“What’s up with you?” can just be a simple question that doesn’t imply something is wrong but the following two phrases (obviously the last one!) indicate that there is a problem. Tone is everything. Say “what’s up with you?” with a smile and it’s just a way to start a conversation. Say it with a different tone of voice and it takes on a different meaning.

"what's up with you ?" based on the connotations in your voice could either be a greeting similar to "how are you?" OR if said another way after someone did something you did not like it could mean "what is wrong with you?"