The control of body mass and energy balance in the body is very complex. Recent research suggests hundreds of genes to be involved in the regulation and thus in the development of obesity. As yet only a small percentage of them have been identified. It is believed that ligand-receptor interaction is a key mechanism underlying the dysregulation of body mass. Novel studies in mice and humans suggest that Neurobeachin (Nbea), a regulator of intracellular targeting of membrane proteins, is directly involved in the regulation of body mass. Nbea+/- mice develop moderately elevated body mass during early adulthood while two intronic SNPs are associated with body mass and body-mass index (BMI) in humans.
Data on heterozygous disruption of the NBEA gene in humans were linked with autism and multiple myeloma. Accordingly the inactivation of the Nbea gene in mice was expected to produce a model for autism. Homozygous knockout mice die perinatally due to breathing paralysis, heterozygous Nbea +/- mice are viable and fertile. Manfred Kilimann from the Department of Neuroscience at the Uppsala University in Sweden and his colleagues aimed to analyze the haploinsufficient Nbea+/- mice in the German Mouse Clinic (GMC) to check for autism related phenotypes. Unexpectedly the scientists of the energy metabolism and dysmorphology screens of the GMC discovered in the primary systemic screening that male and female mutant mice were slightly but significantly heavier and showed higher body fat content than wildtype controls. Obesity is the result of disturbed regulation of energy balance. Food intake and the efficiency of energy extraction from the diet were investigated to assess which side of the energy balance equation was affected. Absolute food intake was higher in the mutants but not higher as expected for a heavier mouse. The efficiency of energy extraction from food (food assimilation coefficient) did not differ between genotypes. To check if reduced spontaneous activity is the reason for a positive energy balance, several behavioural tests (modified Hole Board, modified SHIRPA protocol) were conducted in the GMC. No differences were found between wildtype and mutant mice, in particular, no reduction of motor activity parameters.
By specifically analysing food intake and energy assimilation as well as energy expenditure in eight week old mice by indirect calorimetry it turned out that both mutant and control mice were in positive energy balance. However, the surplus of energy in Nbea+/- mice was significantly increased by about 3kJ per day. This was regarded as sufficient to build up excess fat stores of about 1 g over less than two weeks. The reason for the shift in energy balance was a slight increase in food intake which alone could not be shown to be significantly different between genotypes. Only the parallel monitoring of energy intake and expenditure revealed the mechanism for the development of moderate obesity in Nbea+/- mice. Specific challenge experiments supported these findings. When Nbea+/- mice were challenged with a high-fat/high-sugar diet after fasting they ate significantly more than wildtype controls. Also palatable fluids (Intralipid fat emulsion, sucrose, glucose, fructose) were consumed in higher amounts from Nbea+/- animals.
Interestingly, in humans two relatively common SNPs lie in the introns of the NBEA gene. Genotyping in two cohorts revealed significant association for the SNPs rs17775456 and rs7990537 with BMI as a continuous trait and trends for weight among overweight adult men: carriers of the minor allele were heavier and had higher BMI than non-carriers.
The NBEA gene had been linked to autism and multiple myeloma. According to the results presented in this study, the involvement in medical conditions has to be extended for obesity. Autism, cancer and obesity are all typical polygenic disorders, and in combination with different sets of additional risk genes, NBEA misexpression may contribute to different manifestations.
Olszewski et al., Neurobeachin, a Regulator of Synaptic Protein Targeting, Is Associated with Body Fat Mass and Feeding Behavior in Mice and Body-Mass Index in Humans, PloS Genetics, March 2012 | Volume 8 | Issue 3 | e1002568