title: Ribosomal S6K1 in POMC and AgRP Neurons Regulates Glucose Homeostasis but Not Feeding Behavior in Mice.
abstract: Hypothalamic ribosomal S6K1 has been suggested as a point of convergence for hormonal and nutrient signals in the regulation of feeding behavior, bodyweight, and glucose metabolism. However, the long-term effects of manipulating hypothalamic S6K1 signaling on energy homeostasis and the cellular mechanisms underlying these roles are unclear. We therefore inactivated S6K1 in pro-opiomelanocortin (POMC) and agouti-related protein (AgRP) neurons, key regulators of energy homeostasis, but in contrast to the current view, we found no evidence that S6K1 regulates food intake and bodyweight. In contrast, S6K1 signaling in POMC neurons regulated hepatic glucose production and peripheral lipid metabolism and modulated neuronal excitability. S6K1 signaling in AgRP neurons regulated skeletal muscle insulin sensitivity and was required for glucose sensing by these neurons. Our findings suggest that S6K1 signaling is not a general integrator of energy homeostasis in the mediobasal hypothalamus but has distinct roles in the regulation of glucose homeostasis by POMC and AgRP neurons.
authors: Metabolic Signalling Group, Medical Research Council Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London W12 0NN, UK. Electronic address: mark.smith@imperial.ac.uk.
authors: Mark A
authors: MA
authors: Smith
authors: Metabolic Signalling Group, Medical Research Council Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London W12 0NN, UK.
authors: Loukia
authors: L
authors: Katsouri
authors: Metabolic Signalling Group, Medical Research Council Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London W12 0NN, UK.
authors: Elaine E
authors: EE
authors: Irvine
authors: Metabolic Signalling Group, Medical Research Council Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London W12 0NN, UK.
authors: Mohammed K
authors: MK
authors: Hankir
authors: Metabolic Signalling Group, Medical Research Council Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London W12 0NN, UK.
authors: Silvia M A
authors: SM
authors: Pedroni
authors: University of Cambridge, Metabolic Research Laboratories, MRC Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Science, Level 4, Box 289, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
authors: Peter J
authors: PJ
authors: Voshol
authors: Metabolic Signalling Group, Medical Research Council Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London W12 0NN, UK.
authors: Matthew W
authors: MW
authors: Gordon
authors: Metabolic Signalling Group, Medical Research Council Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London W12 0NN, UK.
authors: Agharul I
authors: AI
authors: Choudhury
authors: Cellular Stress Group, Medical Research Council Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London W12 0NN, UK.
authors: Angela
authors: A
authors: Woods
authors: University of Cambridge, Metabolic Research Laboratories, MRC Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Science, Level 4, Box 289, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
authors: Antonio
authors: A
authors: Vidal-Puig
authors: Cellular Stress Group, Medical Research Council Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London W12 0NN, UK.
authors: David
authors: D
authors: Carling
authors: Metabolic Signalling Group, Medical Research Council Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London W12 0NN, UK. Electronic address: d.withers@imperial.ac.uk.
authors: Dominic J
authors: DJ
authors: Withers
mesh_terms: D054369:Agouti-Related Protein / Q000378:metabolism; D000818:Animals; D001835:Body Weight / Q000502:physiology; D004734:Energy Metabolism / Q000502:physiology*; D005247:Feeding Behavior / Q000502:physiology*; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis / Q000502:physiology; D007031:Hypothalamus / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism*; D011333:Pro-Opiomelanocortin / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D054369:Agouti-Related Protein; C515199:Agrp protein, mouse; D011333:Pro-Opiomelanocortin; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C512964:Rps6ka1 protein, mouse; D005947:Glucose