Review
How the association between obesity and inflammation may lead to insulin resistance and cancer

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Abstract

Background and objectives

Obesity is associated with metabolic dysfunction and over nutrition. Increased body mass index and obesity are strongly amalgamated with changes in the physiological function of adipose tissue, leading to altered secretion of adipocytokines, inflammatory mediators release as well as chronic inflammation and insulin resistance. The purposes of this study were to review the evidence of how obesity and inflammation may lead to insulin resistance and cancer.

Summary

Recent findings suggested that increased level of inflammatory mediators in obesity, plays an introductory and cabalistic role in the development of different types of inflammatory disorders including type 2 diabetes mellitus. Link between elevated body mass index and type 2 diabetes mellitus (T2DM). Several of the factors−such as increased levels of leptin, plasminogen activator inhibitor-1, decreased levels of adiponectin, insulin resistance, chronic inflammation etc. consequently result in carcinogenesis and carcinogenic progression too.

Conclusion

This review summarizes how cytokine production in adipose tissue of obese subject creates a chronic inflammatory environment that favors tumor cell motility and invasion to enhance the metastatic potential of tumor cells. High levels of cytokine in the circulation of affected individuals have been associated with a significantly worse outcome. This article also reconnoiters the mechanisms that link obesity to numerous disorders such as inflammation, diabetes, cancers and most specifically combine these processes in a single image. Understanding these mechanisms may assist to understand the consequences of obesity.

Introduction

Excess accumulation of adipose tissue is known as obesity [1]. Normally obesity may be defined as a state of positive energy balance leading to increase in adipose tissue mass. Increased adipose tissue mass is closely related to the changes in the size or number of adipocytes and these cells are good sources of energy consisting of 80% lipid and 20% of water and protein [2,3]. Hypertrophy and hyperplasia of the adipocytes are the main two ways that can increase the adipose tissue mass [2]. Adipogenesis may be described as the formation of adipocytes from preadipocytes; which are the fibroblast-like precursor cells. It is an important regulatory process involved in the development of obesity. These newly developed cells can further increase in size by accumulating more lipid droplets or can increase in cell number, when deplete their own storage capacity. Thus, both increase in cell number (hyperplasia) and cell size (hypertrophy) may easily contribute to adipose mass. Thus, adipogenesis is a continuous process which occurs throughout the lifetime in response to normal cell turnover [4].

In mammals, two available types of adipose tissue are white adipose tissue (WAT) and brown adipose tissue (BAT). They are different in functions, localization and cellular composition [5]. BAT consists of an uncoupling protein named thermogenin or uncoupling protein (UCP)-1 which contributes to thermogenesis [6]. WAT reserves energy as triacylglycerols. Majority of adipose tissues are WAT in human body that is present as subcutaneous or visceral fat. Thus human body can store limitless amount of fat [3]. World Health Organization (WHO) has suggested three classifications of obesity utilizing the body mass index (BMI) which is calculated by dividing weight in kilograms by height in meter square [7]. People with a BMI greater than 25 are considered overweight (class I), Individuals with a BMI greater than 30 are obese or of class II, and those with a BMI over 40 are considered morbidly obese, and have an increased risk of death [7].

In recent times, obesity is the most frequently encountered metabolic disease all over the world and its incidence is rising rapidly [8,9]. Unfortunately, obesity is rapidly becoming pandemic in the developed world1 as well as in many developing nations [10]. Overweight and obese individuals are at an increased risk of developing various chronic disorders [11]. Recent study explored that 1 in 4 adults in the United States is considered obese [12]. According to WHO, there will be about 2.3 billion overweight people aged 15 years and above, and over 700 million obese people worldwide in 2015 [13]. It was recently recommended that overweight is a common condition in Western nations [14]. Moreover, it is observed that the frequency of obesity is highest in the USA, Europe and lowest in East Asia and sub-Saharan Africa [15]. Actually obesity is such a condition in which energy intake exceeds energy expenditure [16]. It is a complex disease caused by various factors including genetic, diet, lifestyle and environmental factors [17]. The danger of obesity is very fearful throughout the world because it occurs in people of almost all aged, even in children and adolescents [18,19].

It has been considered as one of the serious global health problems which has close association with various types of diseases including cardiovascular disease [20], type 2 diabetes [21,22], hypertension, dyslipidemia, liver disease and also several types of cancer [21,23,24]. Recent data indicates that some forms of obesity are commonly associated with chronic low-grade inflammation [25]. We present here a broad overview to develop the mechanisms that link obesity to inflammatory disorders, diabetes and cancers.

