Critical role for hypothalamic mTOR activity in energy balance.
The mammalian target of rapamycin (mTOR) promotes anabolic cellular processes in response to growth factors and metabolic cues. The TSC1 and TSC2 tumor suppressors are major upstream inhibitory regulators of mTOR signaling. Mice with Rip2/Cre-mediated deletion of Tsc1 (Rip-Tsc1cKO mice) developed hyperphagia and obesity, suggesting that hypothalamic disruption (for which Rip2/Cre is well known) of Tsc1 may dysregulate feeding circuits via mTOR activation. Indeed, Rip-Tsc1cKO mice displayed increased mTOR signaling and enlarged neuron cell size in a number of hypothalamic populations, including Pomc neurons. Furthermore, Tsc1 deletion with Pomc/Cre (Pomc-Tsc1cKO mice) resulted in dysregulation of Pomc neurons and hyperphagic obesity. Treatment with the mTOR inhibitor, rapamycin, ameliorated the hyperphagia, obesity, and the altered Pomc neuronal morphology in developing or adult Pomc-Tsc1cKO mice, and cessation of treatment reinstated these phenotypes. Thus, ongoing mTOR activation in Pomc neurons blocks the catabolic function of these neurons to promote nutrient intake and increased adiposity.
Mori
Hiroyuki
H
Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.
Inoki
Ken
K
Münzberg
Heike
H
Opland
Darren
D
Faouzi
Miro
M
Villanueva
Eneida C
EC
Ikenoue
Tsuneo
T
Kwiatkowski
David
D
MacDougald
Ormond A
OA
Myers
Martin G
MG
Guan
Kun-Liang
KL
D000818:Animals; D004734:Energy Metabolism / Q000187:drug effects; D017353:Gene Deletion; D006963:Hyperphagia / Q000150:complications / Q000201:enzymology; D007031:Hypothalamus / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D053486:Melanocortins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D009765:Obesity / Q000150:complications / Q000201:enzymology; D011333:Pro-Opiomelanocortin / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism*; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D053486:Melanocortins; C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; D011333:Pro-Opiomelanocortin; D011494:Protein Kinases; C546843:mTOR protein, mouse; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506255:Ripk2 protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus