For me it was Lisa Goes Gaga. It was focused entirely on Lady Gaga who played herself and was awkwardly inserted, I don't mind the occasional brief celebrity appearance or when they lend their voice to other characters (ex. Meryl Streep playing Jessica Lovejoy in Bart's Girlfriend) but they started to feel so forced. I tried watching the occasional episode afterwards but people like JJ Abrams would show up in Do PizzaBots Dream of Electric Guitars? and I'd lose interest.
I have started watching the show again but I am curious who else has lost interest due to an episode or trend especially those who have been watching the show since its beginning.
I know this thread is old. But the nail in the coffin for me was the "300th" episode (not really). The one with tony hawk. Everything was so forced, just so they could have tony hawk guest start. Before that, guest star mostly played other characters (I know there are exceptions). I was the exact target audience for this episode, and I remember just being annoyed.