Transgenic mice with ectopic expression of constitutively active TLR4 in adipose tissues do not show impaired insulin sensitivity

Kikumi D. Ono-Moore, Ling Zhao, Shurong Huang, Jeonga Kim, Jennifer M. Rutkowsky, Ryan G. Snodgrass, Dina A. Schneider, Michael J. Quon, James L. Graham, Peter J Havel, Daniel H. Hwang

Research output: Contribution to journalArticle

Abstract

Introduction: Chronic low-grade inflammation is associated with obesity and diabetes. However, what causes and mediates chronic inflammation in metabolic disorders is not well understood. Toll-like receptor 4 (TLR4) mediates both infection-induced and sterile inflammation by recognizing pathogen-associated molecular patterns and endogenousmolecules, respectively. Saturated fatty acids can activate TLR4, and TLR4-deficient mice were protected from high fat diet (HFD)- induced obesity and insulin resistance, suggesting that TLR4-mediated inflammation may cause metabolic dysfunction, such as obesity and insulin resistance. Methods: We generated two transgenic (TG) mouse lines expressing a constitutively active TLR4 in adipose tissue and determined whether these TG mice would show increased insulin resistance. Results: TG mice fed a high fat or a normal chow diet did not exhibit increased insulin resistance compared to their wild-type controls despite increased localized inflammation in white adipose tissue. Furthermore, females of one TG line fed a normal chow diet had improved insulin sensitivity with reduction in both adiposity and body weight when compared with wild-type littermates. There were significant differences between female and male mice in metabolic biomarkers and mRNA expression in proinflammatory genes and negative regulators of TLR4 signaling, regardless of genotype and diet. Conclusions: Together, these results suggest that constitutively active TLR4- induced inflammation in white adipose tissue is not sufficient to induce systemic insulin resistance, and that high fat diet-induced insulin resistance may require other signals in addition to TLR4-mediated inflammation.

Original languageEnglish (US)
Pages (from-to)526-540
Number of pages15
JournalImmunity Inflammation and Disease
Volume5
Issue number4
DOIs
StatePublished - Jan 1 2017

Fingerprint

Toll-Like Receptor 4
Transgenic Mice
Insulin Resistance
Adipose Tissue
Inflammation
White Adipose Tissue
Obesity
High Fat Diet
Diet
Adiposity
Regulator Genes
Ectopic Gene Expression
Fatty Acids
Biomarkers
Fats
Genotype
Body Weight
Messenger RNA
Infection

Keywords

  • Adipose tissue
  • Insulin sensitivity
  • TLR4
  • Transgenic

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Transgenic mice with ectopic expression of constitutively active TLR4 in adipose tissues do not show impaired insulin sensitivity. / Ono-Moore, Kikumi D.; Zhao, Ling; Huang, Shurong; Kim, Jeonga; Rutkowsky, Jennifer M.; Snodgrass, Ryan G.; Schneider, Dina A.; Quon, Michael J.; Graham, James L.; Havel, Peter J; Hwang, Daniel H.

In: Immunity Inflammation and Disease, Vol. 5, No. 4, 01.01.2017, p. 526-540.

Research output: Contribution to journalArticle

Ono-Moore, KD, Zhao, L, Huang, S, Kim, J, Rutkowsky, JM, Snodgrass, RG, Schneider, DA, Quon, MJ, Graham, JL, Havel, PJ & Hwang, DH 2017, 'Transgenic mice with ectopic expression of constitutively active TLR4 in adipose tissues do not show impaired insulin sensitivity', Immunity Inflammation and Disease, vol. 5, no. 4, pp. 526-540. https://doi.org/10.1002/iid3.162
Ono-Moore, Kikumi D. ; Zhao, Ling ; Huang, Shurong ; Kim, Jeonga ; Rutkowsky, Jennifer M. ; Snodgrass, Ryan G. ; Schneider, Dina A. ; Quon, Michael J. ; Graham, James L. ; Havel, Peter J ; Hwang, Daniel H. / Transgenic mice with ectopic expression of constitutively active TLR4 in adipose tissues do not show impaired insulin sensitivity. In: Immunity Inflammation and Disease. 2017 ; Vol. 5, No. 4. pp. 526-540.
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AU - Snodgrass, Ryan G.

AU - Schneider, Dina A.

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AB - Introduction: Chronic low-grade inflammation is associated with obesity and diabetes. However, what causes and mediates chronic inflammation in metabolic disorders is not well understood. Toll-like receptor 4 (TLR4) mediates both infection-induced and sterile inflammation by recognizing pathogen-associated molecular patterns and endogenousmolecules, respectively. Saturated fatty acids can activate TLR4, and TLR4-deficient mice were protected from high fat diet (HFD)- induced obesity and insulin resistance, suggesting that TLR4-mediated inflammation may cause metabolic dysfunction, such as obesity and insulin resistance. Methods: We generated two transgenic (TG) mouse lines expressing a constitutively active TLR4 in adipose tissue and determined whether these TG mice would show increased insulin resistance. Results: TG mice fed a high fat or a normal chow diet did not exhibit increased insulin resistance compared to their wild-type controls despite increased localized inflammation in white adipose tissue. Furthermore, females of one TG line fed a normal chow diet had improved insulin sensitivity with reduction in both adiposity and body weight when compared with wild-type littermates. There were significant differences between female and male mice in metabolic biomarkers and mRNA expression in proinflammatory genes and negative regulators of TLR4 signaling, regardless of genotype and diet. Conclusions: Together, these results suggest that constitutively active TLR4- induced inflammation in white adipose tissue is not sufficient to induce systemic insulin resistance, and that high fat diet-induced insulin resistance may require other signals in addition to TLR4-mediated inflammation.

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