Effects of Heterozygous Variants in the Leptin-Melanocortin Pathway on Roux-en-Y Gastric Bypass Outcomes: a 15-Year Case–Control Study

Campos, Alejandro; Cifuentes, Lizeth; Hashem, Anas; Busebee, Bradley; Hurtado-Andrade, Maria D.; Ricardo-Silgado, Maria Laura; Mcrae, Alison; Rosa, Alan De la; Feris, Fauzi; Bublitz, Joshua T.; Hensrud, Donald D.; Camilleri, Michael; Kellogg, Todd A.; Eckel‐Passow, Jeanette E.; Olson, Janet E.; Acosta, Andrés

doi:10.1007/s11695-022-06122-9

Cited by 25 publications

(15 citation statements)

References 46 publications

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“…Our results support already published scientific articles [36,37], and indicate that genetic testing could be useful to predict the outcome of bariatric surgery, and that patients with predicted deleterious variants to genes correlated to obesity could respond less to bariatric surgery.…”

Section: Discussionsupporting

confidence: 88%

“…Moreover, in the preoperative assessment phase of bariatric surgery, genetic tests may be useful in identifying patients that will be responsive to bariatric surgery, as well as in choosing the most suitable bariatric procedure [33][34][35]. Indeed, it has been demonstrated that the variants causing monogenic obesity may be associated with reduced postoperative weight loss, especially variations in genes involved in the leptinmelanocortin pathway [36,37]. Moreover, several international guidelines on bariatric surgery intervention recognize the importance of genetics in obesity onset [38][39][40].…”

Section: Introductionmentioning

confidence: 99%

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Next-Generation Sequencing of a Large Gene Panel for Outcome Prediction of Bariatric Surgery in Patients with Severe Obesity

Bonetti

Dhuli

Ceccarini

et al. 2022

JCM

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Obesity is a chronic disease in which abnormal deposition of fat threatens health, leading to diabetes, cardiovascular diseases, cancer, and other chronic illnesses. According to the WHO, 19.8% of the adult population in Italy is obese, and the prevalence is higher among men. It is important to know the predisposition of an individual to become obese and to respond to bariatric surgery, the most up-to-date treatment for severe obesity. To this purpose, we developed an NGS gene panel, comprising 72 diagnostic genes and 244 candidate genes, and we sequenced 247 adult obese Italian patients. Eleven deleterious variants in 9 diagnostic genes and 17 deleterious variants in 11 candidate genes were identified. Interestingly, mutations were found in several genes correlated to the Bardet–Biedl syndrome. Then, 25 patients were clinically followed to evaluate their response to bariatric surgery. After a 12-month follow-up, the patients that carried deleterious variants in diagnostic or candidate genes had a reduced weight loss, as compared to the other patients. The NGS-based panel, including diagnostic and candidate genes used in this study, could play a role in evaluating, diagnosing, and managing obese individuals, and may help in predicting the outcome of bariatric surgery.

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Section: Discussionsupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Next-Generation Sequencing of a Large Gene Panel for Outcome Prediction of Bariatric Surgery in Patients with Severe Obesity

Bonetti

Dhuli

Ceccarini

et al. 2022

JCM

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“…The weight regain after maximum weight loss was also greater in heterozygous patients with 52.7±29.7 kg compared to 29.8±20.7 kg for non-carriers. These data show a lower long-term efficiency of RYGB in heterozygous variant carriers secondary to more weight regain, possibly due to eating behavior disorders ( 83 ). These results were consistent with a former retrospective genetic analysis in 131 obese adults who underwent SG surgery, showing that the 10 patients carrying heterozygous variants in the leptin-melanocortin pathway had less weight loss over both the short-term and long-term ( 84 ).…”

