Direct control of peripheral lipid deposition by CNS GLP-1 receptor signaling is mediated by the sympathetic nervous system and blunted in diet-induced obesity.
We investigated a possible role of the central glucagon-like peptide (GLP-1) receptor system as an essential brain circuit regulating adiposity through effects on nutrient partitioning and lipid metabolism independent from feeding behavior. Both lean and diet-induced obesity mice were used for our experiments. GLP-1 (7-36) amide was infused in the brain for 2 or 7 d. The expression of key enzymes involved in lipid metabolism was measured by real-time PCR or Western blot. To test the hypothesis that the sympathetic nervous system may be responsible for informing adipocytes about changes in CNS GLP-1 tone, we have performed direct recording of sympathetic nerve activity combined with experiments in genetically manipulated mice lacking beta-adrenergic receptors. Intracerebroventricular infusion of GLP-1 in mice directly and potently decreases lipid storage in white adipose tissue. These effects are independent from nutrient intake. Such CNS control of adipocyte metabolism was found to depend partially on a functional sympathetic nervous system. Furthermore, the effects of CNS GLP-1 on adipocyte metabolism were blunted in diet-induced obese mice. The CNS GLP-1 system decreases fat storage via direct modulation of adipocyte metabolism. This CNS GLP-1 control of adipocyte lipid metabolism appears to be mediated at least in part by the sympathetic nervous system and is independent of parallel changes in food intake and body weight. Importantly, the CNS GLP-1 system loses the capacity to modulate adipocyte metabolism in obese states, suggesting an obesity-induced adipocyte resistance to CNS GLP-1.
Department of Psychiatry, Obesity Research Centre, University of Cincinnati, Cincinnati, Ohio 45226, USA. ruben.nogueiras@usc.es
Ruben
R
Nogueiras
Diego
D
Pérez-Tilve
Christelle
C
Veyrat-Durebex
Donald A
DA
Morgan
Luis
L
Varela
William G
WG
Haynes
James T
JT
Patterson
Emmanuel
E
Disse
Paul T
PT
Pfluger
Miguel
M
López
Stephen C
SC
Woods
Richard
R
DiMarchi
Carlos
C
Diéguez
Kamal
K
Rahmouni
Françoise
F
Rohner-Jeanrenaud
Matthias H
MH
Tschöp
D000273:Adipose Tissue / Q000166:cytology / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D001823:Body Composition / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism*; D004435:Eating / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology; D000067757:Glucagon-Like Peptide-1 Receptor; D050356:Lipid Metabolism / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009765:Obesity / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology*; D010446:Peptide Fragments / Q000494:pharmacology; D011943:Receptors, Adrenergic, beta / Q000172:deficiency; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors
C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D010446:Peptide Fragments; D011943:Receptors, Adrenergic, beta; D018027:Receptors, Glucagon; C055453:glucagon-like peptide 1 (7-36)amide; D052216:Glucagon-Like Peptide 1