ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: Nat Med 2018, May;24(5):551-555

[Comments on 1.1, 1.5, 1.6 and 1.7] All four here presented articles have monogenic obesity as their theme. While patients with monogenic obesity are rare, these individuals bear a heavy disease burden. Furthermore, these rare natural mutations provide us with an intricate insight into the mechanisms of weight regulation. Hence, this is an important topic to study.

First, Kohlsdorf et al. studied the hypothesis that the clinical course could indicate which obese patients to investigate for monogenic obesity. Due to their special cohort, they are able provide us with a reliable and easy to follow suggested cut-offs to suspect a leptin- or leptin receptor deficiency. For simplicity, this is BMI >25kg/m² at age 2 years, and BMI >30kg/m² at age 5 years, which roughly equates to BMI-SDS > 4 at these ages. However, these cut-offs are not applicable for patients with other forms of monogenic obesity, such as heterozygous MC4R mutations. In fact, while some patients with other forms of autosomal-recessive obesity might have comparable early-onset obesity (1), many published cases of monoallelic forms of monogenic obesity show a later and less pronounced increase in BMI (2, 3, 4). For those patients, other cut-offs or indicators for diagnostic work-up have yet to be defined.

Secondly, Saeed et al. tackled another problem in diagnosing patients with monogenic obesity. Even in cohorts with severe early-onset obesity, only 5-10% of patients have a genetic diagnosis identified. In earlier publications, Saeed and other colleagues from Pakistan showed that in a society like in Pakistan, where on the one hand, consanguineous marriages are common, but on the other hand, rates for severe obesity are still low, up to 30% of patients with severe early-onset obesity carry one of the known monogenic obesity variants (5, 6). However, this still leaves 70% undiagnosed. Therefore, here, they performed whole exome sequencing in these patients and in very thorough filtration steps identified homozygous variants in ADCY3. This gene encodes adenylate cyclase 3, a member of a family of 10 related cyclases, catalyzing the synthesis of cAMP from ATP. In genome-wide association studies, an ADCY3 is a known locus for BMI and fat mass (7, 8, 9) and Adcy3 knock-out mice have increased food consumption, reduced physical activity, leptin insensitivity and an age-related increase in adiposity (10). The authors also showed, in at least 3 patients, that their variants led to a reduced cAMP production under stimulation. This is very convincing evidence for a new form of autosomal recessive monogenic obesity. Just as in Adcy3 knock-out mice (11), these 3 patients were also anosmic – a feature that should now be important to assess in patients with severe early-onset obesity. ADCY3 has also been suggested as a new target for anti-obesity drugs (12), making this finding even more relevant.

When initiating molecular diagnostics, the question always arises whether or not the results will be of any benefit to the patient, or more for scientific purposes. It is therefore of special reward to physicians to read about successful intervention-studies. Most forms of monogenic obesity originate from a defect in the leptin-melanocortin pathway leading ultimately to reduced melanocortin-4-receptor (MC4R) activation. However, until very recently, studies of synthetic MC4R agonists failed to significant reduce food intake and body weight, but increased blood pressure and heart rate (13, 14). Then, in 2016, Peter Kühnen and colleagues reported in a seminal publication that patients with pro-opiomelanocortin (POMC)-deficiency were treated very effectively and safely with the MC4R agonist, setmelanotide (15). Two further setmelanotide treatment studies are presented here.

Collet et al. focused on patients with MC4R variants. The MC4 receptor is a seven-transmembrane G-protein coupled receptor. Its activation in turn activates Gαs and increases cAMP production (for review see (16). Collet et al. first thoroughly characterized MC4R variants according to their effects on cAMP production. However, apart from the known observation that biallelic MC4R mutations cause a more severe phenotype (17), they did not find a genotype-phenotype correlation. Next, they examined the ability of setmelanotide in vitro and in vivo to overcome reduced MC4R function. While setmelanotide in vitro stimulated cAMP production, even in loss-of-function mutations, the responses in heterozygous carriers (mice and men) were less than in non-mutation carriers, which is hardly surprising.

Finally, Clément et al. studied a more promising patient group. Patients with leptin receptor mutations lack α-MSH just as much as POMC patients do, hence their response to setmelanotide was similar to that in patients with POMC deficiency. The authors also tried to elucidate the mechanism of action of setmelanotide. As commented above, most earlier research focused on the stimulatory effects of MC4R on cAMP production. However, recent evidence shows that MC4R at least partly promotes satiety via activation of phospholipase C-β (PLC) (18). The authors showed that setmelanotide in vitro increased both cAMP production and PLC activation. In addition, as many of the authors contributed to both intervention studies, Clément et al extended the studies of Collet et al. to show that some MC4R variants, which according to their ability to stimulate cAMP production had been classified as ‘like-wildtype variants’, actually have a reduced ability to activate PLC and this can be rescued by setmelanotide in vitro.

Looking at all four papers together, we can conclude that molecular diagnostics in patients with early-onset obesity is worthwhile as some patients with monogenic obesity can receive a specific treatment. In addition, new diagnostic tools, such as whole exome sequencing, might discover new obesity genes, which in return might inform the development of new anti-obesity drugs. An excellent example is setmelanotide, which represents an extremely promising treatment option for a variety of monogenic disorders with defects upstream of MC4R. Setmelanotide might also be effective for patients with certain MC4R variants, but further research is needed to identify for which variants it is beneficial. Coming back to the first here presented paper, while we now know when to suspect leptin- or leptin receptor deficiency, we need more data to guide diagnostic testing for other forms of monogenic obesity.

