[Iexpedite]

-Does lightening internals actually better gas mileage (about 10 lbs lighter)? Lighter components will reduce your engines rotating mass thereby freeing up power.

-Should I go with a 5.3, 5.7, or 6.0L engine?
I am not familiar with the 5.3, but the larger cubic inch motor should produce more low end torque. Properly geared you can use that to run the engine at a lower RPM. Gearing is going to be the key to this whole thing.

-I assume higher compression is a must?
You will increase the power produced in every cycle by adding compression.

-Higher flow heads give one a better gas mileage or not?
Maximizing flow helps but you still need to ensure you have good velocity. Otherwise your low end torque will suffer.

-Larger fuel injectors use more fuel so they must weaken mpg?
Not sure about this. If your computer is controlling pulse width, then it will adjust for low speed operation by shortening the pulse on a larger injector. I guess it depends on what computer you will be running. A tuned stock or aftermarket computer should be able to adapt. Factory unmodified hardware may increase fuel use.

-Does one want to shorten the stroke or lengthen it?
Long stroke is going to make more torque...not sure what the tradeoffs are.

-Does the piston shape (dome, flattop) have any effect on mpg?
A good hypereutectic piston matched to cylinders in an attempt to reduce quench height will make the most difference.

-What exactly is the best hp curve to aim for with a cam? Should it be a very smooth curve or peaky? Does one want a low hp at low rpm so it uses less fuel?
There are a lot of RV/towing cams out there that make a fair amount of power while producing strong torque numbers.