Methods are provided of treating obesity or an obesity comorbidity in a mammalian subject comprising administering to the subject an amount of an agent effective to treat obesity or the obesity comorbidity, which agent inhibits (i) IκB kinase β (IKKβ) activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) or (ii) Notch signaling in a manner so as to permit the agent to enter the hypothalamus of the subject. Assays are also provided for identifying candidate agents for treating obesity.
