Distinct Roles for JNK and IKK Activation in Agouti-Related Peptide Neurons in the Development of Obesity and Insulin Resistance

Abstract

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.

Knockout of inositol-requiring enzyme 1α in pro-opiomelanocortin neurons decreases fat mass via increasing energy expenditure

“…We speculated that the possible reasons for the different phenotypes observed in our study and those of the other work [42,50] could be as follows: XBP1 splicing represents one of the downstream pathways from the activation of the RNase domain of IRE1α, whereas other signalling pathways might also be activated or inhibited by the knockout of IRE1α, which may contribute to the lean phenotype in PIKO mice. For example, altered expression of hypothalamic c-Jun N-terminal kinases (JNK), as a downstream target of the kinase domain of IRE1α [17], also regulates obesity and its related diseases [51,52]. Interestingly, the expression of ER stress markers, including phosphorylated eukaryotic translation initiation factor 2α (p-eIF2α), BiP and activating transcription factor 4 (ATF4) [27] was decreased in the hypothalamus of PIKO mice under both standard chow diet and HFD (electronic supplementary material, figure S4), suggesting another possibility in explaining the effects of IRE1α deficiency in POMC neurons.…”

AgRP Neurons Control Systemic Insulin Sensitivity via Myostatin Expression in Brown Adipose Tissue

“…Accordingly, it remained undefined whether acute activation of AgRP and POMC neurons exerts acute glucose and insulin sensitivity regulatory effects and if so, which mechanism(s) are involved in this regulation both within the CNS as well as in peripheral organs. Exactly defining the food intake and glucose regulatory functions of these neurons is of critical importance, since obesity-associated hypothalamic inflammation and associated alterations of AgRP neuron activity can contribute to the manifestation of obesity and progression of insulin resistance (Tsaousidou et al, 2014; Kleinridders et al, 2009; Belgardt et al, 2010). Moreover, improved glucose metabolism in high fat diet (HFD)-fed mice upon toxin-mediated ablation of AgRP-neurons further highlights the dependence of metabolic alterations in obesity on the activity of these cells (Joly-Amado et al, 2012).…”

Acetate induces anorexia <i>via</i> up-regulating the hypothalamic pro-opiomelanocortin (<i>POMC</i>) gene expression in rabbits

“…Inhibiting the hypothalamic ERK1/2 and p38 pathways prevent NPY synthesis and secretion (Kim et al, 2010). Additionally, Tsaousidou et al (2014) demonstrated that the inhibition of JNK induces hyperphagia via the up-regulation of AGRP gene expression.…”