Activation of c-Jun N-terminal kinase 1 (JNK1)- and inhibitor of nuclear factor kappa-B kinase 2 (IKK2)-dependent signaling plays a crucial role in the development of obesity-associated insulin and leptin resistance not only in peripheral tissues but also in the CNS. Here, we demonstrate that constitutive JNK activation in agouti-related peptide (AgRP)-expressing neurons of the hypothalamus is sufficient to induce weight gain and adiposity in mice as a consequence of hyperphagia. JNK activation increases spontaneous action potential firing of AgRP cells and causes both neuronal and systemic leptin resistance. Similarly, activation of IKK2 signaling in AgRP neurons also increases firing of these cells but fails to cause obesity and leptin resistance. In contrast to JNK activation, IKK2 activation blunts insulin signaling in AgRP neurons and impairs systemic glucose homeostasis. Collectively, these experiments reveal both overlapping and nonredundant effects of JNK- and IKK-dependent signaling in AgRP neurons, which cooperate in the manifestation of the metabolic syndrome. Display omitted •Inflammatory signaling in AgRP neurons promotes obesity and insulin resistance•JNK and IKK activations in AgRP neurons have distinct metabolic consequences•JNK activation in AgRP neurons causes cellular and systemic leptin resistance•IKK activation in AgRP neurons leads to cellular and systemic insulin resistance Inflammatory signaling in the CNS is crucial in the development of obesity-associated insulin and leptin resistance. Tsaousidou et al. demonstrate that constitutive JNK activation in agouti-related peptide (AgRP)-expressing neurons is sufficient to induce weight gain and leptin resistance in mice, whereas IKK2 activation fails to cause obesity but blunts insulin signaling and impairs systemic glucose homeostasis. The data reveal distinct effects of c-Jun N-terminal kinase (JNK)- and inhibitor of nuclear factor kappa-B kinase (IKK)-dependent signaling in AgRP neurons, which cooperate in the manifestation of the metabolic syndrome.