Not All Obesity is the Same: Rare Genetic Forms of Obesity

Sponsored by Rhythm Pharmaceuticals, Inc.

Obesity is a multifactorial disease that can have a significant detrimental impact on long-term health and well-being. However, not all obesity is the same. General obesity is a subset of obesity that arises from the interactions between an at-risk genetic profile, environmental risk factors (such as physical inactivity, caloric intake, medications, etc.) and socioeconomic status.¹ On the other hand, there are other rare types of obesities resulting from some rare but highly impactful genetic variants or deletions (i.e. Bardet- Biedl Syndrome, POMC deficiency, LEPR deficiency, Prader-Willi Syndrome), or even acquired hypothalamic damage (i.e. acquired hypothalamic obesity) (Figure 1). Rare genetic variants or damage to the hypothalamus can lead to impairment of a critical pathway, the hypothalamic melanocortin-4 receptor (MC4R) pathway, otherwise known as the leptin-melanocortin pathway. This pathway is responsible for regulating hunger and energy expenditure and any impairment in the pathway leads to rare MC4R pathway diseases. ^2-3 It is important to be aware of this unique subset of obesity associated with MC4R pathway diseases as MC4R pathway diseases are likely underdiagnosed and early identification of MC4R pathway diseases is essential for optimal disease management.^4-6

The MC4R signaling pathway regulates hunger, satiety, and energy expenditure, consequently affecting body weight.^7-8 In the hypothalamus, there is a complex interplay between the central and peripheral nervous systems coordinating signaling of the orexigenic agouti-related protein (AgRP) neuron and the anorexigenic Proopiomelanocortin neuron (POMC) and the MC4R-expressing neuron.⁸ Leptin released from peripheral adipose tissue crosses the blood-brain barrier and binds to leptin receptors on POMC and AgRP neurons in the arcuate nucleus of the hypothalamus. This activates the synthesis and release of alpha MSH from POMC neurons which then binds to and activates the MC4 receptor on MC4R-expressing neurons in the paraventricular nucleus to initiate a cascade of neurological signaling that ultimately leads to a suppression of hunger, a decrease in food intake due to increased satiety and an increase in energy expenditure (Figure 2).^7-8 Genetic variants that impair function of genes involved in the MC4R Pathway function, or physical damage to the hypothalamus leads to decreased alpha-MSH and impaired downstream activation of the MC4R pathway. ^7-8 This can result in hyperphagia, a pathological insatiable hunger with impaired satiety, associated abnormal eating behaviors, and obesity.⁹

MC4R pathway diseases caused by rare genetic variants are classified as monogenic or syndromic in nature. ¹⁰ Monogenic obesity refers to obesity due to variants in single genes (e.g. POMC deficiency, LEPR deficiency, PCSK1 deficiency, SRC1 deficiency, SH2B1 deficiency, etc.) along the MC4R pathway. Syndromic obesity refers to obesity that is also due to genetic variants or deletions in the pathway but also associated with additional phenotypes such as organ-specific developmental abnormalities, such as visual impairment, renal anomalies, cognitive impairment, dysmorphic features, etc. (e.g. Bardet-Biedl Syndrome (BBS)).^10-11

Rare Genetic Diseases of Obesity Provider Listing

A patient's diagnostic journey can be complex and may take years. Rhythm Pharmaceuticals, Inc., is helping to shorten this journey by providing patients with a tool to find local specialists who have an understanding of rare genetic diseases of obesity and a desire to manage these complex conditions.

Interested in Participating? Visit RhythmHCPLocator.com

Visit RhythmHCPLocator.com