi selecionado das plataformas SciELO, Google Scholar, Pubmed e Scopus. Inicialmente foi realizada busca por descritores “obesidade. diabete melito tipo 2, TNF-α, IL-6” com busca AND ou OR, considerando o título e/ou resumo. Após, considerando-se somente os que tinham maior relação ao tema, foi realizada a leitura da íntegra dos textos.

Resultado:  Foram avaliados 35 artigos que preenchiam os critérios de inclusão.

Conclusão:  A revisão integrativa demonstra que a inflamação de baixo grau exerce papel central na conexão entre obesidade e diabete melito tipo 2, destacando o TNF-α como o principal marcador pró-inflamatório associado à resistência insulínica. A IL-6, embora relevante, apresenta resultados ainda inconsistentes, indicando necessidade de estudos adicionais. Esses achados reforçam a importância da modulação da resposta inflamatória como potencial estratégia terapêutica na prevenção e no manejo dessas doenças metabólicas.

PALAVRAS-CHAVE:
Obesidade; Diabete melito tipo 2; TNF-α; IL-6

RESUMO VISUAL

INTRODUCTION

The pathophysiology of obesity involves complex interactions between genetic, environmental, neuroendocrine, and immunometabolic factors. One of the main central mechanisms is the dysregulation of the hypothalamic-pituitary axis, especially in the arcuate nucleus of the hypothalamus, where hormones such as leptin, ghrelin, insulin and peptide YY act, responsible for regulating satiety and appetite. In obesity, resistance to leptin is observed, a hormone secreted by adipose tissue that, under normal conditions, inhibits hunger and increases energy expenditure, but loses its effectiveness when levels are chronically high.¹ Obesity poses a global health threat, with rates that have nearly tripled since 1975.²

Middle- and low-income countries concentrate two out of three individuals with obesity, with Brazil being among the five countries with the highest prevalence worldwide. Between 2006 and 2019, obesity in Brazil increased from 11.8% to 20.3%, while the percentage of overweight adults rose from 42.6% to 55.4%. This significant growth does not occur only in adults: projections indicate that, by 2044, about 48% of Brazilian adults will live with obesity, bringing the total number of overweight people to approximately 75% of the population.³

This scenario imposes high direct costs on the Unified Health System (SUS) estimated at US$ 654 million per year only for non-communicable diseases related to excess weight, in addition to representing a significant economic and social burden.⁸ The global prevalence of obesity is expected to reach approximately two billion adults by 2035 and is projected to increase from 14% to 24%.⁵

Thus, it is important to understand in a more in-depth way the inflammatory processes that participate in obesity and type 2 diabetes mellitus, aiming to contribute to the development of new therapeutic strategies capable of modulating the inflammatory response associated with these complex metabolic conditions.

METHOD

This is an integrative review of the literature made by collecting information published on virtual platforms in Portuguese and English. The material for reading and analysis was selected from the SciELO, Google Scholar, Pubmed and Scopus platforms. Initially, a search was carried out for descriptors “obesity, type 2 diabetes mellitus, TNF-α, IL-6” with AND or OR search, considering the title and/or abstract. Afterwards, considering only those that were more related to the theme, the texts were read in full and at the end 35 articles that met the inclusion criteria were evaluated

DISCUSSION

Adipose tissue and inflammation

The pathophysiological mechanism of obesity includes a state of chronic low-grade inflammation, characterized by persistent immune activation and release of systemic inflammatory mediators. This inflammatory cascade is stimulated by the complex interaction existing within adipose tissue. In patients with this condition, adipocytes are hypertrophied, secreting chemokines that recruit and activate immune cells, promoting a microenvironment in favor of inflammation.⁵

In obesity there is intense oxidative stress, caused by the release of reactive oxygen species stimulated by the entry of nutrients existing in obesity, explaining the mechanism of inflammation. In addition, this nutrient overload can promote endoplasmic reticulum stress and unfolded protein response, activating intracellular inflammatory pathways. This inflammation causes the release of inflammatory cytokines such as TNF-α, which can activate several inflammatory signaling molecules, such as JNK (c-Jun N-terminal kinase) and IKKbeta (Inhibitor of nuclear factor kappa-B kinase subunit beta), causing insulin deficit action on adipocytes and hepatocytes, reducing their sensitivity to it. TNF-α inhibits the expression of PPARy (Peroxisome Proliferator-Activated Receptor gamma), which is important for maintaining insulin sensitivity. High levels of TNF-α produced in both the liver and muscle can induce insulin resistance.⁶

The sustained inflammatory environment causes insulin resistance due to TNF alpha and IL-6 inhibiting the translocation of the GLUT4 transporter in the muscle, favoring hepatic steatosis, stimulating lipid production and, reducing their oxidation, causes beta cell dysfunction, since prolonged exposure to interleukin beta (IL-β) decreases insulin production capacity.⁵

