Impaired Insulin Signaling is Associated with Hepatic Mitochondrial Dysfunction in IR+/--IRS-1+/- Double Heterozygous (IR-IRS1dh) Mice.

Andras Franko,Rudolf Wiesner,Ursula Hartmann,Jürgen-Christoph Von Kleist-Retzow,Alexander Kunze,Marlen Böse,Mats Paulsson

doi:10.3390/ijms18061156

Abstract

Mitochondria play a pivotal role in energy metabolism, but whether insulin signaling per se could regulate mitochondrial function has not been identified yet. To investigate whether mitochondrial function is regulated by insulin signaling, we analyzed muscle and liver of insulin receptor (IR)+/−-insulin receptor substrate-1 (IRS-1)+/− double heterozygous (IR-IRS1dh) mice, a well described model for insulin resistance. IR-IRS1dh mice were studied at the age of 6 and 12 months and glucose metabolism was determined by glucose and insulin tolerance tests. Mitochondrial enzyme activities, oxygen consumption, and membrane potential were assessed using spectrophotometric, respirometric, and proton motive force analysis, respectively. IR-IRS1dh mice showed elevated serum insulin levels. Hepatic mitochondrial oxygen consumption was reduced in IR-IRS1dh animals at 12 months of age. Furthermore, 6-month-old IR-IRS1dh mice demonstrated enhanced mitochondrial respiration in skeletal muscle, but a tendency of impaired glucose tolerance. On the other hand, 12-month-old IR-IRS1dh mice showed improved glucose tolerance, but normal muscle mitochondrial function. Our data revealed that deficiency in IR/IRS-1 resulted in normal or even elevated skeletal muscle, but impaired hepatic mitochondrial function, suggesting a direct cross-talk between insulin signaling and mitochondria in the liver.

Highlights

Since mitochondria have a central role in cellular metabolism, there is dynamic and continuous crosstalk between them and other organelles like nucleus, endoplasmic reticulum (ER), and cell membrane, using metabolites like ATP, NAD(P)H, reactive oxygen species (ROS), tricarboxylic cycle (TCA) metabolites as well as calcium as signaling molecules [1]
While in 6-month-old insulin receptor (IR)-IRS1dh mice there seemed to be a tendency of impaired glucose tolerance, 12-month-old IR-IRS1dh mice demonstrated improved glucose metabolism compared to age-matched wt controls (Figure 1A–D)
IR+/−-insulin receptor substrate-1 (IRS-1)+/− double heterozygous (IR-IRS1dh) mice showed attenuated insulin signaling in skeletal muscle and liver [12], which caused a pancreatic β-cell hyperplasia [9,11], in parallel with the elevated insulin levels (Table 1)

Summary

Introduction

Since mitochondria have a central role in cellular metabolism, there is dynamic and continuous crosstalk between them and other organelles like nucleus, endoplasmic reticulum (ER), and cell membrane, using metabolites like ATP, NAD(P)H, reactive oxygen species (ROS), tricarboxylic cycle (TCA) metabolites as well as calcium as signaling molecules [1]. Mitochondrial dysfunction is implicated in many diseases and there is increasing evidence that mitochondrial function in skeletal muscle or liver is altered in insulin resistance and diabetes [2,3]. We already investigated the interaction between insulin resistance and mitochondrial function in different tissues like muscle and liver in various animal models. We found that the ablation of insulin receptor in muscle (MIRKO mice) or insulin deficiency caused by beta-cell reduction (streptozotocin (STZ) treated mice) led to an impairment of skeletal muscle mitochondrial performance [4]. Liver mitochondria of insulin-deficient STZ mice showed better coupling and elevated oxygen consumption [5], suggesting a compensatory capacity of liver in insulin-deficient states [6]

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