Andrzej Milewicz1 and Eliza Kubicka1
(1)
Department of Endocrinology, Diabetology, and Isotope Treatment, Medical University, Wroclaw, Poland
Andrzej Milewicz
Email: andrzej.milewicz@umed.wroc.pl
Obesity is defined as the excess of body fat and results from interactions between genes and the environment. The factors contributing to obesity are unsuitable nutrition and food overproduction, poor physical activity, mental stress, psychoemotional disorders, and metabolic and hormonal disturbances [1].
Among gene candidates predisposing to obesity mutations and polymorphism of the gene of insulin receptor, polymorphism of the gene of PPARγ receptor, polymorphism of the gene of glucocorticoid receptor, and polymorphism of the gene of β3-adrenergic receptor are mentioned [2–5].
To evaluate obesity, body mass index (BMI) is useful (BMI = body weight in kg and high m2 ratio). Obesity is diagnosed when BMI is above 30 kg/m2, whereas overweight is when BMI is above 25 kg/m2. Also fatty tissue percentage (>25 % of body mass in males and >30 % in females) is useful in obesity evaluation. To estimate fat distribution, waist-to-hip ratio (WHR, >1.0 in males and >0.8 in females) and waist circumference (>80 cm in females and >94 cm in males) can be used. More accurate methods used to evaluate fat mass are dual-energy X-ray absortiometry and computed tomography.
In order to evaluate abdominal fat, a dual-energy X-ray absorptiometry (DXA) is used where androidal deposit is assessed at L2–L4 level [6]. The “gold standard” to determine the visceral and subcutaneous abdominal fat is through computer tomography. The evaluation is performed at the level of the intervertebral lumbar disc L4–L5 [7].
The adipose tissue is not only a fat storage but also an active endocrine organ which produces and secretes many hormones and protein factors and plays an important role in metabolic homeostasis. Adipocytes contain over 20 hormone receptors and products or release numerous protein and non-protein substances which play a significant role in the immune system (TNFα, Il-6, TGFβ), blood pressure (angiotensinogen), blood coagulation (PAI-1), glycemic homeostasis (adiponectin, resistin, visfatin, leptin), and angiogenesis (VEGF) [8].
The visceral adipose tissue (VAT) differs from the subcutaneous fat (SCAT) anatomically, hormonally, and metabolically; excessive amount of the former type has been postulated as the key causative factor for metabolic disturbances. Visceral fat is characterized by high density of β-adrenergic, resistin, androgen, and glucocorticoid receptors, which impair insulin sensitivity. Adipocytes in this localization are also resistant to insulin lipogenic effects and more lipolytic. Additionally, adipocytokines are released directly to the portal venous system and influence and affect carbohydrates and lipids metabolism. Visceral fat may enhance truncal SCAT lipolysis as well. Production of inflammatory markers (IL-6) and prothrombotic factors (PAI-1) is higher in visceral adipose tissue than in subcutaneous adipose tissue.
Preadipocytes of the subcutaneous adipose tissue have a greater differentiation and may replenish VAT. Localized subcutaneous adipocytes secrete relatively more atheroprotective adiponectin and leptin while less resistin compared to that of visceral adipose tissue cells, which leads to insulin sensitivity improvement is associated with female phenotype characterized by higher subcutaneous fat accumulation.
Fat distribution depends on gender, age, and ethnicity. For example, Asian and Japanese people have lower deposits of the visceral fat than Caucasians. In men, visceral fat deposits reach 20 % of the whole fat pool; in pre-menopausal women, from 5 to 8 %.
Depending on the body fat distribution and metabolic disturbances presence, there may be mentioned healthy controls, healthy obesity, obesity with metabolic disorders, and obesity with metabolic disorders and normal weight people.