Adipocytes release numerous hormones, inflammatory mediators, and immune system effectors into the bloodstream. In obesity, there is a phenotypic alteration in the cells, creating a chronic low-grade inflammatory environment, characteristic of obesity. Type 1 innate lymphocytes are a type of regulatory cells that make up adipose tissue and are responsible for sustaining homeostasis through the secretion of type 2 interleukins, consequently, preserving adipose tissue macrophages in an anti-inflammatory state. Adipose tissue inflammation in obesity results from a complex interaction between dysfunctional adipocytes and infiltrated immune cells, forming a self-sustaining inflammatory microenvironment, which has a crucial contribution to metabolic dysfunction. As adipose tissue increases in obesity, adipocytes are hypertrophied, subsequently undergo hypoxia and necrosis, releasing molecular patterns related to damage, which are signals that recruit innate and adaptive immune cells.⁵

Adipose tissue expresses high levels of TNF-α, and there is a direct causal relationship between tumor necrosis factor and glucose intolerance. There is an increase in the number of adipose tissue macrophages in obesity in both mice and humans, and macrophages are thought to be the main insulin signals. This is because macrophages in adipose tissue produce factors that act in a paracrine or systemic way and disrupt insulin signaling in target cells. Macrophages produce chemokines and cytokines that stimulate the chemotaxis of circulating monocytes and other immune cells, such as pro-inflammatory M1 macrophages, which make up to 40% of fat cells in obesity.⁶

Macrophage activation occurs through the signaling of the TLR4/NLRP3 (Toll-Like Receptor 4/NOD-Like Receptor Protein 3) inflammosome by SFAsm (Saturated Fatty Acids-mediated) as RANTES-Regulated upon Activation, Normal T cell Expressed and Secreted (CCL5). T lymphocytes have altered polarization, characterized by an increase in Th1 cells, which release IFN-α (Interferon alpha) and promote the activation of macrophages, as well as Th17 cells, which produce IL-17, which acts in synergy with TNF-α, intensifying the inflammatory process. In contrast, there is a reduction in regulatory T lymphocytes, decreasing the release of anti-inflammatory cytokines such as interleukin-10 (IL-10) and TGF-beta.⁵

In addition, dendritic cells contribute to the intensification of the immune response by secretariat Interleukin-12 (IL-12) and Interleukin-18 (IL-18), thereby activating T lymphocytes, while B cells produce autoantibodies and IL-6, further stimulating pro-inflammatory T lymphocytes. Concomitantly, stress-stressed adipocytes as well as infiltrated immune cells release pro-inflammatory cytokines that establish an inflammatory feedback loop, maintaining and aggravating metabolic dysfunction. Expressive weight gain causes hypertrophy and hyperplasia of adipose tissue, which leads to chronic low-grade inflammation of visceral adipose tissue.⁵

Obesity prevention requires a multifactorial approach that involves sustainable lifestyle changes, with an emphasis on healthy eating, regular physical activity, and reducing sedentary behavior. Early interventions, especially in childhood and adolescence, are crucial, considering that inadequate eating habits and low physical activity tend to persist into adulthood. The promotion of school and community environments that favor healthy choices, as well as public policies that encourage clear nutrition labeling, the control of advertising of ultra-processed foods, and the taxation of sugary drinks, have proven to be effective strategies to contain the advance of population obesity.⁷

Diabetes mellitus (DM)

It is a chronic, complicated and non-communicable endocrine disease that has been growing rapidly, which represents a challenge for public health, since it is associated with changes in metabolic development. There are two types, DM1 and DM2. The former presents in children or adolescents, while the latter affects more middle-aged and elderly adults who have had prolonged hyperglycemia due to lifestyle with Western diets and little physical activity. The development of DM2 is related to various polygenic and environmental factors, thus having an important genetic polymorphism, a great diversity of risk factors, and is therefore difficult to cure. Appropriate management includes attention to blood glucose control and attention to risk factors for cardiovascular diseases such as hyperlipidemia, hypertension, and obesity.^8.9

MODY, diabetes-onset in the juvenile, is a heterogeneous disease identified by non-insulin-dependent diabetes. It is usually diagnosed at a young age, usually before the age of 25. This version has an autosomal dominant inheritance pattern and does not have autoantibodies like DM1. Several genes are involved in its pathogenesis, including mutations in hepatocyte nuclear factor-1-alpha (HNF1A), which accounts for about 60% of cases, as well as mutations in the glucokinase gene (GCK), present in 15-32% of cases. However, the genetic explanation of MODY is not completely characterized, since in some individuals with mutations they do not develop the disease, while others with clinical symptoms do not have identifiable mutations.¹¹

