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Introduction to Obesity and Obesity-Related Diseases

Iskandar Idris

The past few decades have seen an exponential rise in the prevalence of overweight and obesity, affecting approximately 1.9?billion adults who were overweight, and of these, 650?million were obese. As such, in 2016, 39% of adults were overweight and 13% were obese worldwide. Alarmingly, this global trend in the prevalence of obesity is projected to rise further with trends of weight gain also reported for children and adolescents. Recent data from the World Health Organization (WHO) have estimated that 40?million children under the age of 5 years were overweight or obese in 2018, and over 340?million children and adolescents aged 5-19 were overweight or obese in 2016. Due to the related threat to public health, the WHO declared obesity a global epidemic, which in many cases remains to be an under-recognised problem within the public health agenda.

Overweight and obesity are defined as abnormal or excessive fat accumulation that may impair health. Body mass index (BMI) is used as a simple index to classify overweight and obesity in adults and is defined as a person's weight in kilograms divided by the square of his height in meters (kg?m-2). WHO defines overweight and obesity as follows (Figure 1.1):

For adults aged (18 years or over):

• overweight is a BMI greater than or equal to 25 or >23 in Asians; and
• obesity is a BMI greater than or equal to 30.

For children under five years of age (Figure 1.2):

• overweight is weight-for-height greater than 2 standard deviations above WHO Child Growth Standards median; and
• obesity is weight-for-height greater than 3 standard deviations above the WHO Child Growth Standards median.

Overweight and obesity are defined as follows for children aged between 5 and 19?years:

• overweight is BMI-for-age greater than 1 standard deviation above the WHO Growth Reference median; and
• obesity is greater than 2 standard deviations above the WHO Growth Reference median (Figure 1.3).

While BMI is widely used to classify overweight and obesity, intra-abdominal and subcutaneous fat accumulation around the abdomen (central, abdominal and visceral) is known to be associated with higher risks for cardiometabolic diseases, independent of BMI when compared with fat accumulation in the subcutaneous regions of hips, thighs and lower trunks (gluteofemoral, peripheral, gynoid, lower body or pear-shaped obesity) - the later considered to be less harmful or even protective against cardiometabolic complications (Figure 1.4).

Obesity is therefore neither just a cosmetic consideration nor simply a risk factor, but rather needs to be considered to be a disease state in its own right. Since obesity is associated with high relapse rate (most people who lose weight regain the weight within five years), obesity should also be considered to be a chronic relapsing and progressive disease, when untreated, it can be a leading risk factor for global deaths. In the United States, approximately 112?000 deaths per year were directly related to obesity, and most of these deaths occurred in patients with a BMI of more than 30. Once patients BMI exceed 40, their life expectancy is significantly reduced. Obesity can progressively cause and/or exacerbate a variety of co-morbidities, such as type 2 diabetes mellitus (T2D), hypertension, dyslipidaemia, cardiovascular disease (CVD), liver dysfunction, respiratory and musculoskeletal disorders, sub-fertility, psychosocial problems and certain types of cancer. The risk of developing a number of obesity-related co-morbidities rises exponentially with increasing BMI over 30?kg?m-2 (Figures 1.5 and 1.6).

Figure 1.1 Adults Aged (18 Years or over); overweight is a BMI greater than or equal to 25 or >23 in Asians; and obesity is a BMI greater than or equal to 30.

Figure 1.2 Charts and tables: WHO child growth standards for children aged under 5 years.

Obesity and Type 2 Diabetes Mellitus

Type 2 diabetes mellitus (T2D) accounts for up to 90% of all types of diabetes cases in adults and is strongly associated with overweight and/or obesity. The parallel rise in T2D and obesity has been seen worldwide; hence, the term 'diabesity' has been introduced to describe this twin epidemic. An important pathogenic feature that links obesity and T2D is insulin resistance, thought to be driven by abnormal production of deleterious inflammatory cytokines from visceral adipose tissues. These inflammatory cytokines, such as interleukins (IL), tumour necrosis factors (TNF)-a, monocyte chemotactic protein (MCP)-1 and PAI-1, are also responsible for the increased risks of cardiovascular diseases seen in individuals who are obese or insulin resistant. Indeed, insulin resistance correlates positively to visceral fat accumulation, which constitutes an independent risk factor for T2D. Accordingly, anthropometric indices of central obesity, such as waist circumference, waist-to-height ratio and the visceral adiposity index, are better indicators of cardiovascular disease risks in people who are obese or with T2D (Figure 1.7).

Figure 1.3 Charts and tables: WHO growth reference for children aged between 5-19 years.

Figure 1.4 Classification of waist circumference threshold that would increase risks of cardio-metabolic diseases in broad ethnic groups.

Figure 1.5 Co-morbidities associated with obesity.

Insulin resistance alone however is not sufficient for the development of T2D. This is because the pancreas has the capacity to compensate by increasing both beta-cell mass and insulin secretion to maintain normoglycaemia. Obesity contributes to premature failure of beta-cells and impaired insulin secretion through various glucotoxic and lipotoxic effects on the pancreatic beta-cells and the liver. The twin-cycle hypothesis describes the mechanism of obesity-induced T2D, where beta-cell lipotoxicity results in the impairment of insulin secretion. This induces hyperglycaemia, which in turn causes hyperinsulinemia. This, in tandem with muscle insulin resistance and calorie overload, causes increased liver and pancreatic fat accumulation, which in turn drives hepatic insulin-resistance and beta-cells lipotoxicity, respectively. This mechanism provides the basis for the role of significant calorie restriction (by means of very low calorie diet) to restore beta-cell function and potentially reverse T2D (Figure 1.8).

Figure 1.6 Relationship between body mass index (BMI) and mortality.

Source: Adapted from Calle et al. (1999).

Figure 1.7 Production of cytokines which drives insulin resistance and pro-atherogenic state in obesity.

Figure 1.8 The twin cycle hypothesis of the aetiology of obesity-induced type 2 diabetes.

Source: Adapted from Taylor (2013).

Obesity and Atherosclerosis

By virtue of the various pro-inflammatory cytokines described previously, increased adiposity is associated with activation of multiple pro-inflammatory signalling pathways that are linked to atherosclerotic risks. Obesity is also characterised by increased levels of fibrinogen and plasminogen activator inhibitor-1 (PAI-1), both of which induce a pro-coagulant state that further accelerates atherogenic processes in obesity. These obesity-related pro-inflammatory pathways mediate deleterious cardiometabolic effects that can lead to various clinical manifestations of the metabolic syndrome. Metabolic syndrome refers to a constellation of metabolic abnormalities, such as glucose intolerance, dyslipidaemia and hypertension, which frequently cluster together (by more than just chance), mediated and linked together by insulin resistance. All these metabolic disorders are recognised risk factors for cardiovascular disease (Figures 1.9 and 1.10).

Figure 1.9 Criteria for metabolic syndrome.

Figure 1.10 Obesity is associated with the metabolic syndrome and a chronic low-grade inflammatory state with increased risk of cardiovascular disease.

Obesity and Non-Alcoholic Fatty Liver Disease

Increased adiposity may cause hyperinsulinemia and hyperglycaemia, which generates ectopic fat accumulation and insulin resistance in the liver. Subsequent impairment of hepatic function results in a spectrum of hepatic abnormalities collectively known as non-alcoholic fatty liver disease (NAFLD). This could range from an initial modest elevation of circulating liver enzyme levels, simple local inflammation (steatosis), to more severe liver diseases, such as non-alcoholic...