Cited by 483Regulation of Appetite and ObesityAdipokines, Inflammation, and Metabolic DiseasesNeuroinflammation and Neurodegeneration Mechanisms

MyD88 signaling in the CNS is required for development of fatty acid-induced leptin resistance and diet-induced obesity

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Kleinridders, André, Schenten, Dominik, Könner, A. Christine, Belgardt, Bengt F., Mauer, Jan, Okamura, Tomoo, Wunderlich, F. Thomas, Medzhitov, Ruslan +1 more·2009·Cell Metabolism

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 (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.

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Crossref · 10.1016/j.cmet.2009.08.013

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  • Prolonged saturated fat intake can impair central leptin and insulin signaling in rodents.

    “Prolonged saturated fat intake can interfere with energy homeostasis by stimulating visceral adipose deposition and inflammation in humans [23] and impairing central leptin and insulin signaling in rodents [24,25].”

    From The menace of obesity to depression and anxiety prevalence (2022) · cites this paper as [25]

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  1. Posey KA Clegg DJ Printz RL Byun J Morton GJ Vivekanandan-Giri A Pennathur S Baskin DG Heinecke JW Woods SC Hypothalamic proinflammatory lipid accumulation, inflammation, and insulin resistance in rats fed a high-fat diet Am J Physiol Endocrinol Metab 2009 296 E1003 E1012 19116375 PMC2681305

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Authors
Kleinridders, A., Schenten, D., Könner, A. C., Belgardt, B. F., Mauer, J., Okamura, T., Wunderlich, F. T., Medzhitov, R., & Brüning, J. C.
Affiliations
  • University of Cologne (DE)
  • Howard Hughes Medical Institute (US)
Corresponding author
Brüning, Jens C.
Venue
Cell Metabolism
Publisher
Elsevier BV
Published
2009-10
Volume
10
Issue
4
Pages
249-259
ISSN
1550-4131 (ISSN-L)
OpenAlex
W2075792687
Cited by
483
References
61
Citations by year
2026: 6 · 2025: 10 · 2024: 11 · 2023: 19 · 2022: 29 · 2021: 25 · 2020: 28 · 2019: 33 · 2018: 31 · 2017: 48 · 2016: 33 · 2015: 29 · 2014: 41 · 2013: 38 · 2012: 43
FWCI
15.27
Type
journal article
Language
en
Open access
Locations
  • Cell Metabolism (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institute of Allergy and Infectious Diseases (R01AI055502, AI055502)
Topics
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
  • Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
MyD88, TLR4 signaling, leptin resistance, diet-induced obesity, high-fat diet, palmitate, central nervous system, STAT3, insulin resistance, glucose metabolism, neuronal signaling, appetite regulation
MeSH terms
Animals, Central Nervous System, Diet, Dietary Fats, Eating, Energy Metabolism, Enzyme Activation, Female, Glucose, Homeostasis, Humans, Insulin, Insulin Resistance, Male, Mice, Inbred C57BL, Mice, Transgenic, Motor Activity, Obesity, Signal Transduction, Weight Gain, Palmitic Acid, Leptin, Mice, I-kappa B Kinase, Myeloid Differentiation Factor 88

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