The current prevalence of T2DM is 10.5% worldwide, equivalent to about 536.6 million adults. The disease has a higher prevalence in high-income countries (11.1%) than in low-income countries (5.5%), due to lifestyle and diets that favor the increase in obesity rates and also due to the fact that low-income countries have underestimated these values due to underdiagnosis.¹⁰

The pathophysiology is not yet completely explained, since it is multifactorial. However, it is known that insulin resistance, typical of DM2, is associated with excess fatty acids and the presence of inflammatory cytokines, which compromise glucose transport, in addition to stimulating lipolysis. Due to this insufficient insulin response, there is a stimulus to increase glucagon production, further contributing to hyperglycemia.¹¹

Genomic studies have identified genetic variants that influence insulin secretion and action, such as TCF7L2 (Transcription Factor 7 Like 2), PPARG (Peroxisome Proliferator-Activated Receptor Gamma) and FTO (Fat Mass and Obesity- Associated gene). In addition, epigenetic modifications, such as DNA methylation and histone acetylation modulated by factors such as diet and physical activity, have a great influence on the expression of genes involved in glucose regulation.⁹

The gut microbiota also plays an important role in the pathogenesis of DM2, since gut dysbiosis affects glucose metabolism through inflammation, which increases intestinal permeability, leading to changes in the production of short-chain fatty acids. Such microbial changes directly influence insulin sensitivity.⁹

Chronic hyperglycemia is responsible for the non-enzymatic glycation of proteins and lipids, which is monitored by the glycated hemoglobin (HbA1c) test. This glycative process causes damage to small vessels, such as those of the retina, kidneys, and peripheral nerves, conferring the typical clinical condition of the complication of hyperglycemia, which includes retinopathy, nephropathy, and neuropathy. If left unchecked, these complications can progress to blindness, dialysis, and amputations, all of which are potentially preventable with appropriate treatment.¹²

Chronic low-grade inflammation

This inflammation with pro-inflammatory cytokines impairs insulin signaling. Immune cells such as macrophages and T lymphocytes also participate actively, especially in adipose tissue, promoting a pro-inflammatory environment, aggravating insulin resistance.⁹ This chronic low-grade inflammation plays a central role in the pathophysiology of DM2, being strongly associated with insulin resistance and β pancreatic cell dysfunction. Hypertrophied adipocytes and macrophages infiltrated in adipose tissue secrete pro-inflammatory cytokines, such as TNF-α, IL-6, and C-reactive protein (CRP), which interfere with insulin signaling pathways through the phosphorylation of insulin substrates in serine residues, impairing their action on target tissues. In addition, these cytokines contribute to oxidative stress and activation of the innate immune system, perpetuating the inflammatory state and worsening glycemic control. Interventions aimed at reducing this inflammatory process have shown therapeutic potential in the prevention and management of T2DM.^11.13

Treatment of diabetes

The therapeutic pattern of T2DM has been changing its trend, focusing on the pathophysiology and its metabolic comorbidities and long-term complications, focusing on the management of obesity to prevent the condition. This is because weight reduction has been reported to be the most responsible for better glycemic control, including remission of the disease.¹⁰

It is important that there is attention directed to patient education and lifestyle habits. Support of community health agents has shown benefits in the education and self-management of DM, especially in vulnerable populations. Regular physical activity should be encouraged, with realistic goals indicated on an individual basis and based on the assessment of the patient’s initial level. The practice of aerobic exercises, resistance, flexibilit and balance help in physical fitness, in addition to reducing HbA1c levels. For people who are overweight or obese, weight loss must combine several approaches, including calorie restriction, increased energy expenditure, drug review that induces weight gain, use of weight loss drugs and, in specific cases, bariatric surgery.¹⁰

Drug therapy for T2DM includes injection of insulin-like agents and administration of hypoglycemic agents. In the case of DM1, insulin is crucial for treatment since there is a lack of beta cells.⁸

The initial treatment of T2DM usually starts with metformin, which reduces glucose, has a low risk of hypoglycemia, does not cause weight gain, is safe and easy to use. However, risks such as atherosclerotic cardiovascular disease, heart failure, and kidney disease should be evaluated. The choice of drugs should be made in a shared way with the patient, prioritizing drugs that reduce cardiovascular and renal risks.¹⁰

Lowering glucose to achieve glycemic goals should also be taken into account when choosing medication. A GRADE (Grading of Recommendations, Assessment, Development and Evaluation) study showed that insulin and GLP-1 receptor agonists (Glucagon-Like Peptide-1) are more effective in reducing HbA1c than sulfonylureas or DPP4 inhibitors (Dipeptidyl peptidase-4). There is a tendency to start combined treatment early, instead of following the slow progression between medications, aiming at better long-term control. In cases of marked hyperglycemia (HbA1c > 10%), it is recommended to start insulin or insulin combined with GLP1RA (Glucagon-Like Peptide-1 Receptor Agonist).¹⁰

