21.1

Introduction

• 1.
  

  Obesity has reached epidemic proportions globally and nearly tripled worldwide between 1975 and 2016.

  
  
• 2.
  

  According to the World Health Organisation (WHO) in 2016, more than 1.9 billion adults aged 18 years and older were overweight, and of those over 650 million adults were obese.

  
  
• 3.
  

  Overall approximately 13% of world’s adult population (11% of men and 15% of women) was obese in 2016.

  
  
• 4.
  

  A dramatic rise in overweight and obesity has been reported among children and adolescents aged 5–19 years over the last four decades.

  
  
• 5.
  

  Obesity is a complex condition with serious pathophysiological, social, and psychological implications that affects virtually all ages and socioeconomic groups.

  
  
• 6.
  

  Obesity has a negative impact on fertility as well as causing increased rates of congenital malformations and adverse obstetric outcomes.

  
  
• 7.
  

  Obese women have more saturated subcutaneous fat stores and tend to accumulate fat more centrally than lean women.

  
  
• 8.
  

  Obesity is a state of chronic inflammation, and it is this that is thought to result in the increase in insulin resistance (IR), via modulation of insulin signalling.

  
  
• 9.
  

  Central obesity is associated with metabolic syndrome, including gestational diabetes mellitus (GDM), gestational hypertension, and preeclampsia.

  
  
• 10.
  

  The incidence of preeclampsia has increased (25% rise in the United States) between 1987 and 2004, and in particular there is an increase in severe preeclampsia reported in the United States in parallel with a threefold rise in obesity.

21.2

Classification of body mass index

• 1.
  

  The prevalence of overweight and obesity is commonly assessed by using body mass index (BMI), defined as the weight in kilograms divided by the square of the height in metres (kg/m ² ) ( Table 21.1 ).

  
  
  
  

  Table 21.1

  
  

  The international classification of BMI in adults (WHO classification).

  
  

  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  

  Weight group	BMI range	Additional cut-off
  Underweight	<18.50	<18.50
  Severe thinness	16.00–	<16.00
  Moderate thinness	16.00–17.99	16.00–16.99
  Mild thinners	17.00–18.49	17.00–18.49
  Normal	18.5–24.9	18.50–22.99 23.00–24.99
  Overweight	=/>25.00	=/>25.00
  Preobese	25.00–29.99	25.0–27.99 27.50–29.99
  Obese class 1	>30.00 30.00–34.99	>30.00 30.00–32.99 32.50–34.99
  Obese class 2	35.00–39.99	35.00–37.49 37.50–39.99
  Obese class 3	=/>40.00	=/>40.00

   
  
  

BMI is a relatively simple anthropometric index of total adiposity that does not discriminate between muscle and fat mass.

There is a linear relationship between BMI and some of the adverse metabolic effects on:

• 1.
  

  Blood pressure (essential hypertension and PET)

  
  
• 2.
  

  Cholesterol and triglycerides

  
  
• 3.
  

  IR (GDM and diabetes mellitus T2)

  
  

  However markers of absolute and relative accumulation of abdominal fat, such as increased waist circumference and waist-to-hip ratio are more sensitive.

21.3

Increased disease burden secondary to obesity

21.4

Other comorbidities

• 1.
  

  Ischaemic heart disease

  
  
• 2.
  

  Cerebrovascular disease (stroke, neurodegenerative disease, and cognitive impairment)

  
  
• 3.
  

  Gallstones (nonalcoholic steatohepatitis)

  
  
• 4.
  

  Osteoarthritis

  
  
• 5.
  

  Sleep apnoea

  
  
• 6.
  

  Psychological illness

  
  
• 7.
  

  Impaired physical functioning

21.5

Physiological changes during pregnancy in normal weight women

In normal pregnancy, the first and second trimester is a state of anabolism and in the anabolic phase there is hyperphagia, reduced IR, and increased fat storage.

By late pregnancy there is a catabolic state. IR facilitates increased lipolysis and gluconeogenesis to allow for foetal growth and weight gain.

21.6

First and second trimester of pregnancy

• 1.
  

  All women increase maternal fat stores in early pregnancy irrespective of prepregnancy adiposity.

  
  
• 2.
  

