A Postsynaptic AMPK→p21-Activated Kinase Pathway Drives Fasting-Induced Synaptic Plasticity in AgRP Neurons.
AMP-activated protein kinase (AMPK) plays an important role in regulating food intake. The downstream AMPK substrates and neurobiological mechanisms responsible for this, however, are ill defined. Agouti-related peptide (AgRP)-expressing neurons in the arcuate nucleus regulate hunger. Their firing increases with fasting, and once engaged they cause feeding. AgRP neuron activity is regulated by state-dependent synaptic plasticity: fasting increases dendritic spines and excitatory synaptic activity; feeding does the opposite. The signaling mechanisms underlying this, however, are also unknown. Using neuron-specific approaches to measure and manipulate kinase activity specifically within AgRP neurons, we establish that fasting increases AMPK activity in AgRP neurons, that increased AMPK activity in AgRP neurons is both necessary and sufficient for fasting-induced spinogenesis and excitatory synaptic activity, and that the AMPK phosphorylation target mediating this plasticity is p21-activated kinase. This provides a signaling and neurobiological basis for both AMPK regulation of energy balance and AgRP neuron state-dependent plasticity.
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 3 Blackfan Circle, Boston, MA 02215, USA; Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02215, USA; Department of Neuroscience, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02135, USA. Electronic address: dong.kong@tufts.edu.
Dong
D
Kong
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 3 Blackfan Circle, Boston, MA 02215, USA.
Yossi
Y
Dagon
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 3 Blackfan Circle, Boston, MA 02215, USA.
John N
JN
Campbell
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 3 Blackfan Circle, Boston, MA 02215, USA; Department of Neuroscience, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02135, USA.
Yikun
Y
Guo
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 3 Blackfan Circle, Boston, MA 02215, USA.
Zongfang
Z
Yang
Department of Neuroscience, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02135, USA.
Xinchi
X
Yi
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 3 Blackfan Circle, Boston, MA 02215, USA.
Pratik
P
Aryal
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 3 Blackfan Circle, Boston, MA 02215, USA.
Kerry
K
Wellenstein
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 3 Blackfan Circle, Boston, MA 02215, USA. Electronic address: bkahn@bidmc.harvard.edu.
Barbara B
BB
Kahn
Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02215, USA; Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA. Electronic address: bernardo_sabatini@hms.harvard.edu.
Bernardo L
BL
Sabatini
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 3 Blackfan Circle, Boston, MA 02215, USA; Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA. Electronic address: blowell@bidmc.harvard.edu.
Bradford B
BB
Lowell
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D049229:Dendritic Spines / Q000378:metabolism; D004435:Eating / Q000187:drug effects; D004734:Energy Metabolism / Q000502:physiology; D005215:Fasting; D008822:Mice, Transgenic; D009473:Neuronal Plasticity / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D009478:Neuropeptide Y / Q000378:metabolism; D015398:Signal Transduction; D054462:p21-Activated Kinases / Q000378:metabolism*
D009478:Neuropeptide Y; D054462:p21-Activated Kinases; D055372:AMP-Activated Protein Kinases