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Obesity is a serious health problem because it is rapidly expanding and at the origin of intense morbidity and mortality, especially due to the diabetes that accompanies it.It is not possible to cure it effectively, except with bariatric surgery, which is highly invasive and with many limitations. Trying to understand the mechanism of this efficacy, the studies point towards the correction of the altered control by the CNS of food intake and energy homeostasis. At the biomolecular level, the possibility of a pharmacological therapy based on the modulation of the post-synaptic receptors of glutamate, in particular of the NMDA GluN2A and GluN2B subunits, is foreseen.
1. Introduction
Diabetes and obesity have been classified as the third and fourth leading health risk factors, respectively, in the world [1]. Their growing prevalence cannot be countered or even limited, and they are considered to be epidemics. Adiposity-based chronic disease is probably the greatest noninfectious epidemic of the 21st century.
2. Why Is the Spread of Obesity So Rapid?
Role of Epigenetics: Development Programming
The cause of the rapid spread of obesity is partly related to the spread of a lifestyle characterized by a marked reduction in physical activity and a high-calorie diet.
However, the main cause is to be found in genetic adaptations [2], which cannot involve a change in the DNA sequence (because this would require a very long time to manifest). Rather, the change involves epigenetic modifications, a hereditary process of gene expression independent of the classical Mendelian laws [3]. Epigenetics causes organisms to adapt during the first phase of fetal development in a manner that renders them able to cope with changes in the environment [4]. In this phase, called development plasticity, epigenetic modifications are known to be of crucial importance in the development of neural circuits responsible for energy homeostasis and in the integration of autonomic reflexes [5][6].
3. How Can Negative Environmental Conditions Influence The Development of Obesity?
According to the theory of development programming [7], maternal conditions cause adaptive epigenetic changes in the fetus that influence the development of its organs, particularly the brain [4], in view of an adverse post-natal environment [8]. Nutritional excesses are among the most important stimuli of negative fetal programming [9]. In the case of obesity, a metabolic aptitude to caloric accumulation is transferred to the unborn child who, in a subsequent environment with abundant food availability, would be predisposed to the obesogenic phenotype (evolutionary mismatch) [4]. This phenotype is transmitted to subsequent generations even in the absence of further environmental stimuli and, indeed, despite their absence (transgenerational effects) [10] (Figure 1).
Figure 1. Maternal obesity and overeating at the origin of epigenetic changes that lead to neurologic-based generational predisposition to obesity.
In animal models, it has also been shown that a change in synaptic activation (synaptic plasticity) is induced in the reward system [4] followed by an inadequate response to the consumption of highly energetic food in concomitance with the pregnancy period [2][11]. This is due to the epigenetic alteration of the expression of dopamine and opioid-related genes present in the mesocorticolimbic circuits [12].
4. How could the dysfunction of energy homeostasis control be responsible for obesity?
The control of energy homeostasis is performed by various brain sectors that interact with each other [13] (Figure 2).