This article delves into the intricate world of chronic low-grade inflammation in adipose tissue (AT) and its profound impact on overall health, particularly in the context of obesity. It explores the complex interplay between various cell types, signaling pathways, and inflammatory mediators within AT, shedding light on the mechanisms underlying obesity-related metabolic diseases.

1. Adipose Tissue Inflammation Overview:

   • Chronic low-grade inflammation in adipose tissue (AT) is intricately linked to obesity and contributes to various disorders, including insulin resistance, type 2 diabetes, cardiovascular diseases, and nonalcoholic fatty liver disease.

2. Roots of AT inflammation:

   • Dysfunction in adipocytes and infiltration of bone marrow-derived immune cells trigger cytokine and chemokine production, leading to chronic low-grade inflammation in expanding adipose depots.

3. White Adipose Tissue Phenotype Shift:

   • With obesity, white adipose tissue undergoes a phenotypic shift marked by inflamed, dysfunctional adipocytes and immune cell infiltration, classifying obesity as an inflammatory immune disease.

4. Macrophages in the Spotlight:

   • Macrophages play a central role in WAT inflammation, infiltrating adipose depots and contributing to adipocyte dysfunction. Recent evidence challenges the classic paradigm of bone-marrow-derived macrophage recruitment.

5. Molecular Intricacies:

   • Molecular studies within macrophages reveal adenosine receptors' influence on suppression and the inositol-requiring enzyme 1α (IRE1α) regulation of endoplasmic reticulum (ER) stress, offering potential avenues for inflammation mitigation.

6. Targeting Inflammation: Therapeutic Prospects:

   • Efforts to mitigate WAT inflammation present a complex landscape. Clinical studies exploring anti-cytokine therapy yield conflicting results, emphasizing the intricate relationship between inflammation and metabolism. Interventions such as calorie restriction, exercise, and bariatric surgery showcase varied impacts on adipose tissue inflammation, highlighting the need for a nuanced approach.

In the realm of global health challenges, obesity stands out as an epidemic intricately linked to a spectrum of disorders, including insulin resistance, type 2 diabetes mellitus (T2DM), cardiovascular diseases (CVD), immune disorders, and nonalcoholic fatty liver disease (NAFLD). This discourse embarks on unravelling the scientific intricacies surrounding chronic low-grade inflammation in adipose tissue (AT) and its profound implications for overall health.

Unveiling the Tapestry of Inflammation

Numerous lines of preclinical and clinical research substantiate the mechanistic link between chronic low-grade inflammation in AT and metabolic diseases. The questions that persist stem from the intricate cross-talk of pro- and anti-inflammatory signaling cascades within expanding adipose depots.

Adipose Tissue in the Spotlight

The roots of AT inflammation delve into dysfunctional adipocytes secreting inflammatory adipokines and the infiltration of bone marrow-derived immune cells, triggering cytokine and chemokine production. Despite the low-grade nature of this cascade, its impacts on remote organ function contribute significantly to the complications of obesity.

Understanding White Adipose Tissue Phenotype

White adipose tissue (WAT), a pivotal fat-storing depot and endocrine organ, undergoes a phenotypic shift with obesity. This transformation is characterized by inflamed, dysfunctional adipocytes and immune cell infiltration, marking obesity as an inflammatory immune disease.

The Dichotomy of Adipose Tissue Depots

The inflammatory reaction intensifies in visceral WAT (VAT) compared to subcutaneous WAT (SAT) in obesity. VAT, rich in macrophages, plays a pivotal role in metabolic disorders, while SAT inflammation adds complexity to the obesity-related inflammatory landscape.

Dynamics of Bone Marrow Adipose Tissue

Approximately 10% of adipose tissue resides in the bone marrow, influencing whole-body energy metabolism and inflammatory responses. While the debate continues about their contribution to obesity-related complications, bone marrow adipocytes play a vital role in immune cell production, sustaining AT inflammation.

