Association of Adipose Tissue and Adipokines with Development of Obesity-Induced Liver Cancer

Obesity is rapidly dispersing all around the world and is closely associated with a high risk of metabolic diseases such as insulin resistance, dyslipidemia, and nonalcoholic fatty liver disease (NAFLD), leading to carcinogenesis, especially hepatocellular carcinoma (HCC). It results from an imbalance between food intake and energy expenditure, leading to an excessive accumulation of adipose tissue (AT). Adipocytes play a substantial role in the tumor microenvironment through the secretion of several adipokines, affecting cancer progression, metastasis, and chemoresistance via diverse signaling pathways. AT is considered an endocrine organ owing to its ability to secrete adipokines, such as leptin, adiponectin, resistin, and a plethora of inflammatory cytokines, which modulate insulin sensitivity and trigger chronic low-grade inflammation in different organs. Even though the precise mechanisms are still unfolding, it is now established that the dysregulated secretion of adipokines by AT contributes to the development of obesity-related metabolic disorders. This review focuses on several obesity-associated adipokines and their impact on obesity-related metabolic diseases, subsequent metabolic complications, and progression to HCC, as well as their role as potential therapeutic targets. The field is rapidly developing, and further research is still required to fully understand the underlying mechanisms for the metabolic actions of adipokines and their role in obesity-associated HCC.

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Adipocytokines in obesity and metabolic disease

Journal of Endocrinology ◽

10.1530/joe-13-0339 ◽

2014 ◽

Vol 220 (2) ◽

pp. T47-T59 ◽

Cited By ~ 315

Author(s):

Haiming Cao

Keyword(s):

Adipose Tissue ◽

Metabolic Diseases ◽

Therapeutic Potential ◽

Clinical Settings ◽

Low Grade ◽

Endocrine Organ ◽

Metabolic Inflammation ◽

The Past ◽

Wide Range ◽

Low Grade Inflammation

The current global obesity pandemic is the leading cause for the soaring rates of metabolic diseases, especially diabetes, cardiovascular disease, hypertension, and non-alcoholic hepatosteatosis. Efforts devoted to find cures for obesity and associated disorders in the past two decades have prompted intensive interest in adipocyte biology, and have led to major advances in the mechanistic understanding of adipose tissue as an essential endocrine organ. Adipose tissue secretes an array of hormones (adipokines) that signal key organs to maintain metabolic homeostasis, and their dysfunction has been causally linked to a wide range of metabolic diseases. In addition, obesity induces production of inflammatory cytokines (often referred to together with adipokines as adipocytokines) and infiltration of immune cells into adipose tissue, which creates a state of chronic low-grade inflammation. Metabolic inflammation has been increasingly recognized as a unifying mechanism linking obesity to a broad spectrum of pathological conditions. This review focuses on classic examples of adipocytokines that have helped to form the basis of the endocrine and inflammatory roles of adipose tissue, and it also details a few newly characterized adipocytokines that provide fresh insights into adipose biology. Studies of adipocytokines in clinical settings and their therapeutic potential are also discussed.

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Mechanisms Mediating Anti-Inflammatory Effects of Delta-Tocotrienol and Tart Cherry Anthocyanins in 3T3-L1 Adipocytes

Nutrients ◽

10.3390/nu12113356 ◽

2020 ◽

Vol 12 (11) ◽

pp. 3356

Author(s):

Lexie Harlan ◽

London T. Mena ◽

Latha Ramalingam ◽

Shasika Jayarathne ◽

Chwan-Li Shen ◽

...

Keyword(s):

