BF - Good query - Can't resist taking a shot at it, but am not a certifiable aerodynamicist, so what follows is speculative in part:
1) Real world aircraft designs must accomodate constraints across the envelope. Some of the biggies are a) reasonable rotate / stall speeds at an AOA angle somewhat consistent with placement of the landing gear b) adequate elevator control authority at all allowed weights at all allowed speeds, including manoeuvers in steep banks, stall recovery, crosswind, engines out, etc. c) various vibration damping, balance, and stability issues in level flight, climb, turns, etc.
2) In order to satisfy the many constraints of 1), some aerodynamic efficiency is sacrificed for stability and controlability. As a result, the most efficient performance at any given speed / weight / altitude combination is not going to be wholly intuitive, and the parameters move around a lot for different speeds.
3) As aircraft grow bigger, they grow wider. While a circular cross-section is likely most efficient from pov of drag, an elipse or even a rectangle are vastly more efficient from the manufacturing and operational perspecitves of simpler structures, more flexible load capacity, passenger comfort, turnaround convenience, etc. so aerodynamic compromises are made for operational reasons as well as whole-envelope aerodynamics. As a result, practical large capacity aircraft tend to have 'fat bottoms'.
4) All of the above is pretty evident. The parts I am a little less sure about - from memory - are these: a)control and balance requirements from 1) require a lot more horizontal tail than simple efficiency would dictate. In level flight in a streamlined configuration, that big tail is actually burning energy to push the nose down. The efficient cruise configuration lets the tail drop into a more neutral zone of operation where it just holds up its end of the aircraft, contributing useful net lift with less opposition to the wing and thus less overall drag. This combines with b) the angular cant of the cabin portion of the airframe into the relative wind. The fuselage is designed to surf the breeze somewhat in long range cruise - acting as a lifting body - so in the tail-low surfing approach, the fuse actually increases lift/drag at appropriate speeds, squeezing out more forward inches per pound of fuel, even while making it harder to manage a cart in the aisles.