Obesity is defined as a common chronic disorder of excessive body fat and has become a global epidemic which is present not only in the industrialized world but also in many developing and even in underdeveloped countries. At present, the prevalence of obesity (defined as body mass index [BMI] ≥30kg/m²) is in the range 15–30% in the adult populations in Europe, North America and in many Arabic countries, with an unequivocal trend for further increases [1]. This condition increases the risk of developing a variety of adverse consequences to human health ranging from metabolic disturbances including type 2 diabetes mellitus (T2DM) and cardiovascular complications to disorders of the locomotor system and many types of cancer [2]. In addition, obesity impairs the subjective quality of life in affected people and can reduce life expectancy [3]. Although there is a very specific close relationship between excessive body weight and the risk of diabetes, the presence of obesity may induce many other disturbances that may aggravate the diabetic state.

A large body of clinical data consistently demonstrates a close relationship between body fat mass and the risk of diabetes. It is noteworthy that in contrast to other obesity-associated metabolic disturbances, the diabetes risk already increases in the upper normal range of BMI. This has been shown for both men and women. In the prospective Nurses’. Health Study, women in the upper normal range with a BMI of 23.0–24.9 kg/m² had a four- to fivefold increased risk of developing diabetes over a 14-year observation period compared with women with a BMI of <22kg/ m². In women with a BMI of 29.0–30.9 kg/m² the risk of diabetes was 27.6-fold higher than in the lean reference group. Almost two-thirds of newly diagnosed women with T2DM were obese at the time of diagnosis [4]. Similar observations were made for males in the Health Professionals’ Study [5]. Moreover, changes in body weight also predicted the risk of diabetes. Weight gain in women after the age of 18 of 11.0–19.9kg, which is the average range of weight change between adolescence and menopause in industrialized countries, was found to be associated with a 5.5-fold higher risk of diabetes compared with weight-stable women, whereas weight reduction of the same extent reduced the risk of diabetes by about 80% [4]. Very similar data were reported for men [5]. A recent analysis of the EPIC Potsdam cohort revealed that a weight gain of 1 BMI unit between the age of 25 and 40 years increased the relative risk of T2DM by 25% and had a greater effect than the same weight gain between 40 and 55 years of age [6]. It is also important to note that the duration of obesity has a strong impact on the risk of developing T2DM.

It is well known from family, adoption and twin studies that obesity, like T2DM, has a strong genetic basis. In the classic adoption study by Stunkard et al. [10] there was no resemblance between the adult BMI of adopted Danish children and the BMI of the adopting parents, but a significant correlation to the BMI of the biologic parents, especially to the BMI class of the biologic mother. In a twin study of obesity, concordance rates for different degrees of overweight were twice as high for monozygotic twins as for dizygotic twins. This high heritability for BMI was seen at the age of 20 years and to a similar extent at a 25-year follow-up, suggesting that body fatness is under substantial genetic control [11]. There is also a very close correlation in monozygotic twins who were reared apart, also indicating a high heritability of the BMI trait. In a recent study of 5092 twins living in the London area, the authors estimated the heritability of BMI and waist circumference as 0.77, further supporting the strong effect of the genetic components irrespective of the force of the obesogenic environment [12].

During the last decade, a number of monogenic disorders that result in human obesity have been uncovered. These genetic disorders were only found in rare cases, however, usually children and adolescents with early onset of obesity. At present, a variety of homozygous and compound heterozygous mutations have been described in the leptin–melanocortin signaling pathway, some of them with functional consequences resulting in human obesity. Functional mutations in the melanocortin-4-receptor gene are considered to be the most frequent cause of monogenic obesity in children with a frequency of 2–4% of all obese cases. It is striking that these defects affect genes that are involved in the central control of food intake [13].

