Enhanced leptin-stimulated Pi3k activation in the CNS promotes white adipose tissue transdifferentiation.
The contribution of different leptin-induced signaling pathways in control of energy homeostasis is only partly understood. Here we show that selective Pten ablation in leptin-sensitive neurons (Pten(DeltaObRb)) results in enhanced Pi3k activation in these cells and reduces adiposity by increasing energy expenditure. White adipose tissue (WAT) of Pten(DeltaObRb) mice shows characteristics of brown adipose tissue (BAT), reflected by increased mitochondrial content and Ucp1 expression resulting from enhanced leptin-stimulated sympathetic nerve activity (SNA) in WAT. In contrast, leptin-deficient ob/ob-Pten(DeltaObRb) mice exhibit unaltered body weight and WAT morphology compared to ob/ob mice, pointing to a pivotal role of endogenous leptin in control of WAT transdifferentiation. Leanness of Pten(DeltaObRb) mice is accompanied by enhanced sensitivity to insulin in skeletal muscle. These data provide direct genetic evidence that leptin-stimulated Pi3k signaling in the CNS regulates energy expenditure via activation of SNA to perigonadal WAT leading to BAT-like differentiation of WAT.
Department of Mouse Genetics and Metabolism, Institute for Genetics, University of Cologne and Center of Molecular Medicine Cologne (CMMC), D-50674 Cologne, Germany.
Leona
L
Plum
Eva
E
Rother
Heike
H
Münzberg
F Thomas
FT
Wunderlich
Donald A
DA
Morgan
Brigitte
B
Hampel
Marya
M
Shanabrough
Ruth
R
Janoschek
A Christine
AC
Könner
Jens
J
Alber
Akira
A
Suzuki
Wilhelm
W
Krone
Tamas L
TL
Horvath
Kamal
K
Rahmouni
Jens C
JC
Brüning
D002001:Adipose Tissue, Brown / Q000254:growth & development / Q000378:metabolism; D052436:Adipose Tissue, White / Q000254:growth & development* / Q000378:metabolism*; D000818:Animals; D054338:Cell Transdifferentiation; D002490:Central Nervous System / Q000378:metabolism*; D004789:Enzyme Activation; D005947:Glucose / Q000378:metabolism; D020738:Leptin / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008820:Mice, Obese; D008822:Mice, Transgenic; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D015398:Signal Transduction; D013851:Thinness
D020738:Leptin; D019869:Phosphatidylinositol 3-Kinases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D005947:Glucose