Cigarette　smoking　promotes　body　weight　reduction　in　humans　while　paradoxically　also　promoting　insulin　resistance　(IR)　and　hyperinsulinemia.　However,　the　mechanisms　behind　these　effects　are　unclear.　Here　we　show　that　nicotine,　a　major　constituent　of　cigarette　smoke,　selectively　activates　AMP-activated　protein　kinase　alpha　2　(AMPK　alpha　2)　in　adipocytes,　which　in　turn　phosphorylates　MAP　kinase　phosphatase-1　(MKP1)　at　serine　334,　initiating　its　proteasome-dependent　degradation.　The　nicotine-dependent　reduction　of　MKP1　induces　the　aberrant　activation　of　both　p38　mitogen-activated　protein　kinase　and　c-Jun　N-terminal　kinase,　leading　to　increased　phosphorylation　of　insulin　receptor　substrate　1　(IRS1)　at　serine　307.　Phosphorylation　of　IRS1　leads　to　its　degradation,　protein　kinase　B　inhibition,　and　the　loss　of　insulin-mediated　inhibition　of　lipolysis.　Consequently,　nicotine　increases　lipolysis,　which　results　in　body　weight　reduction,　but　this　increase　also　elevates　the　levels　of　circulating　free　fatty　acids　and　thus　causes　IR　in　insulin-sensitive　tissues.　These　results　establish　AMPKa2　as　an　essential　mediator　of　nicotine-induced　whole-body　IR　in　spite　of　reductions　in　adiposity.