1. Krude H, Biebermann H, Luck W, Horn R, Brabant G, Gruters A: Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nature genetics 1998;19:155-157

2. Montagne L, Raimondo A, Delobel B, Duban-Bedu B, Noblet FS, Dechaume A, Bersten DC, Meyre D, Whitelaw ML, Froguel P, Bonnefond A: Identification of two novel loss-of-function SIM1 mutations in two overweight children with developmental delay. Obesity (Silver Spring, Md) 2014;22:2621-2624

3. Holder JL, Jr., Butte NF, Zinn AR: Profound obesity associated with a balanced translocation that disrupts the SIM1 gene. Human molecular genetics 2000;9:101-108

4. Doche ME, Bochukova EG, Su HW, Pearce LR, Keogh JM, Henning E, Cline JM, Saeed S, Dale A, Cheetham T, Barroso I, Argetsinger LS, O’Rahilly S, Rui L, Carter-Su C, Farooqi IS: Human SH2B1 mutations are associated with maladaptive behaviors and obesity. The Journal of clinical investigation 2012;122:4732-4736

5. Saeed S, Butt TA, Anwer M, Arslan M, Froguel P: High prevalence of leptin and melanocortin-4 receptor gene mutations in children with severe obesity from Pakistani consanguineous families. Molecular genetics and metabolism 106:121-126

6. Fatima W, Shahid A, Imran M, Manzoor J, Hasnain S, Rana S, Mahmood S: Leptin deficiency and leptin gene mutations in obese children from Pakistan. Int J Pediatr Obes 2011;6:419-427

7. Stergiakouli E, Gaillard R, Tavare JM, Balthasar N, Loos RJ, Taal HR, Evans DM, Rivadeneira F, St Pourcain B, Uitterlinden AG, Kemp JP, Hofman A, Ring SM, Cole TJ, Jaddoe VW, Davey Smith G, Timpson NJ: Genome-wide association study of height-adjusted BMI in childhood identifies functional variant in ADCY3. Obesity (Silver Spring, Md) 2014;22:2252-2259

8. Warrington NM, Howe LD, Paternoster L, Kaakinen M, Herrala S, Huikari V, Wu YY, Kemp JP, Timpson NJ, St Pourcain B, Davey Smith G, Tilling K, Jarvelin MR, Pennell CE, Evans DM, Lawlor DA, Briollais L, Palmer LJ: A genome-wide association study of body mass index across early life and childhood. International journal of epidemiology 2015;44:700-712

9. Wen W, Cho YS, Zheng W, Dorajoo R, Kato N, Qi L, Chen CH, Delahanty RJ, Okada Y, Tabara Y, Gu D, Zhu D, Haiman CA, Mo Z, Gao YT, Saw SM, Go MJ, Takeuchi F, Chang LC, Kokubo Y, Liang J, Hao M, Le Marchand L, Zhang Y, Hu Y, Wong TY, Long J, Han BG, Kubo M, Yamamoto K, Su MH, Miki T, Henderson BE, Song H, Tan A, He J, Ng DP, Cai Q, Tsunoda T, Tsai FJ, Iwai N, Chen GK, Shi J, Xu J, Sim X, Xiang YB, Maeda S, Ong RT, Li C, Nakamura Y, Aung T, Kamatani N, Liu JJ, Lu W, Yokota M, Seielstad M, Fann CS, Wu JY, Lee JY, Hu FB, Tanaka T, Tai ES, Shu XO: Meta-analysis identifies common variants associated with body mass index in east Asians. Nature genetics 2012;44:307-311

10. Wong ST, Trinh K, Hacker B, Chan GC, Lowe G, Gaggar A, Xia Z, Gold GH, Storm DR: Disruption of the type III adenylyl cyclase gene leads to peripheral and behavioral anosmia in transgenic mice. Neuron 2000;27:487-497

11. Wu L, Shen C, Seed Ahmed M, Ostenson CG, Gu HF: Adenylate cyclase 3: a new target for anti-obesity drug development. Obesity reviews : an official journal of the International Association for the Study of Obesity 2016;17:907-914

12. Diamond LE, Earle DC, Rosen RC, Willett MS, Molinoff PB: Double-blind, placebo-controlled evaluation of the safety, pharmacokinetic properties and pharmacodynamic effects of intranasal PT-141, a melanocortin receptor agonist, in healthy males and patients with mild-to-moderate erectile dysfunction. International journal of impotence research 2004;16:51-59

13. Greenfield JR, Miller JW, Keogh JM, Henning E, Satterwhite JH, Cameron GS, Astruc B, Mayer JP, Brage S, See TC, Lomas DJ, O’Rahilly S, Farooqi IS: Modulation of blood pressure by central melanocortinergic pathways. The New England journal of medicine 2009;360:44-52

14. Kuhnen P, Clement K, Wiegand S, Blankenstein O, Gottesdiener K, Martini LL, Mai K, Blume-Peytavi U, Gruters A, Krude H: Proopiomelanocortin Deficiency Treated with a Melanocortin-4 Receptor Agonist. The New England journal of medicine 2016;375:240-246

15. Tao YX: The melanocortin-4 receptor: physiology, pharmacology, and pathophysiology. Endocr Rev 2010;31:506-543

16. Farooqi IS, Keogh JM, Yeo GS, Lank EJ, Cheetham T, O’Rahilly S: Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. The New England journal of medicine 2003;348:1085-1095

17. Li YQ, Shrestha Y, Pandey M, Chen M, Kablan A, Gavrilova O, Offermanns S, Weinstein LS: G(q/11)alpha and G(s)alpha mediate distinct physiological responses to central melanocortins. The Journal of clinical investigation 2016;126:40-49

18. Wang Z, Li V, Chan GC, Phan T, Nudelman AS, Xia Z, Storm DR: Adult type 3 adenylyl cyclase-deficient mice are obese. PloS one 2009;4:e6979