Rare Genetic Forms of Obesity: Clinical Approach and Current Treatments in 2016

Abstract

Obesity results from a synergistic relationship between genes and the environment. The phenotypic expression of genetic factors involved in obesity is variable, allowing to distinguish several clinical pictures of obesity. Monogenic obesity is described as rare and severe early-onset obesity with abnormal feeding behavior and endocrine disorders. This is mainly due to autosomal recessive mutations in genes of the leptin-melanocortin pathway which plays a key role in the hypothalamic control of food intake. Melanocortin 4 receptor(MC4R)-linked obesity is characterized by the variable severity of obesity and no notable additional phenotypes. Mutations in the MC4R gene are involved in 2-3% of obese children and adults; the majority of these are heterozygous. Syndromic obesity is associated with mental retardation, dysmorphic features, and organ-specific developmental abnormalities. Additional genes participating in the development of hypothalamus and central nervous system have been regularly identified. But to date, not all involved genes have been identified so far. New diagnostic tools, such as whole-exome sequencing, will probably help to identify other genes. Managing these patients is challenging. Indeed, specific treatments are available only for specific types of monogenic obesity, such as leptin deficiency. Data on bariatric surgery are limited and controversial. New molecules acting on the leptin-melanocortin pathway are currently being developed.

Fig. 1

The leptin/melanocortin pathway. POMC neurons in the arcuate nucleus are activated by leptin and produce the α-melanocyte stimulating hormone (α-MSH), which then activates the MC4R receptor in the paraventricular nucleus resulting in a satiety signal. A separate group of neurons expressing NPY and AGRP produce molecules that act as potent inhibitors of MC4R signaling. The downstream roles of SIM1, BDNF, and TKRB are currently being explored. AGRP = agouti-related protein; BDNF = brain-derived neurotropic factor; LEPR = leptin receptor; NPY = neuropeptide Y; POMC = proopiomelanocortin; SIM1 = single-minded 1; TRKB = tyrosine kinase receptor.

Fig. 2

Historical steps leading to the discovery of genetic mutations in obesity. ACP1 = acid phosphatase 1, soluble; BBS = Bardet-Biedl syndrome; FTO = fat mass and obesity; GWAS = genome wide scan association study; KSR2 = kinase suppressor of Ras 2; LEP = leptin; LEPR = leptin receptor; MYT1L = myelin transcription factor 1-like; TMEM18 = transmembrane protein 18; TUB = tubby bipartite transcription factor.

Fig. 3

Genetic diagnosis prioritization for severe early-onset obesity [4,5,6,7,20,22,26,36,75]. BDNF = brain-derived neurotropic factor; LEP = leptin; LEPR = leptin receptor; MAGEL2 = MAGE-like 2; MC4R = melanocortin 4 receptor; NTRK2 = neurotrophic tyrosine kinase receptor 2; PCSK1 = proprotein convertase subtilisin/kexin type 1; POMC = proopiomelanocortin; SIM1 = single-minded 1.