One of the mechanisms that is thought to affect long term weight gain is the following:

Your body offets heat loss by burning calories from food intake. In healthy people this is well regulated so that the body radiates off about as much heat as you gain through food. Some medications or conditions however can mess with hormones involved in regulating your body's temperature. Even just being slightly colder (it's imperceptible, you won't be shivering or anything) kickstarts a different homeostasis mechanism which essentially tries to make up for the heat difference by upping the other side of the equation: more food intake. That means you feel more hungry than usual and eat a little more than you need. Over time this adds up and you gain weight.

Of course in the real world many more factors are involved, for example how much you move or how much sleep you get. But it's still an interesting piece of the puzzle.