5 183 C Poitou and others Treatments in genetic obesity 183:5 R149–R166 Review MECHANISMS IN ENDOCRINOLOGY Update on treatments for patients with genetic obesity C Poitou1,2, H Mosbah1 and K Clément1,2 1Assistance Publique-Hôpitaux de Paris, Reference Center for Rare Diseases (PRADORT, Prader-Willi Syndrome and Correspondence Other Rare Forms of Obesity with Eating Behavior Disorders), Nutrition Department, Pitié-Salpêtrière Hospital, Paris, should be addressed France and 2Sorbonne Université, INSERM, Nutrition and Obesity: Systemic Approaches (NutriOmics) Research Unit, to K Clément Paris, France Email [email protected] Abstract Obesity, defined by an excess of body fat impacting on health, is a complex disease resulting from the interaction between many genetic/epigenetic factors and environmental triggers. For some clinical situations with severe obesity, it has been possible to classify these obesity forms according to the molecular alterations. These include: (i) syndromic obesity, which associates severe early-onset obesity with neurodevelopmental disorders and/or polymalformative syndrome and (ii) non-syndromic monogenic obesity, due to gene variants most often located in the leptin- melanocortin pathway. In addition to severe obesity, patients affected by these diseases display complex somatic conditions, eventually including obesity comorbidities, neuropsychological and psychiatric disorders. These conditions render the clinical management of these patients particularly challenging. Patients’ early diagnosis is critical to allow specialized and multidisciplinary care, with a necessary interaction between the health and social sectors. Up to now, the management of genetic obesity was only based, above all, on controlling the patient's environment, which involves limiting access to food, ensuring a reassuring daily eating environment that limits impulsiveness, and the practice of adapted, supported, and supervised physical activity. Bariatric surgery has also been undertaken in genetic obesity European Journal of Endocrinology cases with uncertain outcomes. The context is rapidly changing, as new innovative therapies are currently being tested both for syndromic and monogenic forms of obesity. This review focuses on care management and new therapeutic opportunities in genetic obesity, including the use of the melanocortin 4 agonist, setmelanotide. The results from ongoing trials will hopefully pave the way to a future precision medicine approach for genetic obesity. European Journal of Endocrinology (2020) 183, R149–R166 Invited Author’s profile Karine Clément (MD, PhD) is a Medical Doctor and Full Professor of Nutrition at Pitié- Salpêtrière hospital and Sorbonne University, Paris. Since 2002, her research unit at INSERM (www.nutriomique.org) works on the pathophysiology of obesity and related disorders. From 2011 to 2016, she created and was the director of the Institute of CardiometAbolism and Nutrition (ICAN). Prof Clément has been primarily involved in genetics of obesity and contributed to the identification of monogenic forms of obesity. Her group is also exploring the link between environmental changes (as changes in lifestyle and nutrition), gut microbiota, immune system and tissue functional modifications (adipose tissue fibrosis and inflammation). https://eje.bioscientifica.com © 2020 European Society of Endocrinology Published by Bioscientifica Ltd. https://doi.org/10.1530/EJE-20-0363 Printed in Great Britain Downloaded from Bioscientifica.com at 09/30/2021 01:43:16PM via free access -20-0363 Review C Poitou and others Treatments in genetic obesity 183:5 R150 Introduction body composition, with increased fat mass and reduced muscle mass (4), endocrine abnormalities (growth Technological advances in recent years, such as candidate hormone deficiency, hypogonadism), intellectual gene approaches, next-generation sequencing (NGS), impairment, and learning difficulties, as well as behavioral genome-wide association studies (GWAS), and expression disorders, and dysmorphic traits (5). The evolution of studies using microarrays, have led to the discovery PWS from childhood to adulthood is often marked by of hundreds of genes involved in the development of the development of severe obesity, mostly associated with obesity. There is a proposed continuum between obesity a switch from difficulties eating to uncontrolled eating due to polygenic inheritance, the most common form, behavior. Of note this critical period in the developmental in which the environment has a critical impact on the trajectory is markedly influenced by the nature of the phenotypic development, and the rare forms of genetic patient’s environmental care (i.e. provided by caregivers) obesity, which are often severe and show an early