MyD88 Signaling in the CNS Is Required for Development of Fatty Acid-Induced Leptin Resistance and Diet-Induced Obesity

André Kleinridders, Dominik Schenten, A. Christine Könner, Bengt F. Belgardt, Jan Mauer, Tomoo Okamura, F. Thomas Wunderlich, Ruslan Medzhitov, Jens C. Brüning

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302 Scopus citations

Abstract

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 (MyD88ΔCNS). Compared to control mice, MyD88ΔCNS 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.

Original languageEnglish (US)
Pages (from-to)249-259
Number of pages11
JournalCell Metabolism
Volume10
Issue number4
DOIs
StatePublished - Oct 7 2009
Externally publishedYes

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Keywords

  • HUMDISEASE
  • MOLNEURO

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

Cite this

Kleinridders, A., Schenten, D., Könner, A. C., Belgardt, B. F., Mauer, J., Okamura, T., Wunderlich, F. T., Medzhitov, R., & Brüning, J. C. (2009). MyD88 Signaling in the CNS Is Required for Development of Fatty Acid-Induced Leptin Resistance and Diet-Induced Obesity. Cell Metabolism, 10(4), 249-259. https://doi.org/10.1016/j.cmet.2009.08.013