Metabolic Diseases ◽

Combined Treatment ◽

Low Grade ◽

Tart Cherry ◽

Metabolic Complications ◽

Inflammatory Protein ◽

Anti Inflammatory ◽

Low Grade Inflammation ◽

Macrophage Inflammatory Protein

Chronic low-grade inflammation is a primary characteristic of obesity and can lead to other metabolic complications including insulin resistance and type 2 diabetes (T2D). Several anti-inflammatory dietary bioactives decrease inflammation that accompanies metabolic diseases. We are specifically interested in delta-tocotrienol, (DT3) an isomer of vitamin E, and tart cherry anthocyanins (TCA), both of which possess individual anti-inflammatory properties. We have previously demonstrated that DT3 and TCA, individually, reduced systemic and adipose tissue inflammation in rodent models of obesity. However, whether these compounds have combinatorial effects has not been determined yet. Hence, we hypothesize that a combined treatment of DT3 and TCA will have great effects in reducing inflammation in adipocytes, and that these effects are mediated via the nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB), a major inflammatory transcription factor. We used 3T3-L1 adipocytes and treated them with 1–5 µM doses of DT3 along with tart cherry containing 18–36 µg anthocyanin/mL, to assess effects on inflammation. Neither DT3 nor TCA, nor their combinations had toxic effects on adipocytes. Furthermore, pro-inflammatory markers interleukin-6 (IL-6) and p-65 (subunit of NFkB) were reduced at the protein level in media collected from adipocytes with both individual and combined treatments. Additionally, other downstream targets of NFkB including macrophage inflammatory protein 2 (Mip2), and Cyclooxygenase-2 (Cox2) were also significantly downregulated (p ≤ 0.05) when treated with individual and combined doses of DT3 and TCA with no additional combinatorial effects. In summary, DT3 and TCA individually, are beneficial in reducing inflammation with no additional combinatorial effects.

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Metabolic endotoxemia: possible causes and consequences

Obesity and metabolism ◽

10.14341/omet12750 ◽

2021 ◽

Vol 18 (3) ◽

pp. 320-326

Author(s):

V. A. Beloglazov ◽

I. A. Yatskov ◽

E. D. Kumelsky ◽

V. V. Polovinkina

Keyword(s):

Adipose Tissue ◽

Defense Mechanisms ◽

Mutual Influence ◽

Immune Defense ◽

The Body ◽

Low Grade ◽

Endocrine Organ ◽

Depth Study ◽

Low Grade Inflammation ◽

The Relationship

This review article presents data from the literature, which provide an idea of the relationship between metabolic disorders occurring against the background of obesity and endotoxinemia, as well as the effect of these conditions on the maintenance of low-grade inflammation in the body. A description of the hormonal and immune restructuring of white adipose tissue, the main routes of entry and metabolism of endotoxin is given. Particular attention is paid to the mechanisms of the mutual influence of obesity and endotoxinemia. Described by Yakovlev M.Yu. in 1988 «endotoxin aggression» and Cani P.D. et al. in 2007, «metabolic endotoxinemia», in our opinion, is one of the most important triggers for the development and progression of a whole spectrum of acute and chronic diseases. Based on the data of recent years, adipose tissue is an active endocrine organ capable of influencing both metabolic processes and the state of innate and acquired immune defense mechanisms. It has now been proven that high-calorie diets lead not only to an increase in overweight, but also to an increase in the level of endotoxin circulating in the blood. An in-depth study of the ability of obesity and endotoxinemia to potentiate the mutual pro-inflammatory effect can help both in understanding the pathogenesis of the main cardiovascular, autoimmune, allergic and infectious (including viral) diseases, and in the development of methods for non-pharmacological and drug correction of these conditions.

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Mitochondrial oxidative stress in obesity: role of the mineralocorticoid receptor

Journal of Endocrinology ◽

10.1530/joe-18-0163 ◽

2018 ◽

Vol 238 (3) ◽

pp. R143-R159 ◽

Cited By ~ 10

Author(s):

Clara Lefranc ◽

Malou Friederich-Persson ◽

Roberto Palacios-Ramirez ◽

Aurelie Nguyen Dinh Cat

Keyword(s):

