Loss of Toll-Like Receptor 4 Function Partially Protects against Peripheral and Cardiac Glucose Metabolic Derangements During a Long-Term High-Fat Diet

Abstract

Diabetes is a chronic inflammatory disease that carries a high risk of cardiovascular disease. However, the pathophysiological link between these disorders is not well known. We hypothesize that TLR4 signaling mediates high fat diet (HFD)-induced peripheral and cardiac glucose metabolic derangements. Mice with a loss-of-function mutation in TLR4 (C3H/HeJ) and age-matched control (C57BL/6) mice were fed either a high-fat diet or normal diet for 16 weeks. Glucose tolerance and plasma insulin were measured. Protein expression of glucose transporters (GLUT), AKT (phosphorylated and total), and proinflammatory cytokines (IL-6, TNF-α and SOCS-3) were quantified in the heart using Western Blotting. Both groups fed a long-term HFD had increased body weight, blood glucose and insulin levels, as well as impaired glucose tolerance compared to mice fed a normal diet. TLR4-mutant mice were partially protected against long-term HFD-induced insulin resistance. In control mice, feeding a HFD decreased cardiac crude membrane GLUT4 protein content, which was partially rescued in TLR4-mutant mice. TLR4-mutant mice fed a HFD also had increased expression of GLUT8, a novel isoform, compared to mice fed a normal diet. GLUT8 content was positively correlated with SOCS-3 and IL-6 expression in the heart. No significant differences in cytokine expression were observed between groups, suggesting a lack of inflammation in the heart following a HFD. Loss of TLR4 function partially restored a healthy metabolic phenotype, suggesting that TLR4 signaling is a key mechanism in HFD-induced peripheral and cardiac insulin resistance. Our data further suggest that TLR4 exerts its detrimental metabolic effects in the myocardium through a cytokine-independent pathway.

Endothelial Stanniocalcin 1 Maintains Mitochondrial Bioenergetics and Prevents Oxidant-Induced Lung Injury via Toll-Like Receptor 4

“…Pyruvate can then either enter the tricarboxylic acid (TCA) cycle in the mitochondria, where it undergoes oxidative phosphorylation in a process that requires oxygen, or it can be further converted into lactate (anaerobic glycolysis) (34). Mice with a loss-of-function mutation in TLR4 (C3H/HeJ) were partially protected against cardiac glucose metabolism dysregulation induced by a long-term high-fat diet (20). TLR4 regulates lipid accumulation in cardiac muscle in type 1 diabetes, which contributes to cardiac dysfunction (7).…”

Adverse Metabolic Effects of Diltiazem Treatment During Diabetic Cardiomyopathy

“…GLUT4 is the key player in insulin-mediated glucose transport and its protein content is decreased in insulin-sensitive tissues of patients with diabetes. 38,58 -60 Accordingly, in the current study, STZ-treated rodents had significantly less GLUT4 protein content in a crude membrane extract of striated muscle than their control counterparts. Not only was this decrease not rescued by treatment with diltiazem, but it was further worsened in both cardiac and skeletal muscle.…”

Metabolism and Metabolic Disorders and the Microbiome: The Intestinal Microbiota Associated With Obesity, Lipid Metabolism, and Metabolic Health—Pathophysiology and Therapeutic Strategies

“…Several studies further confirmed the protective metabolic effects of TLR4 deficiency [63][64][65][66] , as reviewed in 67 . Finally, the relevance of TLR4 was suggested in humans, as TLR4 expression, protein content and signaling is higher in muscle tissue of individuals with obesity and T2D than in lean controls 68 .…”