One way of thinking about the physical meaning of the equation is by thinking of some bound system which contains various forms of energy--the rest mass energies of all the particles in the system plus the kinetic energy of the particles, and the binding energy (i.e. the difference in potential energy between the bound state and the potential energy they'd have if all the particles were far apart from one another). If you try to accelerate the system and see how much energy is needed, or you put the system on a scale and weigh it while in an accelerating room (or weigh it in Earth's gravity since inertial mass and gravitational mass are the same), you'll find that this is proportional to the total energy, not just the sum of the rest mass energies. So, for example, a hot brick would weigh slightly more than a cold brick because the heat gives the particles extra kinetic energy, and an atomic nucleus weighs slightly less than the sum of the rest masses of the protons and neutrons that make it up because the potential energy is less in the bound state than when they're far apart.