Genetic obesity: an update with emerging therapeutic approaches

Abstract

Based on the genetic contribution, childhood obesity can be classified into 3 groups: common polygenic obesity, syndromic obesity, and monogenic obesity. More genetic causes of obesity are being identified along with the advances in the genetic testing. Genetic obesities including syndromic and monogenic obesity should be suspected and evaluated in children with early-onset morbid obesity and hyperphagia under 5 years of age. Patients with syndromic obesity have early-onset severe obesity associated specific genetic syndromes including Prader-Willi syndrome, Bardet-Biedle syndrome, and Alstrom syndrome. Syndromic obesity is often accompanied with neurodevelopmental delay or dysmorphic features. Nonsyndromic monogenic obesity is caused by variants in single gene which are usually involved in the regulation of hunger and satiety associated with the hypothalamic leptin-melanocortin pathway in central nervous system. Unlike syndromic obesity, patients with monogenic obesity usually show normal neurodevelopment. They would be presented with hyperphagia and early-onset severe obesity with additional clinical symptoms including short stature, red hair, adrenal insufficiency, hypothyroidism, hypogonadism, pituitary insufficiencies, diabetes insipidus, increased predisposition to infection or intractable recurrent diarrhea. Identifying patients with genetic obesity is critical as new innovative therapies including melanocortin 4 receptor agonist have become available. Early genetic evaluation enables to identify treatable obesity and provide timely intervention which may eventually achieve favorable outcome by establishing personalized management.

Physiological Appetite Regulation and Bariatric Surgery

“…The hormone α-MSH is an agonist of the melanocortin-4-receptors (MC4R), found in the paraventricular nucleus. The MC4R receptor has anorectic activity [ 6 , 12 ]. AgRP inhibits the MC4R agonist activity of melanocortin peptides ( Figure 1 a–c).…”

“…Options available are (i) GLP-1 analogues, (ii) MC4R agonists, and (iii) recombinant leptin. These drugs are reviewed extensively elsewhere [ 12 , 231 ].…”

Adipose Tissue Hyperplasia and Hypertrophy in Common and Syndromic Obesity—The Case of BBS Obesity

“…Syndromic obesity is characterized by a significant heterogeneity and is linked to various molecular mechanisms, such as chromosomal abnormalities (e.g., aneuploidies, microdeletions, duplications, and rearrangements), trinucleotide repeats, imprinting alterations, and monogenic mutations [175]. Over 140 distinct syndromes associated with obesity have been identified, with more than half of them being mapped to specific chromosome regions or locations that involve a causative gene [187,218]. While relatively uncommon, the discovery of genes related to syndromic obesity provides valuable insights for screening and treating common forms of obesity.…”

The genetics of obesity: A narrative review

“…Patients with monogenic obesity gains body weight rapidly starting early infancy, and the velocity of increasing BMI reach to peak during childhood [3]. Therefore, clinicians should suspect monogenic obesity when patients have extreme obesity (BMI ≥ 120% of the 95th percentile or ≥ 35 kg/m 2 ) during childhood, fast weight gain in the first several years after birth, with hyperphagia [6]. Patients with monogenic obesity can have additional clinical manifestations, such as short stature, red hair, susceptibility to infection, recurrent diarrhea, or endocrine defects, including pituitary insufficiencies, diabetes insipidus, adrenal insufficiency, hypothyroidism, or hypogonadism [3,6].…”