My favorite for years has been "King-Sized Homer". I think like the “Bart Sells His Soul” eppy, it does deal with a serious topic - obesity and the health problems that can arise from it. I know Homer did it to himself purposely but the underlying theme about obesity’s effects on a person is a serious topic.
So:
Homer can’t stand the thought of participating in Burnsie’s mandatory morning calisthenics, so he concocts a crackpot plan to gain 61 pounds so he’ll be heavy enough to go on disability and work from home.
He confides in Bart about his plan and Bart, of course, wants to do all he can to help:
**Bart: If you gain 61 pounds they’ll let you work at home?
Homer: Y’uh huh, that’s the deal. No more exercise program, no more traffic, no more blood drives or charity walks.
A very, very close second - a tie, really - for me is The Shinning. I love all the Simpsons Halloween eppies, but my favorite is Treehouse of Horror V. Good times!
Bart: Dad, I know we don’t do a lot together but helping you gain 61 pounds is something I want to be a part of. **
Naturally, Lisa objects strenuously:
**Lisa: Obesity is really unhealthy; any doctor will tell you that.
Homer: Oh yeah? Well we’ll just see about that little miss smart guy!
Cut to Dr. Hibbert’s office, where Homer wants advice on how to gain the weight.
Hibbert: (gasps) My God, that’s monstrous. I’ve never heard of anything so negligent – I’ll have no part of it!
Homer: Can you recommend a doctor who will?
Hibbert: Yes!**
The supermarket sequence where Homer is filling up his cart with all the unhealthy crap he can find to eat so he can gain the weight always sets me off on this crazy laughing jag.
And at the end, when Homer seals off the release of the toxic gas by falling into the hole:
**Lisa: I think it’s ironic that Dad saved the day, while a slimmer man would’ve fallen to his death.
Bart: And I think it’s ironic that, for once, Dad’s butt prevented the release of toxic gas.
Marge: Bart! ** 
A very, very close second - a tie, really - for me is Treehouse of Horror V. “The Shinning” is my favorite mini-ep in that show. My favorite exchange:
**
Mr. Burns: Yes, by cutting off cable TV and the beer supply, I can ensure an honest winter’s work out of those low-lives.
Smithers: Sir, did you ever stop to think that maybe it was doing this that caused the previous caretakers to go insane and murder their families?
Mr. Burns: Hmm, perhaps. Tell you what. We come back and everyone’s slaughtered, I owe you a Coke. **