New studies are being directed to gene therapy with the incorporation of the exogenous normal gene, being an option for the cure of DM1, being responsible for modulation and gene editing. Another therapeutic option would be with stem cells, which aims to replace dysfunctional pancreatic cells, using pluripotent or multipotent stem cells.⁸

Experimental obesity in animals

The litter reduction model is an experimental approach widely used in studies with rodents, such as rats and mice, for the early induction of obesity and metabolic programming. This method is based on a simple principle: by reducing the number of puppies per litter soon after birth, the availability of breast milk per puppy is increased during the lactation period. As consequence the remaining puppies consume a greater amount of milk, which leads to high energy intake in the first weeks of life, favoring accelerated weight gain and the early accumulation of adipose tissue.¹⁴

The procedure usually consists of standardizing litters to a reduced number of puppies, usually between 3-4 animals per mother, in the first 24-48 h after birth. In contrast, control litters maintain the usual physiological number, which can vary from 8-12 puppies, depending on the species and lineage used. Early overfeeding provided by less competition for breastfeeding results in persistent metabolic alterations, such as hyperphagia (increased food intake), insulin resistance, dyslipidemia, and adipocyte hypertrophy, typical characteristics of obesity.¹⁵

From a physiological point of view, the effects of litter reduction are not limited to the neonatal period. Studies show that the offspring overfed in this model present, throughout their lives, alterations in the hypothalamic-pituitary-adrenal axis, greater expression of genes related to lipid metabolism and inflammation, in addition to a predisposition to the development of metabolic syndromes when exposed to high-calorie diets in adulthood. This makes the model highly relevant for investigations into early metabolic programming, i.e., how nutritional stimuli in the early stages of life affect long-term metabolic health.¹⁶

This model is particularly advantageous because it is non-invasive, low-cost, and mimics real clinical conditions, such as excessive early nutrition in human neonates, either by excessive breastfeeding or artificial feeding. In addition, it allows for a more accurate analysis of the influence of the neonatal nutritional environment on the regulation of appetite, body composition, and endocrine function. For these reasons, litter reduction is considered a robust and reliable experimental model for the study of obesity and its comorbidities, such as T2DM, metabolic syndrome, and chronic low-grade inflammation.¹⁷

The Lee index is a morphometric parameter used mainly in studies with rodents, such as rats and mice, to indirectly assess relative body obesity, especially in experimental models involving metabolic disorders, such as diabetes or induced obesity. It is a formula that relates the animal’s body weight to its nasoanal length (from the snout to the base of the tail), providing a standardized measure of body size as a function of mass. This index is considered an adaptation of the body mass index (BMI) used in humans, allowing the identification of excessive body fat accumulation in a simple and non-invasive way. Under normal conditions, the Lee Index presents relatively constant values, and significant increases are indicative of body fat gain, even in situations where the total weight of the animal does not seem to change. It is worth mentioning that the index should be interpreted in conjunction with other parameters, such as visceral fat analysis, blood glucose and lipid profile, for a more complete assessment of the animal’s nutritional and metabolic status.¹⁸

Whitten effect for obtaining litter

The Whitten effect is a physiological and behavioral phenomenon observed in rodents, especially in mice and rats, in which exposure of females to pheromones present in the urine of sexually mature males induces or synchronizes the estrous cycle. Discovered by researcher Wesley K. Whitten in the 1950s, this effect is based on the ability of male pheromones to act as potent chemical signals, which, when detected by the olfactory system of females, especially by the vomeronasal organ, cause neuroendocrine modulation in the hypothalamic-pituitary-gonad axis. As a result, there is a pulsatile release of gonadotrophic hormones (LH and FSH), promoting the entry or synchronization of estrus in exposed females. This effect is especially relevant in situations where females are in anestrus or in less fertile phases of the cycle. In experimental practice, it can be induced by putting females in indirect contact with males, for example, by exposing them to the bull impregnated with urine and other odors of the male, without the need for direct physical contact. The Whitten effect highlights the importance of sensory and social stimuli in the reproductive physiology of rodents.¹⁹

Experimental models of DM

There are different experimental approaches for the induction of DM in animal models, varying according to the type of diabetes to be simulated and the objectives of the research. Among these strategies are: the destruction of β cells of the pancreas by chemical means, partial or total surgical removal of the pancreas (pancreatectomy), induced lesions in the ventromedial hypothalamus, diets high in fat or sugar, malnutrition during pregnancy (intrauterine nutritional restriction) and the administration of high doses of hormones that antagonize the action of insulin, such as glucocorticoids. Despite this variety of methods, the most widely used model today is chemical induction performed through the application of cytotoxic substances that act selectively on pancreatic β cells. The two main drugs used in this context are alloxan (AL) and streptozotocin (STZ), both of which are capable of causing persistent hyperglycemia by compromising endogenous insulin production.²⁰

