Continuing Education Activity

Obesity is a chronic disease having a major public health concern. Obesity is a mild state of chronic inflammation of adipose tissue and a state of malnutrition by excess, which leads to a defective hormonal and immune system. This activity reviews the pathophysiology of obesity, inflammatory markers secreted by excessive fat deposition in adipose tissue, and their effects on chronic diseases such as hypertension, diabetes, and dyslipidemia.

Objectives:

• Describe obesity as a mild state of chronic inflammation of adipose tissue.
• Explain the role of inflammatory markers released by adipose tissue in worsening chronic conditions such as hypertension, diabetes, and dyslipidemia.
• Describe obesity in light of hormonal considerations and as an immune disease.
• Explain the role of the interprofessional team in managing patients with obesity.

Introduction

Obesity is one of the most common preventable diseases.[1][2] It is a major public health concern. Obesity has a multifactorial etiology that includes genetic, environmental, socioeconomic, and behavioral or psychological influences.[3] Obesity results from a chronic positive energy balance regulated by a complex interaction between endocrine tissues and the central nervous system.[4] 

Obesity measurement can also be used to estimate morbidity and mortality. Body mass index (BMI) has been used to screen overweight and obese individuals. However, waist circumference is the best anthropometric indicator of visceral fat and a better predictor of metabolic disorders such as diabetes, hypertension, and dyslipidemia.[5] People with a normal BMI with a large waist are at higher risk. However, combining BMI and waist circumference adds relatively less risk prediction since they are collinear in nature. Furthermore, hip circumference is inversely related to metabolic syndrome. Large hip circumference is related to lower risks of diabetes and coronary heart disease. This is probably due to having a large muscle mass in the hip region.[5] 

Compared to the Body Mass Index (BMI), the Visceral Adiposity Index (VAI) is a more specific and sensitive examination tool. The VAI is, therefore, a reliable indicator of increased patient risk for cardiometabolic diseases.[6][7] There is currently a lack of scientific knowledge regarding the biochemical and physiologic mechanisms associated with this. A possible explanation for the increased specificity and sensitivity of the VAI is that visceral fat has direct access to the portal venous system, whereas subcutaneous white adipose tissue does not.[8]

Obesity has inflammatory components, directly and indirectly, related to major chronic diseases such as diabetes, atherosclerosis, hypertension, and several types of cancer.[9][10] Overweight and obese individuals have altered circulatory levels of inflammatory cytokines, such as IL-6, TNFα, C-reactive protein (CRP), IL-18, resistin, and visfatin.[11][12] Measures of body fat have a stronger correlation with inflammatory markers than BMI.[13][1]. Exercise and dietary restrictions have been strongly advocated to reduce weight gain and its related complications. Caloric restriction has been proven effective in reducing inflammation in obesity.[14][15] However, a few studies showed that dietary weight loss has less impact on a long-term anti-inflammatory intervention.[16] On the other hand, regular exercise significantly affects chronic inflammation related to obesity and obesity-associated conditions such as hypertension, diabetes, dyslipidemia, etc.[16]

It is well-documented that obesity and its inflammatory markers have significant effects on hypertension, diabetes, and other chronic conditions. This review provides detailed insight into chronic inflammation, immune and hormonal disturbance related to the pathophysiology of obesity and their effects on chronic conditions.

Issues of Concern

Obesity: An immune Disease?

Obesity is a state of malnutrition by excess that leads to defective immune function. Excess body fat is associated with changes in leukocyte count such as monocyte, lymphocyte, and neutrophil counts but lower B- and T-cell mitogen-induced proliferation.[17] Based on current research, it is too early to say that an altered immune system underlies the onset of obesity. Most of the studies showed that immune dysfunction involves obesity-associated alterations like inflammation and insulin resistance. Macrophages aggregates grew larger with increasing degree of obesity, similar to those observed in other inflammatory conditions, led to the idea that macrophages aggregate could explain the obesity-related inflammatory state to a certain extent.[18] 

There are two types of phenotypic macrophages described that have been related to obesity: M1 (classically activated) acts as pro-inflammatory, and M2 (alternatively activated) acts as an anti-inflammatory. In obesity, there is a switch from M2 to M1 phenotype, which is pro-inflammatory.[19] Furthermore, most of the research findings showed the lack of M2 phenotype correlated to obesity and inflammation.[20]

Obesity and Inflammatory Markers

Obesity is also referred to as chronic-low grade inflammation or “metabolic inflammation,” which is often the focus in the pathogenesis of several diseases such as coronary artery disease, atherosclerosis, and insulin resistance, etc.[21][22] Adipose tissue is classified as a complex secretory organ that plays many roles in metabolism. It can modulate energy expenditure, appetite, insulin sensitivity, bone metabolism, reproductive and endocrine functions, inflammation, and immunity and act as a triacylglycerol reservoir. Visceral adiposity correlates well with an increased risk of CVD and diabetes compared to a high body mass index (BMI).[23][24] However, the biochemical and physiologic reasons for having a better correlation of visceral adiposity are still unclear. One possible explanation is that visceral fat has direct access to the portal circulation compared to subcutaneous white adipose tissue, leading to the substances produced by visceral fat directly affecting the liver. 