Section: Bariatric Surgerymentioning

confidence: 86%

Current Treatments for Patients with Genetic Obesity

Faccioli¹,

Poitou²,

Clément³

et al. 2023

Jcrpe

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Obesity derives from impaired central control of body weight, implying interaction between environment and an individual genetic predisposition. Genetic obesities, including monogenic and syndromic obesities, are rare and complex neuro-endocrine pathologies where the genetic contribution is predominant. Severe and early-onset obesity with eating disorders associated with frequent comorbidities make these diseases challenging. Their current estimated prevalence of 5-10% in severely obese children is probably underestimated due to the limited access to genetic diagnosis. A central alteration of hypothalamic regulation of weight implies that the leptin-melanocortin pathway is responsible for the symptoms. The management of genetic obesity has so far been only based, above all, on lifestyle intervention, especially regarding nutrition and physical activity. New therapeutic options have emerged in the last years for these patients, raising great hope to manage their complex situation and improve quality of life. Implementation of genetic diagnosis in clinical practice is thus of paramount importance to allow individualized care. This review describes the current clinical management of genetic obesity and the evidence on which it is based. Some insights will also be provided into new therapies under evaluation.

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“…With a broader overview of mutations affecting components along the MC4R pathway, a study included 50 carriers, who were matched based on sex, age, BMI, and years since surgery with 100 non-carriers. 122,123 The study showed that individuals with heterozygous variants experienced progressive and significant weight regain in the mid and long term following RYGB. Similarly, in a case-control study analysing outcomes of transoral outlet reduction due to weight regain after RYGB, carriers exhibited decreased weight loss after undergoing this procedure.…”

Section: Bariatric Surgerymentioning

confidence: 99%

“…The study suggested incorporating genetic testing into the preoperative protocols prior to bariatric surgery, especially for patients with severe early‐onset obesity. With a broader overview of mutations affecting components along the MC4R pathway, a study included 50 carriers, who were matched based on sex, age, BMI, and years since surgery with 100 non‐carriers 122,123 . The study showed that individuals with heterozygous variants experienced progressive and significant weight regain in the mid and long term following RYGB.…”

Section: Treatment Of Monogenic Obesitymentioning

confidence: 99%

The melanocortin‐4 receptor pathway and the emergence of precision medicine in obesity management

Fansa,

Acosta

2024

Diabetes Obesity Metabolism

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Over the past few decades, there has been a global surge in the prevalence of obesity, rendering it a globally recognized epidemic. Contrary to simply being a medical condition, obesity is an intricate disease with a multifactorial aetiology. Understanding the precise cause of obesity remains a challenge; nevertheless, there seems to be a complex interplay among biological, psychosocial and behavioural factors. Studies on the genetic factors of obesity have revealed several pathways in the brain that play a crucial role in food intake regulation. The best characterized pathway, thus far, is the leptin–melanocortin pathway, from which disruptions are responsible for the majority of monogenic obesity disorders. The effectiveness of conservative lifestyle interventions in addressing monogenic obesity has been limited. Therefore, it is crucial to complement the management strategy with pharmacological and surgical options. Emphasis has been placed on developing drugs aimed at replacing the absent signals, with the goal of restoring the pathway. In both monogenic and polygenic forms of obesity, outcomes differ across various interventions, likely due to the multifaceted nature of the disease. This underscores the need to explore alternative therapeutic strategies that can mitigate this heterogeneity. Precision medicine can be regarded as a powerful tool that can address this concern, as it values the understanding of the underlying abnormality triggering the disease and provides a tailored treatment accordingly. This would assist in optimizing outcomes of the current therapeutic approaches and even aid in the development of novel treatments capable of more effectively managing the global obesity epidemic.

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Effects of Heterozygous Variants in the Leptin-Melanocortin Pathway on Roux-en-Y Gastric Bypass Outcomes: a 15-Year Case–Control Study

Cited by 25 publications

References 46 publications

Next-Generation Sequencing of a Large Gene Panel for Outcome Prediction of Bariatric Surgery in Patients with Severe Obesity

Next-Generation Sequencing of a Large Gene Panel for Outcome Prediction of Bariatric Surgery in Patients with Severe Obesity

Current Treatments for Patients with Genetic Obesity

The melanocortin‐4 receptor pathway and the emergence of precision medicine in obesity management

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