The MC4 pathway is a key signaling pathway that can independently regulate energy homeostasis (the body’s energy balance) and appetite. The critical role of the MC4 pathway in weight regulation was validated with the discovery that single genetic defects along this pathway result in early-onset and severe obesity (defined as a body mass index (BMI) of greater than 40 kg/m2).
An expanding set of severe obesity genetic defects are now identified that involve genes in the pathway that are either upstream of the MC4 receptor (MC4R)—specifically, POMC (proopiomelanocortin) deficiency obesity, LEPR (leptin receptor) deficiency obesity, and Prader-Willi syndrome (PWS)—or genes that are downstream of MC4R or that affect MC4R itself. While the downstream genetic defects affect a greater number of people, the upstream genetic defects that completely block the MC4 pathway are known to result in particularly severe disorders.
Leveraging new understanding of these genetic causes and mechanisms underlying severe obesity opens opportunities to improve diagnosis of these patients and to develop innovative new targeted therapies that improve long-term outcomes.
POMC (proopiomelanocortin) deficiency obesity is an ultra rare genetic disorder with severe, early-onset obesity and profound hyperphagia as hallmark clinical features. POMC deficiency obesity results from two different homozygous genetic defects that result either in loss of POMC neuropeptide synthesis or disruption of the required processing of the POMC neuropeptide product to melanocyte-stimulating hormone (MSH). The first disorder involves a loss-of-function defect in the POMC gene itself, where the lack of the POMC gene expression and absence of POMC-derived neuropeptides ultimately results in lack of stimulation of downstream MC4 neurons. This form of POMC deficiency may also be associated with hormonal deficiencies, such as hypoadrenalism, and red hair and fair skin are also common in this disorder. The second genetic defect results from the need for the POMC protein product to be processed by the PCSK1-processing enzyme. The end result of these two defects is the lack of MSH that binds and activates MC4R, leading to severe, early-onset obesity and profound hyperphagia.
POMC deficiency is characterized by voracious infant feeding, rapid weight gain, and severe obesity, often in early infancy, with patients demonstrating remarkable weight increases many standard deviations above the normal weight growth curves.
LEPR (leptin receptor) deficiency also causes hyperphagia and severe, early-onset obesity and can also be associated with mild alterations in immune function, delayed puberty and short stature. Under normal conditions, leptin can activate POMC neurons and the downstream MC4 receptor gene, but like other deficiencies upstream in the MC4 pathway, lack of signaling at LEPR results in loss of function in the MC4 pathway. Therefore, patients with this indication also manifest intense hyperphagia and severe obesity from early childhood.
POMC heterozygous deficiency obesity is caused by the loss of one of the two genetic copies of either the gene for POMC or the gene for PCSK. Animal models support that such heterozygous deficiency in the critical MC4 pathway can result in a strong predisposition to severe obesity.
The effect of heterozygous deficiency was first demonstrated in MC4 heterozygous deficiency obesity (described below). POMC heterozygous deficiency obesity also results in a strong predisposition to obesity, though the epidemiology and clinical characterization of these patients is less well known. It is thought that the obesity of patients with POMC heterozygous deficiency may have a broader spectrum of severity than POMC deficiency obesity.
Prader-Willi Syndrome (PWS), a form of genetic MC4 pathway deficiency, is a life-threatening orphan disease with prevalence estimates ranging from approximately one in 8,000 to one in 52,000, with at least 8,000 diagnosed patients in the U.S. A hallmark of PWS is severe hyperphagia, an overriding physiological drive to eat, which leads to severe obesity as well as behavioral and metabolic complications. PWS patients also exhibit intellectual disability and delayed growth.
The genetics of PWS are complex, involving several genes on chromosome 15 that are not properly expressed. Recent discoveries highlight that a defect in one of these, the melanoma antigen family L2 (MAGEL2) gene, impairs the function of POMC neurons, which are key components of the MC4 pathway. Studies have suggested a link between defects in MAGEL2 in humans with obesity, hyperphagia, autism spectrum disorders, reduced intellectual ability, and most other aspects of behavior and metabolism associated with PWS.
For PWS patients, obesity and hyperphagia are the greatest health threats, and these patients often die at a young age from related complications. Hyperphagia has a significant negative impact on the patients’ quality of life as well as causing obesity and a range of associated co morbidities.
Consistent with POMC heterozygous deficiency, MC4 heterozygous deficiency results in a strong predisposition to early-onset and severe obesity. These patients have a higher risk than the general population for early-onset obesity and complications such as diabetes. Furthermore, MC4 deficiency may offset the beneficial effects of diet and exercise for sustained weight loss, limiting treatment options for these individuals.