Induction through STZ administration has been widely used in studies with rodents, due to its ability to promote gradual progression of the disease, with mild clinical manifestations in the early stages. STZ, a glucosamine-derived nitrosourea, has a high affinity for β-pancreatic cells, being taken up by the GLUT2 transporter. Its cytotoxic action results in selective destruction of these cells, leading to deficiency in insulin production and consequent persistent hyperglycemia.^21,30 The systemic toxicity of STZ is a known and reported factor in several studies, especially when there is variability in the dose, weight of the animals, or inconsistency in the handling and preparation of the substance. In addition to pancreatic toxicity, STZ can induce nephrotoxicity and hepatotoxicity, which contributes to increased lethality, especially when adequate tampons are not used for its preparation or when strict monitoring of the animals is not carried out in the post-induction period.^31,32 STZ can be administered by different routes, such as subcutaneous, intramuscular, or intracardiac; however, the most frequently used routes are the intraperitoneal (IP) and intravenous (IV) routes, as they provide greater reproducibility and efficiency in the experimental model.^21-23

The installation of the diabetic condition occurs in a triphasic and acute way. Initially, in the first 2-4 h after administration, an episode of early hyperglycemia is observed, resulting from the mobilization of hepatic glycogen, without concomitant elevation of serum insulin levels. Between 6-10 h, there is a phase of hypoglycemia, due to the transient increase in insulin secretion. Finally, persistent hyperglycemia is established approximately 24 h after application, characterizing the condition of induced diabetes.

It is important to emphasize that, although there are other strategies for inducing diabetes in animal models, such as partial pancreatectomy, LA administration, or the combination of a high-calorie diet with low doses of STZ to simulate DM2, the use of intraperitoneal STZ is motivated by its speed, low cost, and specificity for β cells, in addition to allowing the achievement of an acute hyperglycemic condition with high predictability in the metabolic parameters evaluated.

It is interesting to mention that the intraperitoneal STZ model warns of the need for technical refinements in the management of the substance and in post-induction care. Strategies such as the use of freshly prepared pH 4.⁵ citrate buffer, administration in fasting conditions, and intensive follow-up in the first hours after injection can contribute to the reduction of mortality and greater homogeneity of the experimental groups.³³

Serum inflammatory markers

TNF-α is a central inflammatory cytokine in the development of insulin resistance, being secreted predominantly by macrophages in white adipose tissue in obese individuals and animal models. It acts through the activation of MAPK and NF-κB pathways, reducing IRS-1 phosphorylation and thus directly impairing insulin signaling and promoting lipolysis, decreased adipogenesis, and reduced adiponectin, aggravating metabolic imbalance.²⁴

IL-6 is a pleiotropic cytokine synthesized by several cell types, such as adipocytes, macrophages, endothelial cells, hepatocytes, and muscle fibers. It plays essential roles in the regulation of the acute inflammatory response, the synthesis of phase proteins (CRP, fibrinogen), and the control of hematopoiesis.²⁵ Approximately 1/3 of circulating IL-6 in the absence of inflammation is produced by adipose tissue, contributing to the proinflammatory state observed in obesity.²⁶ Through classical signaling and trans-signaling via the sIL-6R and gp130 receptor, IL-6 influences metabolic processes, such as insulin resistance, and may also act as muscle-derived myokine, stimulating lipid oxidation and glucose uptake in response to exercise.²⁷ IL-6, secreted by adipocytes, macrophages, hepatocytes, and muscle fibers, is positively correlated with insulin resistance, central adiposity, and CRP elevation, reinforcing its role as a clinical marker of systemic inflammation.

The Markers inflammatory TNF-α and IL-6 are recognized as reliable indicators of chronic inflammation associated with metabolic diseases. The TNF-α, produced predominantly by macrophages in adipose tissue, promotes insulin resistance by inhibiting signaling via IRS-1 and favor lipolysis and metabolic dysfunction.²⁸

Population studies have shown that high levels of these cytokines increase the risk of developing metabolic syndrome and T2DM, which suggests their potential as useful biomarkers in the prevention, diagnosis, and monitoring of therapeutic interventions.^14.24

Previous studies have shown that excess nutrition in the neonatal period can have a lasting impact on energy regulation mechanisms, mainly due to changes in the hypothalamic-pituitary-adrenal axis and in leptin and insulin sensitivity, which favors the development of metabolic syndrome in adulthood.¹⁶ A study using the experimental model of obesity induction with sucrose diluted in water proved to be effective with increased body weight, but without statistical difference, when comparing the Lee index of the obese group with the control group.¹⁸