  Total fat appears to increase to a peak towards the end of the second trimester.

  
  
• 3.
  

  During the early to mid-trimester stage of pregnancy, there is an anabolic state where foetal demands are limited, maternal fat stores increase in part to maternal behaviour, hyperphagia, and increased adipose tissue lipogenesis.

  
  
• 4.
  

  Insulin sensitivity is normal or even slightly improved with peripheral sensitivity to insulin and hepatic glucose production.

  
  
• 5.
  

  Lipogenesis and fat accumulation is favoured by pregnancy-related endocrine changes including increasing levels of oestrogen, progesterone, and cortisol.

21.7

Third trimester

• 1.
  

  During late pregnancy, there is a switch to a state of catabolism with a marked increase in lipolysis rates and a corresponding rise in maternal free fatty acids and glycerol.

  
  
• 2.
  

  This change is enhanced by the increased production and activity of hormone-sensitive lipase and a concomitant decrease in lipoprotein lipase activity.

  
  
• 3.
  

  Exaggerated catecholamine release in response to even modest hypoglycaemia contributes to this switch as well.

  
  
• 4.
  

  Insulin’s effect on lipolysis and fat oxidation in liver and muscle are significantly impaired.

  
  
• 5.
  

  Reduced expression of peroxisome proliferative-activated receptor <SPAN role=presentation tabIndex=0 id=MathJax-Element-1-Frame class=MathJax style="POSITION: relative" data-mathml='γ’>𝛾γ
  γ
  (PPAR <SPAN role=presentation tabIndex=0 id=MathJax-Element-2-Frame class=MathJax style="POSITION: relative" data-mathml='γ’>𝛾γ
  γ
  ) and its target genes may also contribute to accelerated fat metabolism.

  
  
• 6.
  

  This primarily lipid-based metabolism in the mother increases availability of glucose and amino acids for the foetus

  
  
• 7.
  

  With advancing gestation, plasma cholesterol, plasma cortisol, and triglyceride concentrations rise by 25%–50%, 100% – 160% (upto 1.6-fold increase), and 200%–400%, respectively.

  
  
• 8.
  

  The increase in triglyceride concentration is mainly due to VLDL triglycerides that show a threefold increase from 14 weeks gestation to late pregnancy.

  
  
• 9.
  

  There is significant triglyceride enrichment of the HDL, intermediate density lipoprotein, and LDL fractions, compared to the accompanying increase in phospholipids and cholesterol in these fractions.

21.8

In normal weight women fat distribution

• 1.
  

  The majority of fat is accumulated centrally in the subcutaneous component of the trunk and upper thigh,

  
  
• 2.
  

  In the later stages of pregnancy, there is an increase in the thickness of preperitoneal fat (visceral) and the ratio of preperitoneal to subcutaneous fat.

21.9

Amino acid metabolism in normal weight women

• 1.
  

  There is an increase in protein synthesis during the second and third trimester of 15% and 25%, respectively, in maternal tissue, including the liver, breast, and uterus.

  
  
• 2.
  

  A grater maternal protein synthesis in the second trimester is associated with an increase in birth length and accounts for 26% of its overall variance.

21.10

Pathological changes in obese women during pregnancy

BMI is a relatively simple anthropometric index of total adiposity which does not discriminate between muscle and fat mass.

• 1.
  

  Visceral adiposity in early pregnancy appears to correlate better than subcutaneous fat or BMI with metabolic risk factors.

  
  
• 2.
  

  In the third trimester, severely obese women have significantly greater abdominal and visceral fat stores compared with lean women.

  
  
• 3.
  

  In obese women, there is excess fat which accumulates in the visceral tissue and organs.

  
  
• 4.
  

  This happens when the adipose tissue has reached the maximum capacity, a spillover of lipid from adipocytes resulting in the increase of circulating free fatty acids.

  
  
• 1.
  

  The accumulation of excess fat happens at the following ectopic sites:

  
  
  
  
  • a.
    

    Visceral adipose tissue

    
    
  • b.
    

    Intrahepatic

    
    
  • c.
    

    Intramuscular

    
    
  • d.
    

    Renal sinuses

    
    
  • e.
    

    Pericardial

    
    
  • f.
    

