Obesity and diabetes are international concerns that have grown worse over the years. A recent paper published by University of Tartu researchers reveals that the lack of a particular protein, NEGR1, may lead to pre-diabetes mostly among male mice, which lets us assume that the lack of this protein is more likely to promote diabetes also in men.
In 2019, globally, 463 million people were diagnosed with diabetes, and 374 million were at risk of getting type 2 diabetes. In general, type 2 diabetes affects older people, but recently the numbers have significantly grown among children, adolescents and young adults. Bad lifestyle choices or a difficult living environment have often been blamed for developing type 2 diabetes, but genetics also has a strong connection.
One gene that researchers have suspected to be responsible for diabetes is Negr1. This gene expresses as NEGR1 protein, which has been mostly researched in relation to depression and schizophrenia. Recent research has found that it also affects weight, appetite and promotes metabolic disorders. That is why researchers at the University of Tartu Department of Physiology led by Mari-Anne Philips have investigated the NEGR1 protein for some time already. In a recently published study Maria Kaare, a doctoral student at the department, focused on the impact of this protein from the aspect of body weight. It was confirmed that NEGR1 is involved with metabolic disorders, and its effect is sex-specific, showing the great significance of sex hormones in developing diabetes.
For the experiments, mice of both sexes were used, which has not been done before in similar studies. Half of them had the NEGR1 protein expressed and the others did not. Mice were given high-fat diet and then their body weight, blood sugar and metabolites (incl. amino acids and fatty acids) were measured. It turned out that mice without Negr1 had gained more weight and their blood sugar had also risen more compared to mice with Negr1, even though the first had eaten less. So, the weight gain had nothing to do with increased food consumption. This was more apparent among male mice. The differences between females were not that significant.
In the glucose tolerance test, the mice without Negr1 had a much lower glucose tolerance than mice with Negr1, and they reached the pre-diabetes state. This effect was again more pronounced in male mice. Similarly, male mice without Negr1 also had more fat in their liver. Their muscle fibre size was also significantly smaller, which indicates that more muscle fibre is metabolised. Maria Kaare explained that Negr1-deficient mice use proteins as a source of energy rather than fat, so fat gets stored in the body while proteins are broken down. It was concluded that NEGR1 is necessary to have a functional fat and blood sugar balance to avoid glucose intolerance and excessive weight gain.
As Negr1 promotes depression and schizophrenia, its effect on body weight has so far been considered rather a side effect of mental disorders. However, the gene has been suspected of promoting diabetes also in the past. The study shows that NEGR1 protein can cause metabolic alternations independently from mental disorders, confirming that NEGR1 protein has a specific role in influencing systemic metabolism, and that the strong correlation of the gene with body mass index is not due to behavioural changes. The fact that Negr1 deficiency affects primarily male mice indicates that sex hormones play an important part in the development of diabetes. According to Kaare, these findings are compatible with previous human studies which have shown that the development of diabetes differs in men and women.
There is still no reason to despair. Associate Professor in Human Physiology Mari-Anne Philips noted that the effect of the Negr1 gene was only apparent when the environmental factor – unhealthy food (45% high-fat diet or “Western diet”) – was added. So, the study shows that by eating healthy low-fat food, it is possible to prevent diabetes even with less favourable genes. Once people start to eat unhealthy food, it can be seen who has the Negr1 gene expressed and who does not. Although all mice had metabolic problems while eating high-fat food, only mice without NEGR1 protein developed diabetes or glucose intolerance.
In conclusion, it can be said that the NEGR1 protein affects body weight, appetite and mental health, including the development of diabetes and psychiatric disorders. Sex hormones influence the effect of NEGR1 protein and, in the future, it is worthwhile to take this protein and its effects into account when diagnosing or preventing any NEGR1-related disorders.
Associate Professor in Human Physiology
University of Tartu
University of Tartu