The investigation of the inflammatory response through the analysis of serum levels of TNF-α and IL-6 in experimental models of obesity and T2DM represents a fundamental approach to understand the immunometabolic mechanisms underlying these chronic diseases. Both conditions are associated with the state of chronic low-grade inflammation, characterized by the persistent production of pro-inflammatory cytokines, which contribute to insulin resistance, endothelial dysfunction, and the development of metabolic complications.³⁴

In 2013, studies stated that animal models, particularly rodents with obesity and induced DM2, offer a standardized and controlled system to validate inflammatory biomarkers, such as TNF-α and IL-6, allowing not only the characterization of the inflammatory profile, but also the evaluation of possible therapeutic interventions.³⁵

The validation of these markers is especially relevant in the context of the development of new drugs aimed at controlling the inflammatory process and preventing associated complications, such as nephropathy, neuropathies, and cardiovascular diseases.

CONCLUSION

The present integrative review shows that subclinical inflammation is a determining link between obesity and type 2 diabetes mellitus, revealing TNF-α as a more consistent and metabolically disruptive pro-inflammatory mediator, whose high expression in obese and diabetic models reinforces its central role in insulin resistance. In contrast, the contribution of IL-6 remains ambiguous and methodologically heterogeneous, requiring further investigations to elucidate its relevance at the interface between adipose tissue and glycemic homeostasis. Thus, the findings not only deepen the understanding of the inflammatory mechanisms that fuel the progression of these chronic diseases, but also signal the need for therapeutic strategies aimed at the selective modulation of this inflammatory response.

