Ongoing genetic research has helped evolve the understanding of how genes link to obesity. Primary causes such as lifestyle and environment have been and continue to be studied. Still, expansion into the exploration of hormonal and genetic factors adds to the knowledge of what obesity susceptibility means and what effective pharmacology can be developed. Recently the first-ever FDA approval for treatment of several rare genetic disorders of obesity was granted, which is a significant milestone for chronic weight management.
Specialized management is required for genetic causes of obesity. While most forms of obesity do not yet have established therapy, some new treatments are now available for specific genetic mutations. One of these is the newly FDA-approved drug Imcivree (setmelanotide)
, which is a subcutaneous injection used for long-lasting weight management in patients aged 6 years and older who are obese because of a specific enzyme deficiency ([proopiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency]). After being treated with setmelanotide for one year, 80% of patients with POMC or PCSK1 deficiency and 46% of patients with LEPR deficiency achieved at least 10% weight loss. The daily dose of setmelanotide is determined by the weight of the patient. Setmelanotide has been found to cause spontaneous penile erection and changes in sexual arousal that happen without any sexual activity in female patients. Other known side effects include depression and suicidal thoughts or actions, increases in skin pigmentation and darkening of existing skin lesions (moles or nevi), and benzyl alcohol toxicity.
As a melanocortin-4 receptor (MC4R) agonist, setmelanotide has the potential to reestablish pathway activity of energy-regulating MC4R. MC4R-linked obesity is identified by excessive or abnormal fat accumulation with no additional remarkable phenotypes. Recent studies have recorded MC4R gene mutations in nearly 3% of children and adults with obesity, with most identified as heterozygous. The progress being made in understanding genetic obesity mechanisms has shed light on severe obesity and the association with mutations that disrupt the leptin-melanocortin pathway. Interference in pathway signaling can cause POMC deficiency that results in severe obesity very early in life. POMC deficiency can be caused by a variant in the PCSK1
gene, also located on the MC4R pathway. POMC expression is positively regulated by leptin, expressed in the hypothalamus. Addressing irregularities in the MC4R pathway activity can result from the body regulating satiety hormones better, leading to reduced hunger and promotion of weight loss as caloric intake decreases.
Advancements in treatments such as setmelanotide offer a foundation for how to help rare genetic disorders of obesity. Further research and understanding of genetic obesity mechanisms are needed in order to improve the prognosis of rare causes for obesity. Better insight will help physicians identify even more anomalies and expand the comprehension of obesity biology. Learning how genes link to obesity may help treat all forms of the condition, from common to the very rare, and aid in the ways care and health management can be provided for all affected patients.