A v6 with a standard transmission will give you the best fuel mileage with a 4x4. The 4bangers don't handle towing or oversized tires or extra weight in general very well.
If you drive mostly highway the auto will get better MPG, I'm guessing because the auto is a 6 speed and the manual is a 5 speed. The manual is rated at 16/19 and the auto at 16/21. The only time I have gotten as bad as 16 is when there has been snow on the road and I drove in 4x4. If you keep the RPMs at 2k or less (around 68 mph) you can get 22+ strictly highway.
I ran 33 12.50s on my 08 and got around 17. Anything over a 265/75/16 (32s) really starts to kill the gas mileage in these trucks.
Eta I was hoping that Toyota would change to the dual VVTi engine that's in the new 4runners when they changed the 12s, but I guess they are waiting until they do a full redesign to upgrade the motor.
This post was edited on 11/7 at 8:07 pm