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

Cell Rep. 2014 Nov 20;9(4):1495-506. doi: 10.1016/j.celrep.2014.10.045. Epub 2014 Nov 13.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects
  • Adiposity / drug effects
  • Agouti-Related Protein / metabolism*
  • Animals
  • Body Weight / drug effects
  • Enzyme Activation / drug effects
  • Glucose / metabolism
  • Homeostasis / drug effects
  • I-kappa B Kinase / metabolism*
  • Insulin / metabolism
  • Insulin Resistance*
  • JNK Mitogen-Activated Protein Kinases / metabolism*
  • Leptin / pharmacology
  • MAP Kinase Signaling System / drug effects
  • Male
  • Mice, Inbred C57BL
  • Mutant Proteins / metabolism
  • Neurons / drug effects
  • Neurons / enzymology*
  • Obesity / enzymology*

Substances

  • Agouti-Related Protein
  • Insulin
  • Leptin
  • Mutant Proteins
  • I-kappa B Kinase
  • JNK Mitogen-Activated Protein Kinases
  • Glucose