Recent genome-wide association (GWA) studies in large cohorts with BMI as phenotype reported common genetic variants on various chromosomes. These polymorphisms predisposing to obesity at the population level are also largely related to central pathways of food intake [14–16]. Thus, human obesity may represent a heritable neurobehavioral disorder that is highly sensitive to environmental conditions, especially an energy-dense palatable foods which are abundantly available in many societies [13]. Despite these remarkable advances in our understanding of the genetic factors related to obesity, the effect size of most of the novel “obesity genes” is rather modest. Only individuals who are homozygous for the high-risk allele of the FTO gene weigh on average 3 kg more than individuals with two low-risk alleles [14]. The gene is encoding a 2-oxoglutarate-dependent nucleic acid demethylase which is mainly expressed in the brain and in the arcuate nucleus of the hypothalamus [17]. Among the almost 20 gene variants found in GWA studies so far, variants near to the FTO and the MC4R gene appear to have the strongest effect size on body weight. All other recently discovered gene polymorphisms influence body weight by far less than 1 kg.

Thus, it is apparent from recent work that obesity represents a rather heterogeneous disorder in terms of genetic background and susceptibility to etiologic environmental factors. In addition, the risk for developing co-morbidities including T2DM may strongly depend on the individual genetic predisposition towards such diseases. In the case of T2DM, the lifetime risk of developing this disease is about 30% in the white North American population and similar in other ethnic groups [18]. It is currently assumed that only those obese subjects who exhibit a genetic failure of the pancreas to compensate for insulin resistance, which is a characteristic consequence of obesity, will develop T2DM [19]; even among severely obese subjects (BMI ≥40kg/m²) only 30–40% will develop diabetes throughout life. Thus, the development of T2DM requires the presence of “diabetes genes” which probably limit β-cell function.

A new component that may have a major role in the development of obesity and T2DM is the modification of gene expression by epigenetic mechanisms during fetal life. Although this is still a poorly defined phenomenon and it is rather unclear which mechanisms may underlie this association, there is some clue that epigenetics may also operate in this context. Observational studies suggest that infants of mothers with gestational diabetes are at increased risk of developing childhood obesity [20]. In another study, siblings born after the mother had developed gestational diabetes (i.e. exposed to diabetes in utero) have a much greater risk of T2DM in young adulthood than siblings not exposed to diabetes in utero (odds ratio 3.7; P = 0.02) [21].

Another interesting clinical observation is that excessive weight gain during pregnancy, independent of initial BMI, may also increase the risk of early development of obesity in the offspring [22,23]. It is speculated that both hyperglycemia and chronic overnutrition during pregnancy may cause fetal hyperinsulinemia, hypercortisolemia and hyperleptinemia. These hormonal changes may result in a persisting malprogramming of hypothalamic centers controlling energy homeostasis and metabolism, thereby increasing the lifetime risk for obesity and T2DM and possibly the risk for other adverse long-term health consequences [24]. The mechanisms mediating these effects are largely elusive, but it is speculated that epigenetic processes such as DNA methylation, histone modification and changes of the microRNA pattern are involved. Animal experiments suggest that this imprinting process may mainly affect central neuroendocrine pathways which may finally modify appetite regulation [24].

Irrespective of the strong genetic influence on body weight, there is also no doubt that the evolving worldwide epidemic of obesity is primarily a consequence of substantial changes in the environment and lifestyle (see Chapter 8). It is rather new to mankind that food is abundant in many countries and that physical activity is no longer a prerequisite for survival. These dramatic changes in environment and the subsequent changes in lifestyle have occurred within a few decades, a period probably too short to result in adaptations of the genetic background and biologic systems to optimize survival. To date, the relative contributions of the various environmental factors to the epidemic of obesity are hard to quantify in detail and there exist considerable differences between populations.