References

• ¹ Pan WW, Myers MG Jr. Leptin and the maintenance of elevated body weight. Nat Rev Neurosci. 2018;19(2):95-105. https://doi.org/10.1038/nrn.2017.168
  » https://doi.org/10.1038/nrn.2017.168
• ² Rimes-Dias KA, Costa JC, Canella DS. Obesity and health service utilization in Brazil: data from the National Health Survey. BMC Public Health. 2022;22(1):1474. https://doi.org/10.1186/s12889-022-13906-2
  » https://doi.org/10.1186/s12889-022-13906-2
• ³ Nilson EAF, Jaime PC, Venancio SI, et al. Trend in the prevalence of overweight and obese adults in São Paulo, Brazil: analysis between the years 2006 and 2019.PLoS One. 2025;20(1):e0308751.https://doi.org/10.1371/journal.pone.0308751
  » https://doi.org/10.1371/journal.pone.0308751
• ⁴ Ferrari G, Giannichi B, Resende B, Paiva L, Falbel F, Rache B, et al. The economic burden of overweight and obesity in Brazil: perspectives for the Brazilian Unified Health System. Public Health. 2022;207:82-7. https://doi.org/10.1016/j.puhe.2022.03.015
  » https://doi.org/10.1016/j.puhe.2022.03.015
• ⁵ Gkrinia EMM, Belancic A. The mechanisms of chronic inflammation in obesity and potential therapeutic strategies: a narrative review. Curr Issues Mol Biol. 2025;47(5):357. https://doi.org/10.3390/cimb47050357
  » https://doi.org/10.3390/cimb47050357
• ⁶ Rohm TV, Meier DT, Olefsky JM, Donath MY. Inflammation in obesity, diabetes, and related disorders. Immunity. 2022;55(1):31-55. https://doi.org/10.1016/j.immuni.2021.12.013
  » https://doi.org/10.1016/j.immuni.2021.12.013
• ⁷ Swinburn BA, Kraak VI, Allender S, Atkins VJ, Baker PI, Bogard JR, et al. The global syndemic of obesity, undernutrition, and climate change: The Lancet Commission report. Lancet. 2019;393(10173):791-846. https://doi.org/10.1016/S0140-6736(18)32822-8
  » https://doi.org/10.1016/S0140-6736(18)32822-8
• ⁸ Aloke C, Ugwuja EI, Aja PM, Obasi NA, Chukwu J, akumadu BO, et al. Current advances in the management of diabetes mellitus. Biomedicines. 2022;10(10):2436. https://doi.org/10.3390/biomedicines10102436
  » https://doi.org/10.3390/biomedicines10102436
• ⁹ Vybhavi VSJ, Bhavsar M, Gusani J, Gohil Y, Paul NK, Garlapati HR, et al. New insights into the pathophysiology of type 2 diabetes: a review article. J Pharm Bioallied Sci. 2025;17(Suppl 2):S1070-2. https://doi.org/10.4103/jpbs.jpbs_205_24
  » https://doi.org/10.4103/jpbs.jpbs_205_24
• ¹⁰ Galindo RJ, Trujillo JM, Wang CCL, McCoy RG. Advances in the management of type 2 diabetes in adults. BMJ Med. 2023;2(1):e000372. https://doi.org/10.1136/bmjmed-2022-000372
  » https://doi.org/10.1136/bmjmed-2022-000372
• ¹¹ Sapra A, Bhandari P. Diabetes. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2025. Disponível em: https://www.ncbi.nlm.nih.gov/books/NBK551501/
• ¹² ElSayed NA, Aleppo G, Aroda VR, Bannuru R, Brown FM, Bruemmer D, et al. Glycemic targets: Standards of care in diabetes-2023. Diabetes Care. 2023;46(Suppl 1):S97-S110. https://doi.org/10.2337/dc23-S006
  » https://doi.org/10.2337/dc23-S006
• ¹³ Donath MY, Shoelson SE. Type 2 diabetes as an inflammatory disease. Nat Rev Immunol. 2011;11(2):98-107. https://doi.org/10.1038/nri2925
  » https://doi.org/10.1038/nri2925
• ¹⁴ Plagemann A, Heidrich I, Gotz F, Rohde W, Dorner G. Lifelong enhanced diabetes susceptibility and obesity after temporary intrahypothalamic hyperinsulinism during brain organization. Exp Clin Endocrinol. 1992;99(2):91-5. https://doi.org/10.1055/s-0029-1211143
  » https://doi.org/10.1055/s-0029-1211143
• ¹⁵ Velkoska E, Cole TJ, Dean RG, Burrell LM, Morris MJ. Early undernutrition leads to long-lasting reductions in body weight and adiposity whereas increased intake increases cardiac fibrosis in male rats. J Nutr. 2008;138(9):1622-7. https://doi.org/10.1093/jn/138.9.1622
  » https://doi.org/10.1093/jn/138.9.1622
• ¹⁶ Coupé B, Ishii Y, Dietrich MO, Komatsu M, Horvath TL, Bouret SG. Loss of autophagy in pro-opiomelanocortin neurons perturbs axon growth and causes metabolic dysregulation. Cell Metab. 2012;15(2):247-55. https://doi.org/10.1016/j.cmet.2011.12.016
  » https://doi.org/10.1016/j.cmet.2011.12.016
• ¹⁷ Habbout A, Li N, Rochette L, Vergely C. Postnatal overfeeding in rodents by litter size reduction induces major short- and long-term pathophysiological consequences. J Nutr.2013;143(5):553-62. ps://doi.org/10.3945/jn.112.172825
• ¹⁸ Tabushi FT, Scomparin RC, Machado RS, Oliveira BC, Silva-Filho VJ, Coelho FF, et al. Vertical gastrectomy in overweight and non-overweight rats. Acta Cir Bras. 2016;31(10):689-96. https://doi.org/10.1590/S0102-865020160100000008
  » https://doi.org/10.1590/S0102-865020160100000008
• ¹⁹ Mattaraia VGM, da Silva APR, Sartori DR da S, Tavora M de FCLF, Rodrigues VB, Moreira VB, et al. Efeito macho na indução do estro em ratas Wistar (Rattus norvegicus). Vet Zootec. 2009;16(4):669-77. Disponível em: https://rvz.emnuvens.com.br/rvz/article/view/1266
  » https://rvz.emnuvens.com.br/rvz/article/view/1266
• ²⁰ Silva VD, Nogueira RMB. Diabetes mellitus experimental induzido com aloxana em ratos Wistar. Rev Ciênc Farm Básica Apl. 2015;36(1):9-15.
• ²¹ Szkudelski T. The mechanism of alloxan and streptozotocin action in B cells of the rat pancreas. Physiol Res. 2001;50(6):537-46.
• ²² Takada J, Machado MA, Peres SB, Brito LC, Borges-Silva CN, Costa CEM, et al. Neonatal streptozotocin-induced diabetes mellitus: a model of insulin resistance associated with loss of adipose mass. Metabolism. 2007;56(7):977-84. https://doi.org/10.1016/j.metabol.2006.05.021
  » https://doi.org/10.1016/j.metabol.2006.05.021
• ²³ McNeill JH, editor. Modelos experimentais de diabetes. New York: Routledge; 2018. Disponível em: https://www.niddk.nih.gov/health-information/health- statistics/overweight-obesity
• ²⁴ Hotamisligil GS. Inflammation and metabolic disorders. Nature. 2006;444(7121):860-7. https://doi.org/10.1038/nature05485
  » https://doi.org/10.1038/nature05485
• ²⁵ Erta M, Quintana A, Hidalgo J. Interleukin-6, a major cytokine in the central nervous system. Int J Biol Sci. 2012;8(9):1254-66. https://doi.org/10.7150/ijbs.4679
  » https://doi.org/10.7150/ijbs.4679
• ²⁶ Scheller J, Chalaris A, Schmidt-Arras D, Rose-John S. The pro- and anti- inflammatory properties of the cytokine interleukin-6. Biochim Biophys Acta. 2011;1813(5):878-88. https://doi.org/10.1016/j.bbamcr.2011.01.034
  » https://doi.org/10.1016/j.bbamcr.2011.01.034
• ²⁷ Febbraio MA, Pedersen BK. Muscle-derived interleukin-6: mechanisms and implications. FASEB J. 2002;16(11):1335-47. https://doi.org/10.1096/fj.01- 0876rev
  » https://doi.org/10.1096/fj.01-
• ²⁸ Mohammadi M, Gozashti MH, Aghadavood M, Mehdizadeh MR, Hayatbakhsh MM. Clinical significance of serum IL-6 and TNF-a levels in patients with metabolic syndrome. Rep Biochem Mol Biol. 2017;6(1):74-9. https://pmc.ncbi.nlm.nih.gov/articles/PMC5643447/
  » https://pmc.ncbi.nlm.nih.gov/articles/PMC5643447
• ²⁹ Kern PA, Ranganathan S, Wood L, Ranganathan G. Adipose tissue tumor necrosis factor and interleukin-6 expression in human obesity and insulin resistance. Am J Physiol Endocrinol Metab. 2001;280(5):E745-51. https://doi.org/10.1152/ajpendo.2001.280.5.E745
  » https://doi.org/10.1152/ajpendo.2001.280.5.E745
• ³⁰ Lenzen S. The mechanisms of alloxan- and streptozotocin-induced diabetes. Diabetologia. 2008;51(2):216-26. https://doi.org/10.1007/s00125-007-0886-7
  » https://doi.org/10.1007/s00125-007-0886-7
• ³¹ Yang H, Scheff AJ, Schalch DS. Effects of streptozotocin-induced diabetes mellitus on growth and hepatic insulin-like growth factor I gene expression in the rat. Metabolism. 1990;39(3):295-301. https://doi.org/10.1Furman BL. Streptozotocin-induced diabetic models in mice and rats. Curr Protoc Pharmacol. 2015;70:5.47.1-20. https://doi.org/10.1002/0471141755.ph0547s70
  » https://doi.org/10.1Furman
• ³² Ganda OP, Rossini AA, Like AA. Studies on streptozotocin diabetes. Diabetes. 1976;25(5):595-603. https://doi.org/10.2337/diab.25.7.595
  » https://doi.org/10.2337/diab.25.7.595
• ³³ Furman BL. Streptozotocin-induced diabetic models in mice and rats. Curr Protoc Pharmacol. 2015;70:5.47.1-20. https://doi.org/10.1002/0471141755.ph0547s70
  » https://doi.org/10.1002/0471141755.ph0547s70
• ³⁴ Hotamisligil GS. Foundations of immunometabolism and implications for metabolic health and disease. Immunity. 2017;47(3):406-420. doi: http://doi.org/10.1016/j.immuni.2017.08.009
  » http://doi.org/10.1016/j.immuni.2017.08.009
• ³⁵ Akash MS, Rehman K, Chen S. Role of inflammatory mechanisms in pathogenesis of type 2 diabetes mellitus. J Cell Biochem. 2013;114(3):525-31. https://doi.org/10.1002/jcb.24402
  » https://doi.org/10.1002/jcb.24402

