MyD88 signaling in the CNS is required for development of fatty acid-induced leptin resistance and diet-induced obesity.
Obesity-associated activation of inflammatory pathways represents a key step in the development of insulin resistance in peripheral organs, partially via activation of TLR4 signaling by fatty acids. Here, we demonstrate that palmitate acting in the central nervous system (CNS) inhibits leptin-induced anorexia and Stat3 activation. To determine the functional significance of TLR signaling in the CNS in the development of leptin resistance and diet-induced obesity in vivo, we have characterized mice deficient for the TLR adaptor molecule MyD88 in the CNS (MyD88(DeltaCNS)). Compared to control mice, MyD88(DeltaCNS) mice are protected from high-fat diet (HFD)-induced weight gain, from the development of HFD-induced leptin resistance, and from the induction of leptin resistance by acute central application of palmitate. Moreover, CNS-restricted MyD88 deletion protects from HFD- and icv palmitate-induced impairment of peripheral glucose metabolism. Thus, we define neuronal MyD88-dependent signaling as a key regulator of diet-induced leptin and insulin resistance in vivo.
Kleinridders
André
A
Department of Mouse Genetics and Metabolism, Institute for Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center of Molecular Medicine Cologne (CMMC), University of Cologne, D-50674 Cologne, Germany.
Schenten
Dominik
D
Könner
A Christine
AC
Belgardt
Bengt F
BF
Mauer
Jan
J
Okamura
Tomoo
T
Wunderlich
F Thomas
FT
Medzhitov
Ruslan
R
Brüning
Jens C
JC
D000818:Animals; D002490:Central Nervous System / Q000378:metabolism*; D004032:Diet; D004041:Dietary Fats / Q000378:metabolism; D004435:Eating; D004734:Energy Metabolism; D004789:Enzyme Activation; D005260:Female; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D020738:Leptin / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000502:physiology; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism*; D019308:Palmitic Acid / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D015430:Weight Gain
D004041:Dietary Fats; D007328:Insulin; D020738:Leptin; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D019308:Palmitic Acid; D051550:I-kappa B Kinase; D005947:Glucose