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- Title
Inhibition or Deletion of the LPS Receptor Toll-Like Receptor 4 (TLR-4) Confers Partial Protection Against Lipid-Induced Insulin Resistance.
- Authors
Radin, Michael S.; Sinha, Sandeep; Bhatt, Bankim A.; Dedousis, Nikolaos; O'Doherty, Robert M.
- Abstract
A role for increased activity of the innate immune system in the pathogenesis of insulin resistance (IR) in obesity/Type II diabetes has been proposed and is supported by a number of studies. However, elements of the immune system that may play a role in the development of IR and the mechanisms of their activation remain unclear. The current study addressed the potential role of one component of the innate immune system, the LPS receptor Toll-like Receptor-4 (TLR-4), in lipid-induced IR in rat L6 myotubes and in TLR-4 null mice in vivo. In L6 myotubes, inhibition of TLR-4 activity reduced the capacity of the saturated fatty acid palmitate (PAL, Figure 1) to induce IR. In vivo, an absence of TLR-4 conferred partial protection against the capacity of acute hyperlipidemia to induce IR (Figure 2). In response to a high fat diet, TLR4 null mice developed similar levels of IR, but had reduced adiposity, steatosis, and weight gain compared to wild-type mice. To address potential mechanisms for the beneficial effects of TLR-4 inhibition/absence on insulin action the consequence of inhibition/absence of TLR-4 on lipid-induced activation of the NF-kappaB pathway was addressed, PAL activated the NF-kappaB pathway in L6 myotubes and mouse skeletal muscle. Importantly, these effects were blocked by inhibition of TLR-4 in L6 cells and absence of TLR-4 in skeletal muscle. We conclude that inhibition or absence of TLR-4 confers partial protection against the detrimental effects of lipids on insulin action. We speculate that one mechanism for the beneficial effects of TLR-4 inhibition/deletion is a reduced capacity of lipids to activate the NF-kappB pathway in skeletal muscle. ADA-Funded Research
- Subjects
LIPIDS; INSULIN resistance; OBESITY; CELL receptors; LABORATORY mice
- Publication
Diabetes, 2007, Vol 56, pA85
- ISSN
0012-1797
- Publication type
Article