TLR4 in bone marrow-derived cells is a mediator of obesity-related insulin resistance

Author(s)

Daniela Soares Razolli

• Document type: Doctoral Thesis
• Press: Campinas, SP.
• Institution: Universidade Estadual de Campinas (UNICAMP). Faculdade de Ciências Médicas
• Defense date: 2014-07-15

Examining board members

Licio Augusto Velloso; Alicia Juliana Kowaltowski; Jean Pierre Schatzmann Peron; Helena Coutinho Franco de Oliveira; Gabriel Forato Anhê

• Advisor: Licio Augusto Velloso

Abstract

Saturated fatty acid-induced activation of TLR4 is one of the most important mechanisms involved in the development of insulin resistance. However, it is not clear if this effect is due to activation of TLR4 present in bone marrow (BM)-derived cells, in cells present in tissues that are targets for insulin action, or in both. The aim of the present study was to investigate if a defective TLR4 signaling in bone-marrow (BM) derived cells is sufficient to modulate the whole-body insulin action. TLR4-mutant (TLR4-/-) and wild-type (WT) mice were irradiated in a cobalt 60 source and submitted to bone marrow transplantation (BMT). TLR4-/- received BM from WT and vice-versa. After recovery, mice were fed on a high fat diet (HFD) or standard chow for eight weeks. We evaluated body mass gain, food intake, energy expenditure and markers of thermogenesis in brown adipose tissue (BAT). Insulin sensitivity was analyzed by GTT, ITT and AKT phosphorylation in liver and adipose tissue. In addition, markers of inflammation were evaluated in both tissues by real-time PCR. WT submitted to BMT from TLR4-/- donors were protected from HFD-induced obesity and insulin resistance. In TLR4-/- submitted to BMT from WT donors this effect was blunted and mice gained weight and became insulin resistant. Phenotype transfer regarding body mass was accompanied by change in energy efficiency and expression of UCP1 in brown adipose tissue. Phenotype transfer regarding insulin resistance was accompanied by changes in insulin signal transduction through AKT in liver and adipose tissue. Particularly, in the liver, the presence of a functional TLR4 in BM-derived cells was a determinant factor for the development of steatosis. Finally, the presence of a functional TLR4 in BM-derived cells was accompanied by the increased expression of inflammatory cytokines and reduced expression of at least one anti-inflammatory cytokine in the liver and adipose tissue. Thus, we conclude that the presence or absence of TLR4 in BM-derived cells is both sufficient and necessary for the induction of obesity and insulin resistance induced by diet (AU)

• FAPESP's process: 11/08935-3 - The role of Toll-like receptor 4 in metabolic pathways of mice C3H/HeJ and C3H/HePas with diet-induced obesity
• Grantee: Daniela Soares Razolli
• Support Opportunities: Scholarships in Brazil - Doctorate