Introductory Chapter: An Overview of Metabolic Syndrome and Its Prevention

*Naofumi Shiomi*

### **1. Introduction**

Diseases, including type 2 diabetes, heart disease, hypertension, stroke, chronic renal failure, and nonalcoholic hepatitis, are caused by incorrect diet, irregular lifestyle, and environmental factors. Hence, these diseases are called "lifestyle-related diseases" in Japan. They are characterized by the onset of obesity and the concomitant development of one or more other diseases. In the group with diabetes, the risk of developing hypertension is twice and that of ischemic heart disease is approximately thrice as high. The risk of heart disease augments with an increase in the number of diverse risk factors, including obesity, diabetes, hypertension, hyperlipidemia, and heart disease, poses about 36 times higher risk when 3–4 risk factors are present simultaneously [1]. Furthermore, these diseases are known to enhance the risk of cancer, immunodeficiency, aging, and dementia, which are not directly linked to lifestylerelated diseases [2, 3]. This condition wherein diseases develop one after another, such as domino falling, triggered by obesity, is termed "metabolic syndrome (MetS)" [4].

The number of obese and MetS patients continues to rise not only in developed but also in developing countries with altering diets and environments, and it is reported that 18% of individuals over 19 years of age are obese globally [5]. According to a 2015–2016 survey in the United States, 39.8% of adults were obese, and diabetes and prediabetes rates were 9.4% and 33.9%, respectively [6]. In China, the incidence of MetS has increased by 2% in urban areas over the past decade since 1992, reaching 15.5% in 2017 [7]. According to a study by the Japanese Ministry of Health, Labor, and Welfare, one in two men and one in five women over the age of 40 years fall into MetS and its pre-groups.

In this introductory chapter of the book, I will outline (1) the mechanism of MetS and (2) recent research trends on the effective use of brown and beige adipocytes, which have gained attention as an approach for enhancing MetS reserves.

#### **2. Mechanisms triggering MetS**

White adipose tissue (WAT) predominantly contains white adipocytes that are accountable for triglyceride storage. They also serve as endocrine organs by secreting diverse hormones, including adipokines. More than 10 hormones and miRNAs, including TNF-α, PAI-1, leptin, adiponectin, resistin, apelin, and chemelin, are

adipokines secreted by white adipocytes [8]. These act as paracrine and perform crosstalk with nerves and several organs to help control blood glucose and lipid levels [8, 9]. When normal body weight is maintained, the ratio of progenitor cells to white adipocytes is balanced and adipokines aid to control them with insulin. However, if excessive intake of sugar and fat pursues, progenitor cells differentiate into white adipocytes, which then enlarge and attain their fat storage limit. Under such conditions, adipokines are irregularly secreted by white adipocytes, that are unable to transmit their signals appropriately [10]. WAT hypertrophy and abnormal adipokine secretion, resulting in mild chronic inflammation and insulin resistance, cause MetS development.

Insulin resistance is defined as the inhibition of insulin-mediated signaling pathways, resulting in a hyperglycemic state. The mechanisms of insulin resistance associated with obesity are complex; however, the following are believed to be the major factors [8, 11, 12]. Due to tissue hypertrophy in obese subcutaneous fat, macrophage infiltration occurs through chemokines, including CCL2, triggering inflammation. Macrophages differentiate into M1 macrophages, which activate innate immunity and generate inflammatory mediators. Inflammatory adipokine secretion from hypertrophic WAT also augments. TNF-α and IL-6, inflammatory adipokines, activate inhibitory molecules, including SOCS and JNK, which suppress IRS and inhibit insulin signaling causing insulin resistance. Furthermore, PIP3 is degraded by phospholipid phosphatases, including PTEN, and stresses the endoplasmic reticulum, diminishing its function and inhibiting GLUT-4 migration to the plasma membrane.

Insulin resistance augments free fatty acids (FFAs) throughout the body, which strongly affect inflammation and insulin resistance [13]. The resulting ectopic deposition of FFAs in muscles and the liver results in serine phosphorylation in IRS-1, which inhibits insulin signaling. FFAs also activate the NF-κB pathway and induce inflammation. Ectopic deposition of FFA also elevates diacylglycerol levels in the liver, resulting in reduced hepatic glycogen synthesis. Conversely, white adipocytes secrete anti-inflammatory adipokines, including leptin, adiponectin, and apelin. Apelin promotes insulin sensitivity, glucose uptake, and lipolysis [14]. Recent studies have implied that obese individuals have elevated levels of leptin and apelin, thus causing resistance to these adipokines.

Persistent insulin resistance leads to abnormal glucose and lipid metabolism, resulting in high blood glucose and lipid concentrations. In the hyperglycemic state, ketone bodies are synthesized, causing type II diabetes mellitus (T2DM). Additionally, high LDL cholesterol causes adherence of oxidized lipids to blood vessels, which are phagocytosed by macrophages activated by chronic inflammation, creating plaques, thereby causing atherosclerosis. Hypertrophic WAT increases the secretion of PAI-1, an adipokine that augments blood pressure and causes hypertension. Furthermore, hyperlipidemia, triggered by enhanced FFAs levels, is the source of a variety of other diseases. Although FFAs bind to albumin and other blood proteins and are not toxic, excess FFAs impair the pancreatic mitochondria, causing dysfunction [15] and inability to secrete insulin, resulting in a more advanced form of T2DM. Chronic inflammation and disruption of the immune system cause chronic renal failure (CDK), cancer, and aging [2, 3]. Thus, MetS initiating with obesity leads to a state of insulin resistance and mild chronic inflammation, which in turn triggers consecutive development of diverse diseases.