Oxidative Stress ◽

Adipose Tissue ◽

Mineralocorticoid Receptor ◽

Bioactive Molecules ◽

Low Grade ◽

Metabolic Complications ◽

Mitochondrial Oxidative Stress ◽

Pathophysiological Role ◽

Low Grade Inflammation

Obesity is a multifaceted, chronic, low-grade inflammation disease characterized by excess accumulation of dysfunctional adipose tissue. It is often associated with the development of cardiovascular (CV) disorders, insulin resistance and diabetes. Under pathological conditions like in obesity, adipose tissue secretes bioactive molecules called ‘adipokines’, including cytokines, hormones and reactive oxygen species (ROS). There is evidence suggesting that oxidative stress, in particular, the ROS imbalance in adipose tissue, may be the mechanistic link between obesity and its associated CV and metabolic complications. Mitochondria in adipose tissue are an important source of ROS and their dysfunction contributes to the pathogenesis of obesity-related type 2 diabetes. Mitochondrial function is regulated by several factors in order to preserve mitochondria integrity and dynamics. Moreover, the renin–angiotensin–aldosterone system is over-activated in obesity. In this review, we focus on the pathophysiological role of the mineralocorticoid receptor in the adipose tissue and its contribution to obesity-associated metabolic and CV complications. More specifically, we discuss whether dysregulation of the mineralocorticoid system within the adipose tissue may be the upstream mechanism and one of the early events in the development of obesity, via induction of oxidative stress and mitochondrial dysfunction, thus impacting on systemic metabolism and the CV system.

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The Endocrine Role of Adipose Tissue and Its Management of Obesity-Related Diseases.

10.46940/semrj.01.1004 ◽

2020 ◽

pp. 1-2

Keyword(s):

Adipose Tissue ◽

Fatty Acid Esters ◽

Whole Body ◽

Low Grade ◽

Endocrine Organ ◽

Hydroxyl Fatty Acids ◽

Body Energy ◽

Low Grade Inflammation ◽

Acid Esters

Adipose tissue plays a central role in regulating whole-body energy. Moreover, adipose tissue acts as an endocrine organ and produces numerous bioactive factors called adipokines which communicate with other organs and modulate a range of metabolic pathways: proteins (adiponectin, angiopoietins, chemerin, etc.), lipids (fatty acid esters of hydroxyl fatty acids, lysophosphatidic acids and sphingolipids), metabolites (uric acid and uridine) and microRNAs. However, excessive adipose tissue is associated with a chronic state of low-grade inflammation, caused by unbalanced production or secretion of these adipokines and can contribute to the development of obesity [1].

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Current metabolic perspective on malnutrition in obesity: towards more subgroup-based nutritional approaches?

Proceedings of The Nutrition Society ◽

10.1017/s0029665120000117 ◽

2020 ◽

Vol 79 (3) ◽

pp. 331-337 ◽

Cited By ~ 4

Author(s):

Ellen E. Blaak

Keyword(s):

Adipose Tissue ◽

Metabolic Diseases ◽

Metabolic Health ◽

Metabolic Phenotype ◽

Whole Body ◽

Low Grade ◽

Plasma Metabolome ◽

Subcutaneous Adipose ◽

Low Grade Inflammation

Lifestyle intervention may be effective in reducing type 2 diabetes mellitus incidence and cardiometabolic risk. A more personalised nutritional approach based on an individual or subgroup-based metabolic profile may optimise intervention outcome. Whole body insulin resistance (IR) reflects defective insulin action in tissues such as muscle, liver, adipose tissue, gut and brain, which may precede the development of cardiometabolic diseases. IR may develop in different organs but the severity may vary between organs. Individuals with more pronounced hepatic IR have a distinct plasma metabolome and lipidome profile as compared with individuals with more pronounced muscle IR. Additionally, genes related to extracellular modelling were upregulated in abdominal subcutaneous adipose tissue in individuals with more pronounced hepatic IR, whilst genes related to inflammation as well as systemic low-grade inflammation were upregulated in individuals with primarily muscle IR. There are indications that these distinct IR phenotypes may also respond differentially to dietary macronutrient composition. Besides metabolic phenotype, microbial phenotype may be of importance in personalising the response to diet. In particular fibres or fibre mixtures, leading to a high distal acetate and SCFA production may have more pronounced effects on metabolic health. Notably, individuals with prediabetes may have a reduced response to diet-induced microbiota modulation with respect to host insulin sensitivity and metabolic health outcomes. Overall, we need more research to relate metabolic subphenotypes to intervention outcomes to define more optimal diets for individuals with or predisposed to chronic metabolic diseases.

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Iron metabolism in obese children and adolescents

Voprosy dietologii ◽

10.20953/2224-5448-2021-1-44-49 ◽

2021 ◽

Vol 11 (1) ◽

pp. 44-49

Author(s):

N.N. Smirnova ◽

◽

N.B. Kuprienko ◽

V.P. Novikova ◽

A.I. Khavkin ◽

...