Humans, like other mammals, are characterized by a tight control of energy homeostasis allowing a stable body weight to be maintained. This setpoint of body weight can vary substantially among individuals and may also vary across lifetime. A complex regulatory system controls energy homeostasis which involves central pathways and peripheral components such as the size of adipose tissue which is sensed to the brain via the secretion of leptin. In addition, gut hormones, signals from the gastrointestinal nervous system and nutrients signal to the brain and induce a complex central integration according to the dietary intake and nutrient requirements of the organism. Central pathways are the anorexigenic leptin–melanocortin link and the orexigenic NPY–AgRP pathway. Many other factors such as insulin modify these signaling processes and thereby influence energy balance [25]. This complex and potent homeostatic system also serves to defend body weight against a critical energy deficiency but also against chronic overnutrition. Several adaptive systems are known to restore the initial body weight under such fluctuations of energy intake and expenditure. This may explain why obese humans exhibit a strong tendency to regain weight after intentional dietary weight reduction. The same tendency to return to initial body weight is observed after experimental overfeeding.

The role of energy homeostasis in the development of obesity has been elaborated by previous studies using indirect calorimetry to investigate the contribution of the resting metabolic rate (RMR) to the risk of obesity. In a study of Pima Indians, RMR was found to be a familial trait and to vary considerably across families [26]. In prospective studies in American Indians, a reduced rate of energy expenditure assessed in a respiratory chamber turned out to predict body weight gain over a 2-year follow-up period. This finding was confirmed in another group over a 4-year-follow-up period in the same paper, indicating that a low rate of energy expenditure may contribute to the aggregation of obesity in families [27]. At present, the genetic components for these differences in energy metabolism are still unknown.

T2DM is characterized by an impaired insulin action or a defective secretion of insulin or both. Both defects are thought to be required for the manifestation of the disease and both are present many years before the clinical onset of the disease. To date, the mechanisms by which obesity increases the risk of developing T2DM are only partly understood and the evolving picture is getting more and more complex. The main adverse effect of obesity is on the action of insulin, particularly in liver, muscle and adipose tissue, but obesity also affects insulin secretion. Substantial advances have been made over recent years in our understanding how an excessive fat mass, but also chronic over-nutrition, may cause metabolic disturbances resulting in overt T2DM in those with a genetic predisposition for the disease.

Lipids and insulin resistance

The earliest hypothesis to explain the relationship between obesity and T2DM is the “glucose–fatty acid cycle” which is based on the observation of a competition between glucose and fatty acid oxidation in the heart muscle and was introduced by Randle et al. [35]. The increased supply of non-esterified fatty acids from expanded adipose tissue depots competes with glucose utilization, particularly in muscle, which represents the organ that oxidizes the largest proportion of glucose. The proposed mechanism is an inhibition of the glycolytic enzymes pyruvate dehydrogenase, phosphofructokinase and hexokinase. As a consequence, the rate of glucose oxidation is reduced and glucose concentrations rise. The concomitant increased fatty acid turnover is accompanied by an increased release of glycerol from adipose tissue which is reutilized for hepatic glucose production, further augmenting the imbalance of glucose metabolism. Increased hepatic glucose output is another early disturbance contributing to glucose intolerance.

In addition, it was reported that elevated free fatty acids can directly impair insulin action. Recent studies suggested that obese subjects and those with T2DM have a high intramyocellular lipid accumulation which is an important feature of the insulin-resistant state. Exposure of skeletal muscle to an excessive lipid supply may lead to intramuscular accumulation, not only of neutral fatty acids, but also of lipid-derived metabolites such as ceramide, diacylglycerol and fatty acyl coenzyme A (CoA). This lipid accumulation is associated with coincident disturbances in insulin action mediated by an activation of a serine–threonine kinase cascade leading to serine–threonine phosphorylation of insulin receptor substrate 1 (IRS-1) and IRS-2 which may cause an impairment of insulin signaling including an impaired activation of phosphoinositol-3 kinase and other downstream elements [36]. This condition is also caused and exacerbated by chronic overnutrition with a high dietary fat intake. Thus, the increased availability of fatty acids may be the single most critical factor in disturbing insulin action in obesity.

Lipids and β-cell function