A protein in the nucleus of liver cells is produced in greater quantities when we go hungry; it limits fatty acid uptake and adjusts the metabolism in the liver. However in people with metabolic disorders, the abnormal expression of this protein (GADD45β), which was previously only known to be involved in the regulation of cell division and DNA repair, leads to a dysregulated fat and sugar metabolism. Scientists from the DKFZ and Helmholtz Zentrum München have now found out what happens at the molecular level when we go hungry and why periods of food deprivation may promote health.
Countless experiments with a broad range of different animals and epidemiological studies in humans have shown that food deprivation and temporary hunger and fasting periods reduce the incidence of many chronic and degenerative diseases, improving overall health and increasing life expectancy. The molecular causes behind this are still largely unknown. However, scientists led by Prof. Dr. Stephan Herzig and Dr. Adam J. Rose at the German Cancer Research Center (DKFZ) in Heidelberg have now identified a protein that controls fatty acid transport and glucose metabolism in the liver and is produced in greater quantities in people/animals following an intermittent fasting diet (a normal diet that is interrupted by regular periods with a reduced intake of calories). The protein GADD45β is dysregulated in metabolic diseases such as diabetes and obesity.
Excess weight and obesity have reached epidemic proportions worldwide. They are high risk factors for many diseases and can have serious consequences for health, thus representing one of the most pressing issues for the quality of life and for health systems in modern societies. These diseases include type 2 diabetes and its complications, metabolic syndrome and cardiovascular diseases. Obesity-related diabetes that is characterised by insulin resistance shows that the medical treatment of such diseases often reaches its limits. Other treatment strategies that focus on people changing their eating habits are therefore needed. Can a reduced intake of calories change the situation? “If we understand how fasting affects our metabolism, we might be able to achieve this effect therapeutically,” says Herzig.
The liver plays a crucial role in our fat and sugar metabolisms. The group of researchers used appropriate animal models in conjunction with transcript arrays to study liver cell genetic activity differences caused by fasting. Mice strains at different stages of obesity and diabetes were used as metabolic disease models. The animals were subjected to intermittent fasting, i.e. periods of fasting that alternated with normal food intake periods. The researchers were able to show that the gene for the protein GADD45β was transcribed differently depending on the diet: the greater the hunger the more GADD45β was transcribed. GADD45 stands for growth arrest and DNA damage-inducible 45 protein. As the name suggests, proteins in the GADD45 gene family were previously associated with cell cycle modulation, DNA repair in stress situations and with cancer. So the new finding was quite unexpected.
Some important results of the extensive and complex experiments can be summarised as follows: in healthy animals, the protein GADD45β regulates the absorption of fatty acids in the liver cells and its expression therefore depends on whether large quantities of it are needed or not. Fasting seems to stimulate the production of GADD45β and reduce the absorption of fatty acids in the liver. Mice with a dysregulated metabolism also had a dysregulated GADD45β expression, and this dysregulation was most pronounced when the mice went through a period of hunger. With knock-out mice that lacked the corresponding gene, the researchers were able to show that the fat metabolism in the liver is regulated by the protein GADD45β: these mice were more likely to develop fatty liver disease. When the GADD45β protein was restored, the fat content of the liver normalised and the sugar metabolism also improved. GADD45β production is assumed to be regulated as follows: GADD45β controls the fatty-acid binding protein FABP1, a protein that is responsible for transporting fatty acids back and forth between the cytoplasm and the plasma membranes of the liver cells and the transport of fat into and out of the liver.
The scientists were able to confirm the regulatory function of GADD45β and the dysregulated expression of the protein in people with a dysregulated fat metabolism. The investigations involved liver biopsy samples of slim and obese patients with and without type 2 diabetes who were undergoing stomach or gall bladder surgery. Prior to surgery, the patients had given their written consent to the investigations, which were approved by the local ethics committee. A low GADD45β level was accompanied by increased fat accumulation in the liver and an elevated blood sugar level.
“The stress on the liver cells caused by fasting seems to stimulate GADD45β production, which then adjusts the metabolism to the low food intake,” said Adam J. Rose, head of the “Protein metabolism in health and disease” group at the DKFZ. Herzig and Rose, who were the coordinators of the present study which was recently published in the scientific journal EMBO Molecular Medicine, now want to use the new findings for therapeutic intervention in the fat and sugar metabolism so that the positive effects of food deprivation can be translated into medical treatment. In a recent interview, Herzig also talked about the positive effects of intermittent fasting (involving e.g. two days of reduced calorie intake, or not eating at all, followed by a week with a normal eating pattern) on diabetes and insulin resistance as well as on cardiovascular diseases, and potentially also tumour risk. With the protein GADD45β, the researchers have found a scientific explanation for the positive effects of intermittent fasting.
Jessica Fuhrmeister, Annika Zota, Tjeerd, P. Sijmonsma, Oksana Seibert, Sahika Cıngır, Kathrin Schmidt, Nicola Vallon, Roldan M de Guia, Katharina Niopek, Mauricio Berriel Diaz, Adriano Maida, Matthias Blüher, Jürgen G. Okun, Stephan Herzig und Adam J. Rose: Fasting-induced liver GADD45β restrains hepatic fatty acid uptake and improves metabolic health, EMBO Mol Med (2016) 8: 654–669, DOI: 10.15252/emmm.201505801