Keyword(s):

Adipose Tissue ◽

Iron Metabolism ◽

Iron Deficiency Anaemia ◽

Molecular Mechanisms ◽

Key Words Children ◽

Low Grade ◽

Obese Children ◽

Deficiency Anaemia ◽

Low Grade Inflammation ◽

Excessive Accumulation

The review presents new data about the causes and molecular mechanisms of iron metabolism in obesity. Obesity is associated with dysregulated iron metabolism. Three hypotheses of the hypoferremia of obesity have been proposed: nutrition hypothesis, large blood volume hypothesis, and the inflammation hypothesis. The latter has been better supported, it is consistent with the data about low-grade inflammation taking place in excessive accumulation of adipose tissue. The key role in the development of functional hypoferremia belongs to the hepcidin-leptin association. Key words: children, iron deficiency anaemia, iron metabolism, obesity, adolescents

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Adipose Tissue Dysfunction as Determinant of Obesity-Associated Metabolic Complications

International Journal of Molecular Sciences ◽

10.3390/ijms20092358 ◽

2019 ◽

Vol 20 (9) ◽

pp. 2358 ◽

Cited By ~ 104

Author(s):

Michele Longo ◽

Federica Zatterale ◽

Jamal Naderi ◽

Luca Parrillo ◽

Pietro Formisano ◽

...

Keyword(s):

Adipose Tissue ◽

Energy Homeostasis ◽

Inflammatory Responses ◽

Current Knowledge ◽

Tissue Expansion ◽

Low Grade ◽

Metabolic Complications ◽

Visceral Adipose ◽

Subcutaneous Adipose ◽

Low Grade Inflammation

Obesity is a critical risk factor for the development of type 2 diabetes (T2D), and its prevalence is rising worldwide. White adipose tissue (WAT) has a crucial role in regulating systemic energy homeostasis. Adipose tissue expands by a combination of an increase in adipocyte size (hypertrophy) and number (hyperplasia). The recruitment and differentiation of adipose precursor cells in the subcutaneous adipose tissue (SAT), rather than merely inflating the cells, would be protective from the obesity-associated metabolic complications. In metabolically unhealthy obesity, the storage capacity of SAT, the largest WAT depot, is limited, and further caloric overload leads to the fat accumulation in ectopic tissues (e.g., liver, skeletal muscle, and heart) and in the visceral adipose depots, an event commonly defined as “lipotoxicity.” Excessive ectopic lipid accumulation leads to local inflammation and insulin resistance (IR). Indeed, overnutrition triggers uncontrolled inflammatory responses in WAT, leading to chronic low-grade inflammation, therefore fostering the progression of IR. This review summarizes the current knowledge on WAT dysfunction in obesity and its associated metabolic abnormalities, such as IR. A better understanding of the mechanisms regulating adipose tissue expansion in obesity is required for the development of future therapeutic approaches in obesity-associated metabolic complications.

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Roles of Chronic Low-Grade Inflammation in the Development of Ectopic Fat Deposition

Mediators of Inflammation ◽

10.1155/2014/418185 ◽

2014 ◽

Vol 2014 ◽

pp. 1-7 ◽

Cited By ~ 22

Author(s):

Lulu Liu ◽

Mei Mei ◽

Shumin Yang ◽

Qifu Li

Keyword(s):

Adipose Tissue ◽

Fat Distribution ◽

Underlying Mechanism ◽

Fat Deposition ◽

Low Grade ◽

Ectopic Fat ◽

Metabolic Complications ◽

Novel Therapeutic Strategies ◽

Ectopic Fat Deposition ◽

Low Grade Inflammation

Pattern of fat distribution is a major determinant for metabolic homeostasis. As a depot of energy, the storage of triglycerides in adipose tissue contributes to the normal fat distribution. Decreased capacity of fat storage in adipose tissue may result in ectopic fat deposition in nonadipose tissues such as liver, pancreas, and kidney. As a critical biomarker of metabolic complications, chronic low-grade inflammation may have the ability to affect the process of lipid accumulation and further lead to the disorder of fat distribution. In this review, we have collected the evidence linking inflammation with ectopic fat deposition to get a better understanding of the underlying mechanism, which may provide us with novel therapeutic strategies for metabolic disorders.

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