• How to cite this article
  Tabushi FL, Rodrigues LS, Schuh R, Caron VF, Okimura VN, Pinheiro RS, Tabushi FI. A chama silenciosa da obesidade: inflamação e risco para o diabete. BioSCIENCE. 2026;84:e00013. https://doi.org/10.55684/2026.84.pt.e00013
• Central Message
  It is important to understand in more depth the inflammatory processes that participate in obesity and type 2 diabetes mellitus. This leads to the development of new therapeutic strategies capable of modulating the inflammatory response associated with these complex metabolic conditions.
• Perspective
  TNF-α expression is significantly increased in obesity and diabetics, reinforcing the central role of it in inflammation associated with obesity and type 2 diabetes mellitus, validating its usefulness as a more sensitive biomarker.
• Funding:
  Partly by the Coordination for the Improvement of Higher Education Personnel - Brazil (CAPES) - Funding code 001
• Data availability:
  Data are available from the corresponding author upon reasonable request.

Edited by

• Associate Editor:
  Osvaldo Malafaia https://orcid.org/0000-0002-1829-7071

Data availability

Data are available from the corresponding author upon reasonable request.

Publication Dates

• Publication in this collection
  21 Aug 2026
• Date of issue
  2026

History

• Received
  25 Feb 2026
• Accepted
  14 Mar 2026
• Published
  01 May 2026