Hi Richard,
I hired a (V8 Hemi) Jeep Cherokee in California, and that sucked fuel solo. So solo - two wheel drive and overdrive on for the best mpg.
Think of it this way - every bit of twisty stuff that the engine turns uses fuel, and in 2WD you're turning only half the layshafts, differentials, and other stuff. So 2WD will offer better fuel consumption that 4WD.
Overdrive offers a higher final ratio in the gearbox - meaning that the engine needs to do less turns for the same distance - so fuel consumption should improve - but probably only when driving at a relatively fixed speed - like on a motorway.
Towing? Follow the Jeep manual - if it says you must use 4WD then you must follow that. Overdrive may help - as long as the engine can produce enough torque to maintain the highest gear ratio.
Robert