I'm up 2 in the rear and down one in the front. This changes the feeling of the bike significantly. The bike feels more angry and aggressive, which works for me and my riding style (I only ride for fun - no work or runs to the store). I used to use 6th gear as an overdrive, now I occasionally use it and it will pull pretty hard in 6th. I ride in the 4K -8K range normally, which makes for a bit buzzier cruise on the interstate. I used to roll around 3K on the highway (minding my manners of course) with stock gearing and the bike was very smooth, if a bit lazy. So there are a couple things to think about:
1. Power - go too high on the gearing and the bike can become unrideable
2. Buzzing - higher gearing mean more buzz and noise
3. Gas - mileage and gearing are inversely proportional.
4. Tires - high gearing more tire wear.
5. Smaller front sprockets wear chains more, so for general street use a bigger or smaller rear sprocket is better. If you are racing and looking for every advantage a front sprocket is lighter with less inertia, so you might go there and risk chain wear. I was told this by a knowledgeable source, take it with a grain of salt.
Of course you know all that but some might not so I went through it. Gearing is a big part of setting the bike up to your riding style. It is actually amazing how much you can change the character of the bike. Gear too low and the bike will feel weak and lazy. Gear too high and throttle control becomes more difficult and you can get into trouble much quicker.
Now to your question (finally)! I don't have experience with larger tires but a 250 is not crazy over-stock, so stock gearing will probably be fine. I would not go lower than stock though. I am a heavy guy and that plays into it too. IMHO, I think you will make the bike boring long before you get to any real gas mileage advantages.