Conductors of Inflammation: Macrophages Take the Stage

Macrophages, central players in WAT inflammation, infiltrate expanding adipose depots, contributing to adipocyte dysfunction and metabolic complications. Recent evidence suggests local macrophage proliferation within adipose tissue, challenging the classic paradigm of bone-marrow-derived macrophage recruitment.Obese adipose tissue macrophages (ATMs) adopt a proinflammatory state, marked by increased expression of cytokines such as TNFα and iNOS. Despite maintaining a less inflammatory phenotype than classically activated M1 macrophages, endogenous anti-inflammatory cascades contribute to this nuanced immune response.

PPARγ: Clinical Lens Insights

Perceiving obesity through a clinical lens reveals the involvement of Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) in insulin resistance and inflammation regulation. Modulating PPARγ proves essential in shaping metabolically activated macrophages, suggesting therapeutic avenues for metabolic disorders.

Diverse Immune Cells

While macrophages take the spotlight, other immune cells, including neutrophils and lymphocytes, surface as influential players in adipose tissue inflammation. Understanding their roles in the cascade of events involving macrophages and adipocytes adds layers to the complexity of immune cell involvement in obesity-related inflammation.

Adipokines

Adipocytes contribute to inflammation through the secretion of adipokines, with mediators like adiponectin playing crucial anti-inflammatory roles. The intricate interplay between adipokines, inflammation, and insulin sensitivity underscores the need for a holistic understanding of their regulatory mechanisms.

Adaptive Responses: Friend or foe?

Chronic low-grade inflammation prompts adaptive reactions within adipose tissue, including cellular senescence, hypoxia, and lymphatic dysfunction. While these responses aim to maintain physiological conditions in the face of metabolic challenges, their inflammatory nature adds complexity.

Targeting Inflammation: Therapeutic Prospects

Efforts to mitigate WAT inflammation present a complex landscape. Clinical studies exploring anti-cytokine therapy yield conflicting results, emphasizing the intricate relationship between inflammation and metabolism. Interventions such as calorie restriction, exercise, and bariatric surgery showcase varied impacts on adipose tissue inflammation, highlighting the need for a nuanced approach. Preclinical and clinical studies have sought to uncover strategies to attenuate WAT inflammation as a means to mitigate the adverse outcomes associated with obesity. However, the findings have often been inconsistent, highlighting the challenges of translating results obtained from animal models to human scenarios.

Anti-cytokine Therapy: Targeting TNFα

Clinical reports have explored the potential of anti-cytokine therapy as a strategy to combat insulin resistance in obesity. Elevated levels of TNFα, a proinflammatory cytokine, have been observed in the serum of obese patients. Studies have shown that the administration of TNFα impairs insulin sensitivity in laboratory animals and humans, validating the mechanistic basis of this association. The link between TNFα and insulin sensitivity is multifaceted. Some human studies have indicated that TNFα neutralization can lead to reduced glucose intolerance in overweight individuals and hinder the progression to type 2 diabetes (T2D) in patients with rheumatoid arthritis. However, conflicting results have also emerged, where certain studies failed to demonstrate improved insulin sensitivity following anti-TNFα therapy.

IL-1β Implications and the CANTOS Trial

The recent CANTOS trial investigating IL-1β inhibition with canakinumab further highlights the complexity of the relationship between WAT inflammation and metabolism. Inflammation has been linked not only to TNFα but also to IL-1β. However, the CANTOS trial, despite inhibiting IL-1β with canakinumab, did not result in reduced HbA1c, glucose, or insulin levels in diabetic patients. This underscores the intricate interplay between inflammation and metabolic outcomes and the need for a deeper understanding of the underlying mechanisms.

