Often the gear ratios for a truck are engineered for maximum EPA stats and not for towing. A 4.10 rear end will enable a gas engine to provide power in its sweet spot or power band at towing speeds. Taller gearing is fine when driving at 70 MPH with nothing in tow but keeps the engine operating at suboptimal RPM's when towing at slower speeds.
Weight take energy (gas) to accellerate and to move to a higher elevation. Rolling hills are the worst as the engine speed is constantly changing and you cannot take advantage of the downgrades to help you up the next hill.
At speeds over 50 MPH most of the work the engine is doing is to overcome air resistance which increases with the square of the velocity of an object. At 60 MPH the air resistance is 4 times what it is at 60 MPH and if you are going 70 MPH and have a 20 MPH headwind your gas mileage is going to be very poor. Drag and turbulence also increase the power needed to move any object and it would be difficult to come up with a better shape to maximize both turbulence and drag than a pickup pulling a square trailer. For a good shape look at a Prius.
The only "RV" that gets decent fuel mileage is the Class B motorhome with a diesel engine which is capable of averaging 25-28 MPG. With anything else it is best not to think about "economy" at all. More important is range on a tankful of fuel as that can have an impact on your trip planning.