Factors influencing non-genetic variation in the response to a high fat diet

Despite being almost genetically identical inbred C57BL/6 mice kept in a constant environment show a remarkable diversity in their responses to exposure to a high fat diet (HFD). Some mice increase their body weight by 50% while others hardly change weight at all. These changes seem to depend on two major factors: the level of physical activity prior to exposure to the HFD and the food intake response on exposure to the diet. Mice with high levels of physical activity were more protected from weight gain. High physical activity was correlated with the lean body mass but we do not know the direction of causality for this relationship. Mice that responded more positively to the HFD in terms of change in energy intake gained the most weight. We compared gene expression in the hypothalamus using RNAseq for mice that were responsive and non-responsive to the diets. Gene expression in the dopamine and serotonin signaling pathways were strongly down regulated in the low responders. In addition NPY signaling was also reduced in the low responders, but TNFalpha signaling was generally up regulated. Other data suggest that an additional factor driving the differences in response to the diet may be differences in brown adipose tissue activity.