Obesity: prevalence and genetics
Obesity is associated with an increased probability of premature death. Obesity is recognised as a risk factor for major chronic diseases, thus becoming an important threat to public health [1, 2].
Based on the latest data from the NCD Risk Factor Collaboration (NCD-RisC), the prevalence of obesity has tripled in the last four decades and, if current trends continue, it is expected that 1 billion adults (almost 20% of the world population) will be obese by 2025 [3].
Classically, obesity was distinguished into two categories: monogenic obesity, alterations in a single gene are causative of the condition, it is typically rare, early and severe; polygenic obesity (known as common obesity), the result of a multitude of polymorphisms contributing to the development of obesity [3].
Although often considered two distinct forms, today, thanks to extensive genomic studies, we talk about a very similar basic biology. In particular, genes expressed at the level of the central nervous system (CNS) seem to play a key role for both forms of obesity [4].
Furthermore, a relevant fact concerns the leptin-melanocortine pathway, which is an appetising control circuit [5, 6].
Precision medicine and obesity
There are two “tailored” treatments for obesity.
The first treatment concerns the administration of recombinant human leptin in patients who are leptin-deficient due to variants that fall at the level of the LEP gene (Leptin encoding for leptin). Under physiological conditions, circulating leptin binds to the leptin receptor in the brain, which activates downstream signaling pathways that inhibit nutrition and promote energy expenditure [9]. Variants in this gene are associated with obesity [7, 8]. Congenital leptin deficiency is rare and currently 63 cases have been reported [10]. Leptin replacement therapy is remarkably useful for these patients: it improves quality of life, reducing food intake, body weight and fat mass and normalizes endocrine functioning [7, 8].
The second treatment for obesity is administration of setmelanotide, a selective agonist for MC4R (melanocortin receptor 4). MC4R is a component of the leptin-melanocortine pathway that plays a role in regulation of body weight and interacts with adrenocorticotropic hormones and melanocyte-stimulating hormone (MSH) [11].
Setmelanotide has recently been approved by the FDA for the monogenic form of obesity, e.g. Setmelanotide acts as a substitute for MSH absent in patients with pro-opiomelanocortina deficiency (POMC) due to variants in the POMC gene and in patients with leptin receptor deficiency (LEPR) due to variants in LEPR, which is essential for POMC function [12-17].
Conclusion
Although no standard group of genetic tests for obesity is currently available, some scientific institutions, which research centers and pharmaceutical companies, sequence candidate genes known to identify functional variants that can be causative of an individual’s excess body weight, to develop new “ad hoc” preventive and therapeutic strategies.
Bibliografy
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