Depending on biological age and gender (20–35 % in women, 29 % in men), more often in women and elderly ones, people with a BMI >30.0 kg/m2 show the metabolic healthy obesity (MHO) phenotype without insulin resistance, dyslipidemia, or hypertension. MHO people have waist circumference ≤80 cm, adipose tissue mass >35 %, fasting glucose level <100 mg/dl, serum triglycerides level ≤150 mg/dl, HDL cholesterol >50 mg/dl, and blood pressure ≤130/85 mmHg. Fat accumulates mainly in the region of the hips, buttocks, and thighs with slim waist. This phenotype is characterized by the early development of obesity (before 20 years of age, in 13 % – already in childhood) and increased subcutaneous fat content, excluding the pathological deposition of fat in the liver, muscles, and visceral area. Histologically fatty tissue in people with MHO is characterized by decreased size and number of adipocytes. A relationship between the onset and duration of obesity and insulin sensitivity of tissues as the adaptation mechanism has been postulated [9]. In individuals with this obesity phenotype, an excess of energy delivered with food is directed to subcutaneous fat deposits and/or burnt in the hepatic mitochondria or the muscles. Therefore, the positive energy balance does not increase risk of metabolic disorders. The significantly elevated subcutaneous fat deposit and its ratio to visceral fat deposit reveals protective effect against atherosclerosis and metabolic syndrome [10, 11]. The candidate genes postulated to these modifications are endocanabinoid receptor gene (CNR1), 1 adiponectin receptor gene (ADIPOR1), and hepatic lipase factor 1 (LIPC-OMIM 15167) [12]. Individuals with this phenotype reveal increased physical activity compared with those with obesity with metabolic disorders and more advantageous effect on waist circumference. Differences in the diet of individuals with this obesity phenotype have not been evaluated [13, 14]. The epidemiological study with 5440 participants in the National Health and Nutrition Examination Surveys 1999–2004 did not reveal an increase in the number of stroke episodes or cardiovascular diseases in individuals with MHO in relation to people with normal BMI on follow-up [15]. Observation is recommended because people with MHO who change their physical activity and dietary habits may lead to metabolic syndrome. In therapy, only increase of physical activity is recommended [16].
Metabolic obesity with normal weight (MONW) affects 13–18 % of women aged 20–60. Due to the lack of visible abnormalities, this is difficult to identify. Very often, it is diagnosed in women with polycystic ovary syndrome. In the pathogenesis of these disturbances, increased expression of 11β-hydroxysteroid dehydrogenase type 1 can be suggested [17]. From other abnormalities, in people with MONW, decreased energy use after effort was observed, as well as pathological storage of fat in muscles and liver with decreased storage of fat in subcutaneous adipose tissue. The increased hepatic lipase expression is also postulated [18].
People with MONW have some metabolic disturbances like fasting glucose level ≥100 mg/dl, serum triglycerides level ≥150 mg/dl, HDL cholesterol ≤50 mg/dl, and hypertension ≤130/85 mmHg despite normal anthropometric parameters: waist circumference ≤80 cm, BMI ≤25 kg/m2, adipose tissue mass ≤35 % [19, 20]. In the DXA, abdominal fat deposit increased in these subjects in relation to the control group of healthy individuals (Fig. 14.1) [21].
Fig. 14.1
Abdominal to gynoid deposit ratio (A/G ratio) in different obesity phenotypes of postmenopausal women. Abbreviations: MONW, metabolic obesity with normal weight; MHO, metabolic healthy obesity; OWMD, obesity with metabolic disorders
Serum level of atheroprotective adiponectin in subjects with metabolic healthy obesity is significantly higher in comparision with those with obesity with metabolic disorders; likewise, serum level ofadiponectin in control subjects with normal weight without metabolic disturbances is higher in comparison with those with metabolic obesity with normal weight (Fig. 14.2).
Fig. 14.2
Serum level of adiponectin (μg/ml). * p < 0.001
The adipose tissue distribution is connected with three main obesity phenotypes: “healthy” obesity, obesity with metabolic disorders, and metabolic obesity with normal weight. The excessive visceral fat deposit and the pathological storage of fat in muscles and liver play a key role in metabolic disorders.
The occurrence of metabolic disorders and higher visceral fat deposit in these patients qualifies for lifestyle modification and pharmacotherapy. Who should be treated then? These should be patients with diagnosed obesity with metabolic disorders and metabolic obesity with normal weight. Clinical indictaions fot treatment are waist circumference >80 cm in females and >94 cm in males, BMI >30.0 kg/m2, adipose tissue mass >35 %, fasting glucose level ≥100 mg/dl, serum triglycerides level >150 mg/dl, HDL cholesterol in females <50 mg/dl and in males <40 mg/dl, and hypertension >130/85 mmHg. Metformin is recomended in pharmacological theraphy. There are data that metformin induces alterations in the body composition: reduces total fat tissue mass by 7 % and visceral fat mass by 15 %.
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