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It's basically a more boastful way of asking "Whats up?", it's like asking how someone is doing and saying you're in a good mood at the same time.

Popularized by Method Man in the N.A.S.A song "NASA Music" with E-40, another originator of slang.
Bobby: You man how are you doing?
Joey: Hey what's upper??!
Bobby: Damn why are you in such a good mood?
by Dexter Von Doom February 11, 2009
What's popping my nigga? E-feezy style
What's uppers bitch, i'm a skeet all up on you
by CH, CH ,CH, CHIMP UNIT!! May 07, 2005