Section snippets

Overview of adipose tissue and adipokines

Adipose tissue is essential for the life of mammals. It represents the main source of free fatty acid (FFA) in the postprandial fasting state for energy use and heat production [26]. Adipose tissue is considered as an endocrine organ which secretes a number of peptides named adipokines. These adipokines involve in many bodily functions including inflammation, thermoregulation, atherosclerosis, angiogenesis, blood pressure regulation and so on [27]. Precisely, they work as a network to regulate

Relationship between obesity and inflammatory disorders focusing on adipokines as casual factor

Obesity-induced inflammation or inflammatory disorder is a major feature of adipose tissue dysfunction [35]. Actually, adipose tissue is not only a depot for storage of excess energy in the form of TAG (triacylglycerols), but also an active endocrine organ secreting different peptides called adipocytokines [36]. Adipocytokines produce several types of peptides, hormones and other molecules that affect cardiovascular system, not only in an endocrine mechanism but also by autocrine and paracrine

Relationship between obesity and type 2 diabetes mellitus

Obesity has a complex relationship with diabetes mellitus (DM), especially with type 2 diabetes mellitus (T2DM) [59]. Obesity may be a precursor or risk factor for T2DM, following insulin resistance [60,61]. Nowadays, T2DM in children and adolescents is a public health problem worldwide. The alarming rates of youth T2DM, parallel the escalating rates of obesity, which is a risk factor affecting insulin sensitivity [62]. A few studies have developed a link between insulin resistance and

Relationship between obesity and cancer

The prevalence of obesity among children, adolescents and adults has been increasing during the last decades (Fig. 3). The World Health Organization calculates that there are more than 1.6 billion overweight adults in the world and approximately 400 million of these are obese. Thus, obesity has been recognized as one of the major health hazard and this health problem is linked to several types of cancer [71]. Adipose tissue secretes adipokines or inflammatory molecules into the bloodstream.

Obesity and breast cancer risk

Breast cancer is a common type of cancer throughout the world. Risk of developing breast cancer is increased in obese postmenopausal women [73]. Lorincz et al. [73] have proposed some hypotheses in 2006 to describe the association of postmenopausal breast cancer with obesity. According to one hypothesis, the cause of this association is the elevated estrogens level in circulation in obese postmenopausal women [73]. In postmenopausal women, estrogen biosynthesis occurs normally in adipose tissue

Obesity and prostate cancer risk

Prostate cancer (PC) is the most common cancer in elderly male populations of western countries. Its incidence increases quickly in men over 50 years of old [107]. Several recent studies report positive associations between adiposity and prostate cancer risk. Obesity is positively associated with a metabolic condition, characterized by elevated levels of insulin, IGFs and various cytokines. These three elevated factors are thought to raise the risk of developing high-grade prostate cancer [107

Obesity and colon cancer risk

Colon cancer is the third most available cancer in the world. Incidence rates of this cancer are approximately 10-fold higher in developed than in developing nations [110]. Excess adipokines secreted from adipose tissue during obesity can directly influence colonic dysplasia because adipokines such as IL-6, leptin, and adiponectin modulate tumorigenesis in several models of colon cancer in a paracrine fashion [111]. A possible relation between excess body weight and colon cancer risk has been

Obesity and liver cancer risk

Liver cancer is another common cancer in the world. Its incidence is increasing day by day and hepatocellular carcinoma (HCC) has risen to become the third leading cause of cancer death [131,132]. Obesity has been established by numerous clinical studies as a significant risk factor for liver disorders. A prospective mortality study reported that high BMI was related with higher rates of liver cancer-related death. Compared to subjects with normal BMI, the risk of mortality from liver cancer

Obesity and other cancer risk

According to recent findings IARC identifies eight additional cancer sites linked to overweight and obesity such as cancers of endometrial, esophageal, thyroid, mammary gland, colon, liver, pancreas, skin, ovaries, and pituitary gland. According to cohort and case-control studies obesity increases the risk of endometrial and esophageal cancer [63]. In fact, the development of endometrial cancer risk is about 2–3-fold higher in obese women than in slim women [139]. As in breast cancer, the

Overview of all synoptic mechanism in one feature

Obesity can be characterized by primary deposition of triglycerides in subcutaneous adipose tissue, the increase of which can result in insulin resistance and limit further subcutaneous lipid accumulation, according to several epidemiological studies (Fig. 4). Subsequently, these triglycerides divert to visceral fat depot [58,148]. Visceral fat increases the release of free fatty acids (FFA), resulting in accelerated lipolytic activity. Insulin action and glucose disposal can be affected in

Conclusion

The incidence of obesity has significantly increased worldwide during recent decades. Normally, visceral obesity plays a vital role in the development of T2DM by mobilizing FFAs and stimulating insulin resistance. Besides, obesity and obesity-related disorders constitute a serious threat to the health of all populations on earth. Obesity is responsible for diseases including cancers, atherosclerosis, CVD and diabetes where inflammation plays a significant role in the pathogenesis. Actually,

Conflicts of interest

None of the authors declare a conflict of interest.

Sources of financial support

There is no funding to be disclosed.

Acknowledgements

We would like to thank Mohammad Nurul Amin and Md. Saddam Hussain for the assistance in the literature search and data extraction. We also want to thanks Md. Shahid Sarwar, Md. Mizanur Rahman Moghal, Abhijit Das, Mohammad Zahid Hossain, and Md. Shalahuddin Millat for their support during study design, writing, and finally like to express our gratitude to Mohammad Safiqul Islam for his supervision. All authors have read and approved the manuscript for publication.

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