Excitatory transmission onto AgRP neurons is regulated by cJun NH2-terminal kinase 3 in response to metabolic stress
Santiago Vernia,
Caroline Morel,
Joseph C Madara,
Julie Cavanagh-Kyros,
Tamera Barrett,
Kathryn Chase,
Norman J Kennedy,
Dae Young Jung,
Jason K Kim,
Neil Aronin,
Richard A Flavell,
Bradford B Lowell,
Roger J Davis
Affiliations
Santiago Vernia
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States
Caroline Morel
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States
Joseph C Madara
Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, United States; Harvard Medical School, Boston, United States
Julie Cavanagh-Kyros
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States; Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, United States
Tamera Barrett
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States; Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, United States
Kathryn Chase
Department of Medicine, Division of Endocrinology, University of Massachusetts Medical School, Worcester, United States
Norman J Kennedy
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States
Dae Young Jung
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States
Jason K Kim
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States; Department of Medicine, Division of Endocrinology, University of Massachusetts Medical School, Worcester, United States
Neil Aronin
Department of Medicine, Division of Endocrinology, University of Massachusetts Medical School, Worcester, United States
Department of Immunobiology, Yale University School of Medicine, New Haven, United States; Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, United States
Bradford B Lowell
Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, United States; Harvard Medical School, Boston, United States
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States; Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, United States
The cJun NH2-terminal kinase (JNK) signaling pathway is implicated in the response to metabolic stress. Indeed, it is established that the ubiquitously expressed JNK1 and JNK2 isoforms regulate energy expenditure and insulin resistance. However, the role of the neuron-specific isoform JNK3 is unclear. Here we demonstrate that JNK3 deficiency causes hyperphagia selectively in high fat diet (HFD)-fed mice. JNK3 deficiency in neurons that express the leptin receptor LEPRb was sufficient to cause HFD-dependent hyperphagia. Studies of sub-groups of leptin-responsive neurons demonstrated that JNK3 deficiency in AgRP neurons, but not POMC neurons, was sufficient to cause the hyperphagic response. These effects of JNK3 deficiency were associated with enhanced excitatory signaling by AgRP neurons in HFD-fed mice. JNK3 therefore provides a mechanism that contributes to homeostatic regulation of energy balance in response to metabolic stress.