Adipocytes produce and secrete several proteins called adipokines which play important roles in inflammation. These adipokines include TNF-α, leptin, resistin, visfatin, IL-6, and adiponectin.[25] There are over 50 known adipokines in existence, and they are primarily differentiated by their roles in inflammation. A discrepancy in adipokine secretion has been noted in individuals depending on their BMI; obese individuals have adipose tissue that mainly secretes pro-inflammatory adipokines, while lean individuals secrete anti-inflammatory adipokines. Adipokines implicated in the promotion of inflammation include TNFs, interleukin (IL)- 6, leptin, angiotensin II, visfatin, and resistin.[26][27] Anti-inflammatory adipokines include transforming growth factor-beta (TGF), IL- 4, IL- 10, IL- 13, IL- 1 receptor antagonist (IL- 1Ra), and adiponectin.[28] 

The role of increased pro-inflammatory cytokine secretion in obese patients is currently unknown. It is speculated that the answer to this question is correlated with the enlarged, lipid-rich adipocytes seen in obese individuals. Physiological processes likely exist within the adipose cells that allow for the maintenance and restoration of energy homeostasis in the occurrence of an overwhelmingly large introduction of nutrients. A regulatory mechanism should exist in which the local production of certain adipokines limits the hypertrophied adipocyte(s) from storing excess lipids.[29] The issue arises when this locally occurring instance progresses to systemic, chronic pathology. In sustained obesity cases, an inflammatory response is not sufficient to resolve the ongoing issue. There is a lack of scientific knowledge regarding the physiological and biochemical processes associated with obesity and chronic low-grade inflammation.

Role of Hormones in Obesity

Several studies suggest adipose tissue can collectively secrete more than 50 hormones and signaling molecules termed adipokines. These adipokines play a vital role in immunity and glucose metabolism.[30] The adipose tissue of a lean individual secretes anti-inflammatory adipokines such as transforming growth factor-beta (TGF-beta), interleukins (IL)-10, IL-4, IL-13, IL-1 receptor antagonist (IL-1Ra), adiponectin, and apelin. In contrast, the adipose tissue of an obese individual secretes mainly pro-inflammatory cytokines such as TNFs, IL-6, resistin, visfatin, leptin, angiotensin II, and plasminogen activator inhibitor-1.[31]

Leptin, a hormone that plays a role in appetite and energy balance regulation, along with pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha), are secreted by adipose tissue cells.[32] Leptin is secreted in proportion to the amount of fat stored in adipose tissue. Another hormone secreted by adipose tissue is adiponectin, which decreased in proportion to fat storage in the body.[33] 

Both leptin and adiponectin are associated with the cardiovascular risk profile. The ratio of leptin and adiponectin has been associated with adipose tissue malfunction. Another hormone secreted by adipose tissue is resistin, a pro-inflammatory adipokine characterized as an insulin antagonist.[34] One study showed that resistin exists in a higher concentration in obese diabetic mice versus those that are lean and not diabetic.[35] Previously conducted studies have demonstrated that exogenously administered resistin translates to an increase in the endogenous production of glucose in rodents and an increased amount of overall plasma glucose.[36][37] 

A key difference in resistin production in different species is that humans produce adipokine by only mononuclear cells, such as macrophages and peripheral blood mononuclear cells. In rodents, resistin production can come from both macrophages and adipocytes.[37] Fukuhara et al. identified a new novel adipose tissue cytokine called visfatin.[38] This cytokine is a protein mediator secreted by fat cells (high levels of expression in visceral fat cells), which acts like the enzyme nicotinamide phosphoribosyltransferase (Nampt), which is involved in the NAD+ salvage pathway. Initially, it was identified as a Pre- B cell Colony Enhancing Factor (PBEF) secreted by human peripheral blood lymphocytes.[39] Visfatin has an insulin-mimetic effect originally discovered in the liver, skeletal muscle, and bone marrow as a growth factor for B lymphocyte precursors.[40] 

The concentration of visfatin in circulation is positively correlated with the amount of white adipose tissue (WAT). There are a number of other hormones and cytokines produced by adipose tissue. We still do not know the role of increased cytokine production in obesity. We can only speculate that there must be mechanisms operating within and from the adipose cell to maintain or restore energy homeostasis in a situation of excessive energy storage. There should be a regulatory mechanism constituted by the local production of these cytokines to stop lipid-loaded adipocytes from storing more lipids. The problem arises when this becomes a systemic chronic state from a local reaction when the inflammatory response cannot be resolved due to sustained obesity. The mechanisms between obesity and chronic inflammation are not completely understood, but different likely explanations have been proposed.

Clinical Significance

Multiple organ systems maintain metabolic homeostasis. Adipose tissue and muscles are a few of them. Adipocytes secrete hormones/chemicals known as adipokines which act on multiple cells or organs to regulate metabolism. Further research needs to be done to understand better the concentrations of these hormones in different populations, including elderly and overweight/obese people, and the role these hormones play in obesity.

It is also important to understand how lifestyle choices such as dietary intervention, regular exercise (aerobic or resistance), supplementation, or combination of any of these affect adipokines/hormones concentrations so there is a better insight into their regulation and pathophysiology.

Enhancing Healthcare Team Outcomes

Having a better understanding of the pathophysiology of obesity is important to all the health professionals involved in curbing obesity. To manage and prevent obesity requires an interprofessional healthcare team to be involved in patient management, such as physicians, nurses, nutritionists, dieticians, and exercise physiologists.

As is known, obesity is an autoimmune disease and a chronic low-grade inflammation, and the inflammatory markers secreted by adipose tissue in an obese person lead to other chronic diseases such as hypertension, diabetes, dyslipidemia, and cancer or worsen them, prevention is better than cure. To prevent obesity, the interprofessional team needs to educate patients regarding diet and exercise as a lifestyle change. To make it happen, every interprofessional team member, including clinicians, mid-level practitioners, nurses, dieticians, and pharmacists, needs to understand the pathophysiology of obesity and its consequences to contribute from their specialties and drive better patient outcomes. [Level 5]