Liver-specific reduction of Mfn2 protein by RNAi results in impaired glycometabolism and lipid homeostasis in BALB/c mice

Abstract

Mitofusin-2 (Mfn2) gene expression is positively correlated with insulin sensitivity in patients with type 2 diabetes. However, it is unclear if Mfn2 is involved in carbohydrate metabolism and lipid homeostasis. In order to investigate the specific functions of Mfn2 in glycometabolism and lipid homeostasis in BALB/c mice, a RNA interference technique-mediated hydrodynamic injection was developed, in which short hairpin RNAs (shRNAs) were used to inhibit the Mfn2 expression in vivo. Seventy-two mice were randomly divided into two groups: the Mfn2 reduction group (Mfn2/shRNA) and the negative control group (NC). Intraperitoneal glucose tolerance tests and intraperitoneal insulin tolerance tests were used to evaluate glycometabolism and insulin sensitivity. D-(3-3H) glucose or 3H2O was injected into the tail vein or intraperitoneally to facilitate the calculation of the rate of hepatic glucose production and fatty acid synthesis in vivo. The results showed that, in Mfn2/shRNA mice, the liver Mfn2 protein was significantly decreased, and fasting blood glucose concentrations were increased by approximately 48%, when compared with the NC mice. In parallel with the changes in fasting glucose levels, hepatic glucose production was significantly elevated in Mfn2/shRNA mice. When insulin was administrated, these mice exhibited impaired insulin tolerance. It was also found that the reduction of Mfn2 markedly decreased the rate of fatty acid synthesis in the liver, and the Mfn2/shRNA mice exhibited hypertriglyceridema. Taken together, our results indicate that Mfn2 plays an important role in maintaining glucose and lipid homeostasis, and in the development of insulin resistance in vivo.

Increased Insulin Sensitivity and Distorted Mitochondrial Adaptations during Muscle Unloading

“…Compared to Mfn1, Mfn2 is independent of its role as a mitofusin, and it can also trigger mitochondrial energization by regulating OXPHOS expression [50]. Mfn2 reduction decreased the rate of fatty acid synthesis in the liver, and the Mfn2/shRNA mice exhibited hypertriglyceridema, suggesting that Mfn2 played an important role in maintaining glucose and lipid homeostasis [51]. Repression of Mfn2 reduced glucose oxidation, mitochondrial membrane potential, cell respiration, and mitochondrial proton leak and reduced Mfn2 expression may explain some of the metabolic alterations associated with obesity [52].…”

MFN2 knockdown promotes osteogenic differentiation of iPSC-MSCs through aerobic glycolysis mediated by the Wnt/β-catenin signaling pathway

“…Our previous studies showed that MFN2 knockdown promoted neural ectodermal differentiation of hESCs [ 8 ]. Several studies have shown that it also plays an important role in mitochondrial metabolism and function, mainly manifested in the effect on glucose oxidation and cellular respiration [ 9 ]. Studies have shown that the lack of MFN2 inhibits the expression of OXPHOS complexes, and its participation in mitochondrial metabolism is independent of mitochondrial fusion [ 10 ].…”

MiR‐195 promotes pancreatic β‐cell dedifferentiation by targeting Mfn2 and impairing Pi3k/Akt signaling in type 2 diabetes

“…A key effector appears to be mitofusin-2 (Mfn2), a mitochondrial fusion protein anchored to the outer mitochondrial membrane that participates in maintaining the mitochondrial morphology and function (14). Several studies have identified that Mfn2 is reduced in the liver and skeletal muscle of diabetic animals (15,16). Mfn2 is regulated through different pathways including phosphatidylinositol 3-kinase (Pi3k)/RAC-alpha serine/threonineprotein kinase (Akt) signaling, and it and may be beneficial to glucose and lipid homeostasis in T2DM (17,18).…”