Obesity, ATMs, and Inflammatory Cytokines

Obesity is characterized by the infiltration of adipose tissue macrophages (ATMs) into WAT. While interventions like calorie restriction and rapid weight loss can improve insulin sensitivity, they paradoxically lead to increased ATMs and proinflammatory cytokines. This suggests that the relationship between weight loss, inflammation, and metabolism is more intricate than initially perceived. Calorie restriction, a common approach to weight loss, does not consistently reduce WAT inflammation. Studies have shown that while systemic metabolic functions improve with weight loss, the infiltration of resident macrophages and overall WAT inflammation remain largely unchanged.

Exercise as an Anti-Inflammatory Strategy

Exercise, particularly high-intensity and eccentric exercise, has demonstrated anti-inflammatory effects. It promotes the polarization of macrophages toward anti-inflammatory phenotypes, contributing to the reduction of WAT inflammation. This highlights the potential of exercise as a therapeutic tool in managing obesity-associated inflammation.

Duration vs. Total Reduction in Weight Loss

Research suggests that the duration of weight loss might play a more critical role than the total reduction in mitigating ATM infiltration and WAT tissue inflammation. This insight underscores the importance of longitudinal studies in understanding the relationship between weight loss, inflammation, and metabolic outcomes. Chronic adaptation to weight gain and weight cycling appears to contribute to the link between WAT inflammation and insulin resistance. Understanding the molecular mechanisms that connect these processes could offer valuable insights into novel therapeutic approaches.

Bariatric Surgery: A Mixed Bag of Results

Bariatric surgery, a common intervention for obesity, has yielded inconsistent results concerning its impact on WAT inflammation. While some studies show reductions in inflammation and improved insulin sensitivity post-surgery, others report minor changes or no significant impact on AT inflammation.Certain studies suggest that bariatric surgery can reduce WAT inflammation and enhance insulin sensitivity. However, the relationship between improved inflammation, insulin action in the liver, and systemic glucose homeostasis remains complex, as evidenced by varying outcomes.

Pharmacological and Genetic Strategies in Focus

GSK3 Inhibition: A Path to Reducing Inflammation

Inhibition of glycogen synthase kinase-3 (GSK3), a protein-serine kinase, has demonstrated the potential to reduce WAT inflammation. Its effects include suppressing monocyte migration, favoring macrophage apoptosis, inactivating STAT3, and decreasing levels of FFAs and chemokines secreted by visceral adipose tissue (VAT).

Genetic Modifications

Genetic modifications in mouse models have provided valuable insights into the link between WAT inflammation and insulin resistance. Overexpressing calpastatin, a calcium-dependent protease inhibitor, reduces adipocyte apoptosis and macrophage infiltration in WAT, suggesting a protective effect. Deletion of C1q/TNF-related protein-7 (CTRP7), a member of the C1q family, has shown improvements in WAT inflammation and insulin resistance. The mechanism likely involves a reduction in oxidative stress and endoplasmic reticulum (ER) stress.

Key points

1. Chronic inflammation in fat tissue fuels obesity-related diseases like diabetes and heart problems.

2. Macrophage immune cells play a major role, switching to a pro-inflammatory state in obese individuals.

3. Anti-cytokine therapy shows mixed results, highlighting the delicate balance between inflammation and metabolism.

4. Lifestyle changes like exercise and calorie restriction can help, but inflammation often persists despite weight loss.

5. Bariatric surgery outcomes are inconsistent, and new avenues like melatonin and genetic modifications hold promise.

6. Longitudinal studies are crucial for understanding the complex relationships between inflammation, obesity, and metabolic health.

Reference Articles

Kawai, T., Autieri, M. V., & Scalia, R. (2021). Adipose tissue inflammation and metabolic dysfunction in obesity. American Journal of Physiology—Cell Physiology. https://doi.org/C-00379-2020

Khafagy, R., & Dash, S. (2021, October 25). Obesity and Cardiovascular Disease: The Emerging Role of Inflammation. Frontiers in Cardiovascular Medicine, 8. https://doi.org/10.3389/fcvm.2021.768119

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