onset, and implemented specialized care. In other words, early with a predominant contribution of genetic factors. and closely implemented care can limit the severity of These genetic forms are now considered to represent uncontrolled eating and the development of obesity (6). approximately 5–10% of childhood severe obesity (1). PWS is linked to abnormal parental genomic imprinting As it is described elsewhere (2), we will not describe in with the physical or functional absence of chromosomal detail the clinical progression of obesity from childhood segment 15q11–q13 of paternal origin. The 15q11.2– to adulthood that may give rise to the suspicion of genetic q13 region contains a PWS domain with five paternally obesity and lead to its molecular diagnosis (2). However, it expressed protein-coding genes including MRKN3 should be noted that early-onset obesity (before 6 years of (makorin 3), MAGEL2 (MAGE-like 2), NDN (necdin), age) associated with eating disorders, endocrine anomalies NPAP1 and SNURF-SNRPN (SNRPN uptream reading (hypogonadism, growth abnormality), and/or signs specific frame-small nuclear ribonucleoprotein polypeptide N) of the syndromic form, such as neurodevelopmental and snoRNAs (7). disorders, should alert clinicians and lead to molecular The BBS phenotype is also heterogeneous with testing. Thus, after summarizing the clinical pictures, we autosomal recessive transmission. In addition to severe present the latest advances concerning new therapies that early-onset obesity, patients may show retinal dystrophy, have been developed over the past several years that have polydactyly, kidney abnormalities, hypogonadism, made it possible to propose effective solutions to patients dysmorphia, and learning disabilities. At least 19 genes with genetic obesity. are involved in BBS, all linked to functioning of the European Journal of Endocrinology primary cilium (8). Hair cells are critical for properly functioning cellular machinery and are used to transmit Clinical subtypes of genetic obesity signaling messages from the outside to the inside of cells. Hair cells are also involved in mammalian development, Syndromic obesities (ORPHANET code 240371) are contributing, in particular, to right/left symmetry. The defined as obesity starting early in childhood linked precise mechanisms involved in obesity development to eating behavior disorders and associated with a in BBS are still poorly understood. However, several neurodevelopmental disorder (intellectual impairment, hypotheses have been put forward (9, 10). One proposes a delayed walking, delayed learning, autism spectrum central origin of obesity due to hypothalamic dysfunction disorders) and/or malformative syndrome. More than 80 associated with hyperphagia. For example, the loss of syndromes have been described but not all of them have BBS proteins leads to synaptic aberrations in principal an identified genetic substratum (3). We briefly summarize neurons, especially in structures such as the hippocampus the main phenotypic traits for the most common and amygdala (11). Other hypotheses of a peripheral syndromes sharing physiopathological characteristics origin involving adipose tissue and adipocyte proliferation related to hypothalamus impairment. or other endocrine tissues (pancreas, stomach, intestine) PWS, of which the frequency is between 1/15 000 have also been proposed (10). to 1/20 000 births, is characterized by severe neonatal The 16p11.2 microdeletion syndrome is a disorder hypotonia, eating disorders evolving in several phases caused by a deletion of a small piece of chromosome (from anorexia with suckling disorders in the first months 16, detectable by chromosomal microarray analysis. of life to hyperphagia, with major food impulsivity People with 16p11.2 deletion syndrome usually have appearing at approximately 4–8 years of age), abnormal developmental delay, intellectual disability, and early-onset https://eje.bioscientifica.com Downloaded from Bioscientifica.com at 09/30/2021 01:43:16PM via free access Review C Poitou and others Treatments in genetic obesity 183:5 R151 obesity. The prevalence is estimated to be approximately may depend in part on the environment and the influence 3 in 10 000. In a large cohort of patients with a 16p11.2 of other genes. These forms of obesity account for at least deletion syndrome, satiety was impaired in children 5% of the causes of early and severe obesity (19), but before the onset of obesity occurring in adolescence (12). this prevalence is probably underestimated and may be Among genes encompassed by this deletion, the SH2B1 higher in certain populations, especially those in which gene is involved in regulation of leptin signalization in consanguinity is frequently observed (16, 20, 21). Patients