The Medical Student Notebook: Monogenic Obesity and Bariatric Surgery

by Ann L. Robbins, PhD

Ann L. Robbins, PhD, is a Medical Student, Harvard Medical School in Boston, Massachusetts

Funding: No funding was provided.

Disclosures: The author reports no conflicts of interest relevant to the content of this article.

Abstract: Obesity and its concomitant morbidities have increased in prevalence over recent decades. Investigation into the causes and pathogenesis of this pandemic have revealed several monogenic forms of obesity, including syndromic disorders, such as Prader Willi and Bardet Biedl syndromes and nonsyndromic disorders, which are largely confined to the leptin-melanocortin pathway. Bariatric surgery as a treatment for these disorders has met with mixed success, with studies limited by the rarity of these conditions.

Keywords: Monogenic obesity, Prader Willi, Bardet Biedl, MC4R, leptin-melanocortin, bariatric surgery

Bariatric Times. 2018;15(1): 10–12.

In recent decades, the world has seen expanding waistlines in expanding numbers, and with this, an increased prevalence of metabolic syndrome, a collection of risk factors predisposing toward cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM).^1,2 Within this pandemic, there are patients who are outliers in the development and progression of obesity and insulin resistance. In individuals who have early onset of extreme obesity that is resistant to weight loss attempts, early onset insulin resistance, and a strong family history of these symptoms, obesity may potentially be attributed to a monogenic cause.³ Recent research has focused on these individuals as “experiments of nature,” giving us insight into the physiologic mechanisms of obesity, yet clinical treatments for these patients are often symptomatic in nature.

Monogenic Obesity

Monogenic obesity can broadly be characterized as syndromic or non-syndromic disorders. Syndromic disorders, such as Prader Willi and Bardet Biedel, may include obesity either as a defining or highly associated characteristic of the condition, but the diagnosis of these disorders is often initiated by other signs, namely developmental disabilities, recognized dysmorphic features, and characteristic organ abnormalities.⁴

Nonsyndromic disorders are somewhat more difficult to diagnose because their predominant feature, obesity, is so prevalent. Since the discovery of two leptin deficient children in 1997, investigations into these disorders have focused on the Leptin-Melanocortin pathway and its regulation of appetite and energy homeostasis.⁵ Mutations in leptin (LEP) and its receptor (LEPR), melanocortin 4 receptor (MC4R), pro-opiomelanocortin (POMC), prohormone convertase 1 (PCSK1), brain-derived neurotrophic factor (BDNF), neurotrophic tyrosine kinase receptor type 2 (NTRK2), and single-minded homolog 1 (SIM1) have all been shown to influence appetite and weight gain.^6,7 Leptin is a hormone secreted by adipose tissue which, when bound to its receptor in the arcuate nucleus of the hypothalamus, signals satiety through the melanocortin axis.^7,8 MC4R is a receptor in this axis, and POMC encodes the precursor polypeptide that acts on this receptor, which must first be processed by PCSK1.^5,9 BDNF, its receptor NTRK2, and SIM1 are known downstream targets of MC4R signaling, yet their exact actions are still being elucidated.^10–13

Because mutations in these genes affect neurological development, developmental and cognitive delays can also be associated, blurring the line between syndromic and non-syndromic conditions. Of clinical note, leptin deficiency results in the most severe form of monogenic childhood obesity, and MC4R mutations are thought to be the most common cause of genetic obesity.^7,14,15 Treatment of leptin deficiency is through replacement of the hormone, which has met with great success in these patients.¹⁶ Treatment of other monogenic forms of obesity, however, are more general in nature and include treatment of underlying metabolic syndrome, lifestyle interventions, diet, exercise, and bariatric surgery.³ Pharmacologic therapy targeting the Leptin-Melanocortin pathway in the hypothalamus is still developing; at this time, the genotype of obesity has not guided recommendations for clinical decision making.³

Bariatric Surgery as Treatment

Patients with mutations in MC4R have undergone weight loss surgery, including Roux-en-Y gastric bypass, sleeve gastrectomy, and gastric banding.³ In patients with heterozygous MC4R mutations, reported results were comparable to wild type MC4R patients, with 60 percent excess weight loss reported following gastric bypass and 48 percent excess weight loss reported following gastric banding, although these results are from small cohorts.^3,17–19

Further reports in this field have been hampered by the scarcity of clinical subjects; one of the largest prospective cohort studies to examine gastric banding on multiple patients with heterozygous MC4R mutations was performed in adolescents, and additional reports are often single case studies or retrospective analyses.^3,17–19 Despite successful weight loss in patients with heterozygous MC4R mutations, homozygous loss of gene function is associated with resistance to weight loss following bariatric surgery, as reported in animal models and a case report of a single adult patient.²⁰

In other forms of monogenic obesity, bariatric surgery has met with mixed success; several case reports of patients with LEPR mutations undergoing gastric bypass or vertical gastroplasty have reported some limited success at weight loss, whereas patients with some syndromic obesities, such as Prader Willi and Bardet Biedl Syndromes, report successful weight loss and significant improvement in associated comorbidities.^3,21–23

For the vast majority of the bariatric population who cannot trace their obesity to a monogenic cause, these studies may also yield important prognostication on their surgical outcome. Through genome wide association studies, we have begun to appreciate the polygenic nature of obesity, and the Leptin-Melanocortin pathway has been implicated.⁵ Future studies may reveal how variants in the genes of this pathway can predispose to obesity, and the effects these genotypes have on treatment.

References

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Tags: Bardet Biedl, bariatric surgery, leptin-melanocortin, MC4R, Monogenic obesity, Prader Willi

Category: Medical Student Notebook, Past Articles