Adipose tissues of MPC1^± mice display altered lipid metabolism-related enzyme expression levels

Abstract

Mitochondrial pyruvate carrier 1 (MPC1) is a component of the MPC1/MPC2 heterodimer that facilitates the transport of pyruvate into mitochondria. Pyruvate plays a central role in carbohydrate, fatty, and amino acid catabolism. The present study examined epididymal white adipose tissue (eWAT) and intrascapular brown adipose tissue (iBAT) from MPC1± mice following 24 weeks of feeding, which indicated low energy accumulation as evidenced by low body and eWAT weight and adipocyte volume. To characterize molecular changes in energy metabolism, we analyzed the transcriptomes of the adipose tissues using RNA-Sequencing (RNA-Seq). The results showed that the fatty acid oxidation pathway was activated and several genes involved in this pathway were upregulated. Furthermore, qPCR and western blotting indicated that numerous genes and proteins that participate in lipolysis were also upregulated. Based on these findings, we propose that the energy deficiency caused by reduced MPC1 activity can be alleviated by activating the lipolytic pathway.

Mitochondrial Pyruvate Carriers are not Required for Adipogenesis but are Regulated by High‐Fat Feeding in Brown Adipose Tissue

“…Although our findings show that the loss of MPC expression in vitro has no effect on adipocyte development, other in vivo studies have found that C57BL/6 mice with an adipocyte-specific loss of MPC1 had increased fatty acid oxidation, increased levels of triglycerides in circulation, deficiencies in storage of triglycerides, and mitochondrial damage. It also has been observed that heterozygous MPC1 knockdown mice had decreased body weight, activity, and fat accumulation and low body shell temperatures during cold exposure (8,27).…”

“…Thiazolidinediones inhibit MPCs in several cell types, and in skeletal muscle, inhibition of MPCs is associated with increased glucose uptake and increased insulin sensitivity. Using the CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR‐associated protein 9) system, a heterozygous MPC1 knockdown model was generated, and these mice had reduced lipid accumulation, increased lipolysis, enhanced fatty acid oxidation, and decreased energy expenditure . During adipogenesis, mitochondrial density is increased by 20‐ to 30‐fold along with increases in mitochondrial gene expression and oxidative capacity to meet increasing energy requirements .…”

Blocking mitochondrial pyruvate import in brown adipocytes induces energy wasting via lipid cycling

“…It remains to be determined whether MPC inhibition can promote fat oxidation and lipid cycling in white adipocytes, which would be especially interesting considering that most depots of human adipose tissue are white or beige. Multiple groups have demonstrated that modulation of MPC activity acts as a mitochondrial fuel preference switch in various tissues and conditions (Vacanti et al, 2014;Yang et al, 2014;Gray et al, 2015;Divakaruni et al, 2017;Schell et al, 2017;Zou et al, 2018aZou et al, , 2018b. However, in these studies, pharmacological inhibition, or genetic deletion of the MPC led to reduced or unchanged mitochondrial respiration.…”

“…Multiple groups have demonstrated that modulation of MPC activity acts as a mitochondrial fuel preference switch in various tissues and conditions (Vacanti et al , 2014; Yang et al , 2014; Gray et al , 2015; Divakaruni et al , 2017; Schell et al , 2017; Zou et al , 2018a, 2018b). However, in these studies, pharmacological inhibition, or genetic deletion of the MPC led to reduced or unchanged mitochondrial respiration.…”

Blocking mitochondrial pyruvate import causes energy wasting via futile lipid cycling in brown fat

“…Multiple studies have demonstrated that the modulation of MPC activity can act as a mitochondrial fuel preference switch in various tissues [14,17,31,[34][35][36][37]. However, in these studies, pharmacological inhibition or genetic deletion of the MPC led to reduced or unchanged mitochondrial respiration.…”