Ribosomal S6K1 in POMC and AgRP Neurons Regulates Glucose Homeostasis but Not Feeding Behavior in Mice
Mark A. Smith,
Loukia Katsouri,
Elaine E. Irvine,
Mohammed K. Hankir,
Silvia M.A. Pedroni,
Peter J. Voshol,
Matthew W. Gordon,
Agharul I. Choudhury,
Angela Woods,
Antonio Vidal-Puig,
David Carling,
Dominic J. Withers
Affiliations
Mark A. Smith
Metabolic Signalling Group, Medical Research Council Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London W12 0NN, UK
Loukia Katsouri
Metabolic Signalling Group, Medical Research Council Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London W12 0NN, UK
Elaine E. Irvine
Metabolic Signalling Group, Medical Research Council Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London W12 0NN, UK
Mohammed K. Hankir
Metabolic Signalling Group, Medical Research Council Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London W12 0NN, UK
Silvia M.A. Pedroni
Metabolic Signalling Group, Medical Research Council Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London W12 0NN, UK
Peter J. Voshol
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
Matthew W. Gordon
Metabolic Signalling Group, Medical Research Council Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London W12 0NN, UK
Agharul I. Choudhury
Metabolic Signalling Group, Medical Research Council Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London W12 0NN, UK
Angela Woods
Cellular Stress Group, Medical Research Council Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London W12 0NN, UK
Antonio Vidal-Puig
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
David Carling
Cellular Stress Group, Medical Research Council Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London W12 0NN, UK
Dominic J. Withers
Metabolic Signalling Group, Medical Research Council Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London W12 0NN, UK
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.
