The cJun NH2-terminal kinase (JNK) signaling pathway is implicated in the response to metabolic stress. Indeed, it is established that the ubiquitously expressed JNK1 and JNK2 isoforms regulate energy expenditure and insulin resistance. However, the role of the neuron-specific isoform JNK3 is unclear. Here we demonstrate that JNK3 deficiency causes hyperphagia selectively in high fat diet (HFD)-fed mice. JNK3 deficiency in neurons that express the leptin receptor LEPRb was sufficient to cause HFD-dependent hyperphagia. Studies of sub-groups of leptin-responsive neurons demonstrated that JNK3 deficiency in AgRP neurons, but not POMC neurons, was sufficient to cause the hyperphagic response. These effects of JNK3 deficiency were associated with enhanced excitatory signaling by AgRP neurons in HFD-fed mice. JNK3 therefore provides a mechanism that contributes to homeostatic regulation of energy balance in response to metabolic stress.
Consuming the right amount of food is important for health. Eating too little for a long time causes damage to organs, and overeating can cause harm as well, in the form of conditions such as obesity and type 2 diabetes. Several signaling molecules and brain regions are linked to controlling food consumption and ensuring the body receives the correct amount of nutrients to fuel its activities.
Previous studies have found that two proteins called JNK1 and JNK2, which are found in most tissues of the body, can reduce how much energy cells use. This can trigger insulin resistance and fat accumulation, and so suggests that blocking the activity of these proteins may help to treat type 2 diabetes and obesity. However, the role of another JNK protein – JNK3, which is mostly found in the brain – was not known.
Now, Vernia, Morel et al. have investigated the role of JNK3 in metabolism. It was found that JNK3 reduced the amount of food consumed by mice provided with a cafeteria (high fat) diet. Mice that lacked JNK3 ate far more food and gained more weight on a high fat diet than normal mice. However, JNK3 played no role in food consumption when mice were fed a standard chow diet. Treating normal mice with leptin – an appetite-suppressing hormone – caused them to lose weight, but did not affect mice that lacked JNK3.
Examining the brains of the mice revealed that in normal mice, JNK3 in a specific sub-population of neurons decreases the production of proteins that promote eating. However, the proteins continued to be produced in mice that lacked JNK3, encouraging overeating.
Overall, the results suggest that blocking the activity of all the JNK proteins will not help treat obesity and diabetes as shutting down JNK3 could encourage overeating. Therefore, future investigation into treatments for these conditions should focus on drugs that specifically target JNK1 and JNK2, and not JNK3.