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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 Figure 1: Rare Hypothalamic MC4R Pathway Diseases The MC4R signaling pathway regulates hunger, satiety, and energy expenditure, consequently affecting body weight. 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. 9 Figure 2: Impairment of the MC4R Signaling Pathway 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. 10-11 Rare Genetic Diseases of Obesity Provider Listing A patient's diagnostic journey can be complex and may take years.

Comprehensive obesity management ideally should utilize a spectrum of treatments -- nutrition therapy, physical activity, behavior modifications and medical interventions such as medication management. Medical nutrition therapy is an essential pillar regarding treatment of patients with obesity. Nutrition quality is just as critical as calorie reduction in obesity treatment. By reducing hunger signals, patients may find it easier to adhere to their nutritional goals. The Mediterranean diet, Dietary Approaches to Stop Hypertension (DASH), and plant-forward diets each offer distinct benefits and varying levels of evidence supporting their role in obesity care. Source https://pubmed.ncbi.nlm.nih.gov/32059053/ The Mediterranean diet has the most consistent evidence for weight management and cardiometabolic benefits. The effect of the DASH diet with supervised physical activity decreases body weight, waist circumference, and fat mass. (Source: https://pubmed.ncbi.nlm.nih.go... ) When guiding patients on dietary choices, it is essential to consider cost and accessibility. For clinicians seeking additional guidance, the 2024 OMA Obesity Algorithm—Important Principles for the Effective Treatment of Patients with Obesity is a valuable resource and is free for OMA members.

Obesity is a major risk factor for cardiovascular disease (CVD), contributing to hypertension, dyslipidemia, and metabolic dysfunction. Effective Treatment Strategies for Reducing Cardiovascular Risk A comprehensive approach to obesity treatment can significantly lower cardiovascular risk. Pharmacotherapy plays a critical role in obesity management, particularly for patients at high cardiovascular risk. SGLT2 inhibitors, originally developed for diabetes management, have also shown promise in obesity treatment and cardiovascular protection. These medications offer an innovative approach to obesity and cardiovascular disease management, providing an alternative to or adjunct to traditional lipid-lowering and antihypertensive therapies. The Obesity Medicine Association (OMA) provides a comprehensive Obesity Algorithm® , which outlines individualized treatment strategies, including pharmacologic options tailored to patients with cardiovascular comorbidities. These guidelines reinforce the necessity of an individualized, multidisciplinary approach to obesity management in patients with existing heart disease. Obesity and cardiovascular disease are intricately linked, making obesity management a crucial component of cardiovascular risk reduction. OMA Resources for Clinicians For clinicians seeking to enhance their expertise in obesity and cardiovascular disease management, the Obesity Medicine Association (OMA) offers a variety of resources.

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