"What's up with ___?" is a casual way of asking:

• What is happening?
• Why is something happening?

For example:

What's up with your family these days?

What's up with that cut on your forehead?

What's up with all the earthquakes that have been happening in the last few years?

If someone says:

What's up with this weather?

... they want to know why the weather has been changing so much.