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.
Nogueiras
Ruben
R
Department of Psychiatry, Obesity Research Centre, University of Cincinnati, Cincinnati, Ohio 45226, USA. ruben.nogueiras@usc.es
Pérez-Tilve
Diego
D
Veyrat-Durebex
Christelle
C
Morgan
Donald A
DA
Varela
Luis
L
Haynes
William G
WG
Patterson
James T
JT
Disse
Emmanuel
E
Pfluger
Paul T
PT
López
Miguel
M
Woods
Stephen C
SC
DiMarchi
Richard
R
Diéguez
Carlos
C
Rahmouni
Kamal
K
Rohner-Jeanrenaud
Françoise
F
Tschöp
Matthias H
MH
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