    Myocardial

    
    
  • g.
    

    Perivascular

  
  
  
  
• 2.
  

  The presence of macrophages together with expression of some inflammatory factors is more frequent in omental fat (visceral) than in subcutaneous peripheral fat.

21.11

There is increased mass of metabolic reactive visceral adipose tissue

• 1.
  

  In visceral fat, there is a higher turnover of lipids due to its greater sensitivity to catecholamine-induced lipolysis and decreased sensitivity to insulin.

  
  
• 2.
  

  Liver is exposed to chronic elevation of nonessential fatty acids, which produce an alteration in liver metabolism and promote hepatic IR.

  
  
• 3.
  

  As obese pregnant women have more saturated subcutaneous fat stores, they tend to accumulate fat more centrally than lean women.

21.12

Hyperlipidaemia

• 1.
  

  Physiological hyperlipidaemia of pregnancy is exaggerated in obese women with higher serum TG, VLDL, cholesterol, and FFA concentration than lean women.

  
  
• 2.
  

  There are lower levels of HDL-cholesterol, although LDL-cholesterol and total cholesterol appear similar.

  
  
• 3.
  

  The ability of insulin to suppress lipolysis is also reduced during pregnancy, leading to a greater postprandial increase in FFA, increased gluconeogenesis, and IR.

21.13

Low-grade chronic inflammation

• 1.
  

  Obesity generally is regarded as a state of low-grade chronic inflammation. This inflammation occurring in metabolically important organs, such as the liver and adipose tissue, has been referred to as “meta-inflammation”.

  
  
• 2.
  

  The mechanism that links inflammation and IR is through activation of the kinase JUN-N terminal kinase which occurs in response to a variety of stress signals, including FFAs, proinflammatory cytokines, and reactive oxygen species.

  
  
• 3.
  

  Recently there has been focus on the unfolded protein response (UPR) to ER stress, which activates apoptotic pathways in stressed cells.

  
  
• 4.
  

  The downstream signalling cascade triggered by UPR has three main arms, which can induce inflammation, influence insulin receptor signalling, and activate apoptosis.

  
  
• 5.
  

  The activities of ER stress pathways in liver, adipose tissue, and skeletal muscle are key factors in the development of IR in these organs.

  
  
• 6.
  

  Energy imbalance leads to adipocytes hypertrophy and hyperplasia, thus causing adipocytes dysfunction.

  
  
• 1.
  

  Adipocyte dysfunction leads to elevated levels of adipokines:

  
  
  
  
  • a.
    

    Low adiponectin

    
    
  • b.
    

    Increased leptin levels

    
    
  • c.
    

    Increased IR

    
    
  • d.
    

    Increased androgen

    
    
  • e.
    

    Increased cortisol

    
    
  • f.
    

    Raised free fatty acids

    
    
  • g.
    

    Increased oxidative stress

    
    
  • h.
    

    Reduced immune cell recruitment

    
    
  • i.
    

    Increased inflammatory cytokines

  
  

Table 21.1 changes secondary to the chronic inflammatory milieu due to visceral obesity .

• 1.
  

  There is an exaggerated inflammatory state which leads to:

  
  
  
  
  • a.
    

    endothelial and vascular dysfunction;

    
    
  • b.
    

    leading to excess lipolysis;

    
    
  • c.
    

    increased triglycerides;

    
    
  • d.
    

    increased free fatty acids; and

    
    
  • e.
    

    low high-density lipoprotein and raised LDL.

  
  
  
  
• 2.
  

  They all contribute to:

  
  
  
  
  • a.
    

    hypertension and atherosclerosis;

    
    
  • b.
    

    cardiac muscle dysfunction;

    
    
  • c.
    

    low levels of apoptosis;

    
    
  • d.
    

    increased cell proliferation; and

    
    
  • e.
    

    carcinogenesis,

  
  
  
  
• 3.
  

  IR leads to:

  
  
  
  
  • a.
    

    low sex hormone binding globulin synthesis;

    
    
  • b.
    

    increased circulatory bio available E2, testosterone and free androgens; and

    
    
  • c.
    

    increased insulin-like growth factor (IgF) leading to cell proliferation and cancer.

  
  

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