Impairment of Mitochondrial Respiration in Metabolic Diseases: An Overview.

Mitochondrial dysfunction has emerged as a central pathomechanism in the setting of obesity and diabetes mellitus, linking these intertwined pathologies that share insulin resistance as a common denominator. High-resolution respirometry (HRR) is a state-of-the-art research method currently used to study mitochondrial respiration and its impairment in health and disease. Tissue samples, cells or isolated mitochondria are exposed to various substrate-uncoupler-inhibitor-titration protocols, which allows the measurement and calculation of several parameters of mitochondrial respiration. In this review, we discuss the alterations of mitochondrial bioenergetics in the main dysfunctional organs that contribute to the development of the obese and diabetic phenotypes in both animal models and human subjects. Herein we review data regarding the impairment of oxidative phosphorylation as integrated mitochondrial function assessed by means of HRR. We acknowledge the critical role of this method in determining the alterations in oxidative phosphorylation occurring in the early stages of metabolic pathologies. We conclude that there is a mutual two-way relationship between mitochondrial dysfunction and insulin insensitivity that characterizes these diseases.

Liraglutide improves insulin sensitivity in high fat diet induced diabetic mice through multiple pathways.

Glucagon like peptide-1 (GLP-1) promotes postprandial insulin secretion. Liraglutide, a full agonist of the GLP-1 receptor, reduces body weight, improve insulin sensitivity, and alleviate Non Alcoholic Fatty Liver Disease (NAFLD). However, the underlying mechanisms remain unclear. This study aims to explore the underlying mechanisms and cell signaling pathways involved in the anti-obesity and anti-inflammatory effects of liraglutide. Mice were fed a high fat high sucrose diet to induce diabetes, diabetic mice were divided into two groups and injected with liraglutide or vehicle for 14 days. Liraglutide treatment improved insulin sensitivity, accompanied with reduced expression of the phosphorylated Acetyl-CoA carboxylase-2 (ACC2) and upregulation of long chain acyl CoA dehydrogenase (LCAD) in insulin sensitive tissues. Furthermore, liraglutide induced adenosine monophosphate-activated protein kinase-α (AMPK-α) and Sirtuin-1(Sirt-1) protein expression in liver and perigonadal fat. Liraglutide induced elevation of fatty acid oxidation in these tissues may be mediated through the AMPK-Sirt-1 cell signaling pathway. In addition, liraglutide induced brown adipocyte differentiation in skeletal muscle, including induction of uncoupling protein-1 (UCP-1) and PR-domain-containing-16 (PRDM-16) protein in association with induction of SIRT-1. Importantly, liraglutide displayed anti-inflammation effect. Specifically, liraglutide led to a significant reduction in circulating interleukin-1 ß (IL-1 ß) and interleukin-6 (IL-6) as well as hepatic IL-1 ß and IL-6 content. The expression of inducible nitric oxide synthase (iNOS-1) and cyclooxygenase-2 (COX-2) in insulin sensitive tissues was also reduced following liraglutide treatment. In conclusion, liraglutide improves insulin sensitivity through multiple pathways resulting in reduction of inflammation, elevation of fatty acid oxidation, and induction of adaptive thermogenesis.

Berberine hydrochloride protects against cytokine-induced inflammation through multiple pathways in undifferentiated C2C12 myoblast cells.

Obesity is associated with skeletal muscle insulin resistance and the development of metabolic syndrome. Undifferentiated skeletal muscle cells are sensitive to oxidative stress. Berberine hydrochloride (BBR) improves insulin resistance and exhibits anti-inflammatory properties. However, the underlying mechanism and the cell signaling pathways involved remain largely elusive. We therefore investigated the anti-inflammatory effects of BBR and the signaling pathways using skeletal C2C12 myoblast cells. Undifferentiated C2C12 myoblast cells were treated with interleukin-1ß alone or in combination with tumor necrosis factor-α in the presence or absence of BBR. We found that BBR reduced the cytokine-induced expression of inducible nitric oxide synthase and stress-related kinases including p-38 mitogen-activated protein kinase, nuclear factor kappa B (NF-κB), and stress-activated protein kinases/Jun amino-terminal kinases (SAPK/JNK) in C2C12 myoblast cells. Furthermore, BBR reversed cytokine-mediated suppression of AMP-activated protein kinase (AMPKα), sirtuin-1 (SIRT-1), and PPAR-γ coactivator-1α (PGC-1α). In addition, cytokine-induced reduction of mitochondrial marker proteins and function were rescued after BBR treatment. Catalase, an antioxidant enzyme, was elevated after BBR treatment. Our results demonstrate that BBR ameliorates cytokine-induced inflammation. The anti-inflammatory effect of BBR in skeletal progenitor cells is mediated through pathways including activation of the AMPKα-SIRT-1-PGC-1α, inhibition of the mitogen-activated protein kinase 4 (MKK4)-SAPK/JNK-C-JUN, as well as protection of mitochondrial bioenergetics. BBR may be a potential medication for metabolic syndrome.