Controlling weight normally has a small effect on mileage, except when dealing with very hilly terrain. In that case, additional weight can make a significant difference if it forces one to climb in a lower gear.
For most of us, fighting the wind: e.g. speed is the big factor. Like it or not, the power needed to push our rigs through the air varies as the cube of the airspeed. Suppose you got 10 mpg at 70 mph.... that's:
7 gals/hour, or roughly 70 hp. You'd use 10 gallons of fuel to go 100 miles.
If you slowed down to 60 mph, you'd need less power:
7 gals/hour * 60**3/70**3 = 4.4 gallons/hour... of course, you travel more slowly, but you still would only use 100/60*4.4 = 7.3 gallons to do 100 miles, or 13.6 mpg.
Now, it's actually more complicated than this because of rolling resistance, varying efficiency of engines with load, etc.... but at freeway speeds for our rigs, wind resistance dominates.
So, when there's a stiff headwind, your mileage will suffer significantly. You can help it somewhat by slowing down, of course. When you have a tailwind, you can (subject to safety and legal issues) wick it up a bit, or stay at the same speed and reap the fuel saving benefits.
Unlike the airlines, we don't need to move to keep our traveling aluminum cigars in the air.... in fact, we work hard at keeping them on the ground where they belong.