Lausanne, Switzerland 12th December 2017. Obesity is a global problem, affecting individuals and societies across both the developed and the developing world. Estimates suggest that, by 2030, 50% of the world’s population will be overweight or obese, with an associated rise in type 2 diabetes and cardiovascular diseases.
Obesity is caused by an imbalance between energy intake (i.e. food intake) and energy expenditure (e.g. physical activity). There are numerous reasons why people over-eat, although it is now clear that genetic and other biological factors play a major role in appetite regulation.
“We wanted to learn more about the biological mechanisms that influence whether or not people are successful in managing their weight”, explains Dr Jörg Hager from the Nestlé Institute of Health Sciences (NIHS), who has led the research published today* in Nature Communications. “We know that the levels of many important hormones and other proteins are different in obese compared to normal-weight people, and that these differences may reflect their capacity to successfully maintain their weight. NIHS led a consortium of researchers from the Universities of Toulouse, Copenhagen and the Maastricht University Medical Centre to identify how these hormones and proteins might be regulated.”
A major regulator of food intake is the hormone leptin. Unlike so-called satiety hormones such as ghrelin, PPY or GLP1 which are produced in the gut and regulate hunger acutely to make us eat or feel full, leptin, which is produced in the fat cells, is more a sensor of our energy stores. Higher levels of leptin mean your energy level is good, while low levels mean energy stores are depleted, telling you it’s time to eat. In most obese people, this signal is impaired, so they keep eating, even when their energy and leptin levels are high (this is known as leptin resistance). When obese individuals diet, their leptin levels go down, so when their diet ends, they feel very hungry and start eating again. Regulating leptin levels is therefore key to maintaining weight loss.
“The levels of many proteins, including leptin, vary significantly in obese subjects after weight loss”, Dr Hager continues. “We analysed a set of 1129 proteins in the blood, including hormones like leptin, of 494 obese subjects before and after weight loss to identify genetic factors contributing to genetic variations.”
This work provided evidence for distinct genetic variants associated with the levels of key hormones and proteins involved in obesity and weight maintenance, with leptin unsurprisingly displaying the strongest association. The genetic variants did not directly influence leptin levels, but rather the levels of another protein, FAM46A, found to be involved in the regulation of protein synthesis and degradation, which in turn is associated with leptin levels. The researchers also discovered that a reduction in FAM46A expression results in higher levels of leptin protein secretion from fat cells.
“We have demonstrated that FAM46A has a negative regulatory effect on leptin, and that this regulation happens at the level of the proteins”, Dr Hager concludes. “We believe this is the first evidence to demonstrate the potential of using FAM46A as a new regulator of leptin in human adipose tissue. If we could reduce the activity of FAM46A in obese individuals after weight loss when their leptin levels are too low, we might be able to increase leptin and reduce appetite helping them in long-term weight maintenance. We now need to understand precisely how FAM46A works, in order to be able to develop a potential nutritional intervention strategy.”
NIHS is a biomedical research institute, part of Nestlé’s global R&D network, dedicated to fundamental research aimed at understanding health and disease and developing science-based, targeted nutritional solutions for the maintenance of health. To achieve its aim, NIHS employs state-of-the-art technologies and biological models to characterise health and disease with a holistic and integrated approach. The ultimate goal of the Institute is to develop knowledge that can empower people to better maintain their health through nutritional approaches, especially in relation to their molecular profile and lifestyle status.
|(*) Carayol J, Chabert C, Di Cara A, Armenise C, Lefebvre G, Langin D, Viguerie N, Metairon S, Saris WHM, Astrup A, Descombes P, Valsesia A and Hager J (2017). Protein quantitative trait locus study in obesity during weight-loss identifies a novel leptin regulator. Nature Communications 8:2084. https://www.nature.com/articles/s41467-017-02182-z
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