Professor Martin Wabitsch from Ulm University Hospital has been studying the genetic causes of obesity for quite some time. The discovery of another cause of this complex condition that has key clinical consequences was recently published in the renowned New England Journal of Medicine. Despite the internationally acknowledged success of this research and in contrast to the view of the World Health Organisation and scientific organisations, the health ministry and health insurance companies in Germany still refuse to recognise the condition as a disease.
Wabitsch, who is also the president of the German Adiposity Association, criticises the German stance as political blindness. The scientist believes that this view has terrible consequences, and amongst other things, will continue to contribute to the current and future stigmatisation of obese children and adolescents.
In a case study of an extremely obese little boy, the Ulm researchers showed that the boy produced and secreted the appetite-suppressing hormone leptin in a normal way. However, the protein was rendered ineffective (bioinactive) due to an amino acid substitution (aspartic acid was replaced by tyrosine) that alters the proteohormone in such a way that prevents it from binding to and activating the leptin receptor. This turned out to be the reason for the boy's extreme obesity. The little boy already weighed over 40 kilogrammes at the age of three. Wabitsch's discovery was a scientific success. It also meant that he could start treating the child with recombinant leptin, with the result that the child started eating less and lost weight.
The paediatricians in Wabitisch's group (Paediatric Endocrinology and Diabetology at Ulm University Hospital) are currently treating eight obese patients with leptin deficiency caused by different mutations in the leptin gene (Funcke 2004). A diagnostic test that detects functional, bioactive leptin that can bind to recombinant leptin receptors was recently placed on the market. This antibody-based immunoassay was developed by the Reutlingen-based company Mediagnost in cooperation with Dr. Wabitsch.
The discovery has far-reaching consequences: textbooks, guidelines and recommendations will need to be revised. The medical examination of extremely obese people is currently based on the determination of their blood leptin concentrations. High leptin concentrations suggest that people, including the little boy from Ulm, have sufficiently high levels of this hormone and are usually not treated with synthetic leptin.
Childhood obesity is a major medical issue. Over the past forty years, the prevalence of obesity in children has increased dramatically, reaching epidemic proportions. In developed countries, this affects over 5% of all children. Wabitsch was unable to find a syndromal or monogenic cause of the disease, and therefore suggested a polygenic one. Recessive genetic diseases such as that related to bioinactive leptin are very rare. Mutations in only a few genes are known to lead to the development of severe obesity in early childhood. Most of these genes are involved in the central nervous regulation of hunger and satiety, where leptin and its receptor play a pivotal role. Leptin plays an important role in fat metabolism; it informs the brain about the body's fat content (and hence energy stored) and is therefore regarded as a signal for the regulation of body weight.
Wabitsch explains that his group's findings suggest that obesity is a disease resulting from a fault in a specific feedback loop. Klaus-Michael Debatin, director of the Children's Hospital in Ulm, sees the discovery of bioinactive leptin as groundbreaking because it could also mean that immunological and oncological diseases might result from a signalling molecule's failure to bind to a receptor. Current medical tests do not take this possibility into account.
The changing fortunes of the recombinant human leptin that is now being used to successfully treat the young patient from Ulm make for a rather interesting story. Shortly after its discovery in humans in 1996, the pharmaceutical industry started promoting recombinant leptin as an appetite suppressant for obese people. However, the drug turned out to be ineffective in many individuals due to their resistance to leptin. The biotechnology company Genentech sold the development, which has subsequently changed hands three times. The American company Aegerion acquired the drug in 2014 and has since been selling it as a treatment for lipodystrophy, a medical condition characterised by the loss of adipose tissue. The eight patients that Wabitsch is currently treating are representatives of the target group for which the human leptin analogue was developed and produced.
Martin Wabitsch has long been convinced that obesity is to a considerable extent ("well over 50 percent") determined by an individual's genetic material. His assumptions have now been substantiated by a Nature paper published by an international team of researchers (GIANTS; Genetic Investigation of Anthropometric Parameters) that conducted a meta-analysis of body mass index (BMI). The consortium, including groups from Germany, identified 56 new gene loci that are associated with BMI development. Not long after that (11th March 2015), the BMBF-funded Internet portal biotechnologie.de concluded that the influence of genetic factors on BMI accounted for 40 to 70 percent, and is therefore much higher than previously assumed.
"Although obesity is a complex disease, it is already quite well understood," says Wabitsch. In general, only people who are predisposed to obesity become extremely overweight. Obesity is excellent confirmation of the observation that environmental factors can alter our genetic expression. And our modern, inactive lives no doubt favour the development of obesity. He also highlighted that the prevailing idea that controlling appetite and body weight depends purely on an individual's willpower is completely mistaken.
Body weight is regulated by a complex, closed feedback loop, at least in adults. "It is most likely still open in children, which is why it can still be modulated," says Wabitsch. Body weight, like other parameters, requires homeostatic regulation to maintain a constant internal balance. The hypothalamus in the brain maintains the body's internal balance. However, there is also what is known as cognitive-emotional regulation, i.e. a combination of willpower and hedonistic stimuli and processing. A person can – at least temporarily – control his/her weight by way of the cognitive-emotional system. However, in the medium to long term, this is not possible because the body tries to maintain a constant internal environment (homeostasis), and hence also weight. A large number of hormones is involved in this process.
Wabitsch highlights that a person's homeostatic weight control system is fundamentally important as it is essential to the survival of individuals and the species. In evolutionary terms, this system needs to be resistant to change and kept within a normal range in order to ensure physical function. This is why people find it difficult to lose weight. If an individual tries to lose weight, the body will always try to return to its previous weight. Maximum willpower and a complete change of lifestyle is the key to lasting weight loss.
Body weight is not only determined by a person's genetic make-up, but also by pregnancy and during early childhood: a study carried out by the Ulm researchers ("Ulmer Kinderstudie") showed that the environment in which children grow for nine months before birth plays a key role in their future health. The study showed amongst other things that the production capacity of pancreatic beta cells is determined during pregnancy. A child with a high beta-cell production capacity will therefore have higher insulin levels, eat more and also become fatter than a child with a lower beta-cell production capacity.
The German Ministry of Education and Research has decided to discontinue funding of the German obesity competence network in 2015. It will however continue to finance a study on extremely obese adolescents aged 14 to 21, which started three years ago and is coordinated by researchers from Ulm. It is the only obesity-related research project that will receive funding and Wabitsch finds this hard to swallow.
Wabitsch M, Funcke JB, et al. Biologically Inactive Leptin and Early-Onset Extreme Obesity. N Engl J Med 2015; 1. Januar 2015, DOI: 10.1056/NEJMoa1406653.
Hebebrand J, Hinney A, et al. Molekulargenetische Aspekte der Körpergewichtsregulation. In: Dtsch Arztebl Int 2013; 110(19): 338-44; DOI: 10.3238/arztebl.2013.0338.
Locke AE , Kahali B, et al. Genetic studies of body mass index yield new insights for obesity biology. Nature 518, 12.02.2015, DOI: 10.1038/nature14177.
Funcke JB, von Schnurbein J. Monogenic forms of childhood obesity due to mutations in the leptin gene. Molecular and Cellular Pediatrics 2014,1:3; DOI: 10.1186/s40348-014-0003-1.
"Ulmer Kinderstudie" (formerly referred to as "Säuglingsstudie"): http://www.adipositasforschung-ulm.de/index.php?id=63