Effects of hepatic mitochondrial pyruvate carrier deficiency on de novo lipogenesis and gluconeogenesis in mice

Yiew, Nicole K.H.; Deja, Stanislaw; Ferguson, Daniel; Cho, Kevin; Jarasvaraparn, Chaowapong; Jacome-Sosa, Miriam; Lutkewitte, Andrew J.; Mukherjee, Sandip; Fu, Xiaorong; Singer, Jason M.; Patti, Gary J.; Burgess, Shawn C.; Finck, Brian N.

doi:10.1016/j.isci.2023.108196

Cited by 3 publications

(7 citation statements)

References 46 publications

(83 reference statements)

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“…Disruption of this process does not alter the whole-body phenotypic adaptation to dietary stress, highlighting the remarkable flexibility for mitochondrial substrate selection towards metabolic homeostasis. Our findings are highly consistent with a recent report that loss of liver MPC constrains hepatic DNL during fasted refeeding in mice without impacting hepatic steatosis or circulating lipid concentrations (Yiew et al, 2023). However, our findings provide the first evidence of sexual dimorphism in MPC-gated metabolism and thus advance understanding of the molecular mechanisms underlying sex differences in adipose biology and metabolic physiology.…”

Section: Discussionsupporting

confidence: 93%

“…These findings mirror the partial suppression of glucose synthesis from glycerol via the indirect pathway (i.e. gluconeogenesis) in MPC deficient livers (Yiew et al, 2023). Our tracer methodology cannot discriminate between the direct and indirect synthesis of glycerol-3-phopshate from glucose.…”

Section: Discussionsupporting

confidence: 61%

“…Interestingly, ZFD-fed Mpc1 AD-/females displayed reduced adipose alanine concentrations, suggesting increased alanine utilization under these conditions. However, succinate and malate concentrations were also reduced which, consistent with MPC inhibition in hepatocytes (Yiew et al, 2023), underscores the obligate dependence on the direct import of mitochondrial pyruvate via the MPC to maintain TCA cycle intermediate pool sizes. Notably, lipogenic gene expression was increased in Mpc1 AD-/female adipose, suggesting transcriptional compensation for the loss of glucose-derived lipogenic acetyl-CoA.…”

Section: Discussionsupporting

confidence: 58%

“…Thus, whereas adipose ACLY appears conditionally essential for body fat accretion in females (Fernandez et al, 2019), reliance on MPC-gated metabolism for adipose accumulation may be obviated by compensatory pathways supporting adipose DNL from non-glucose precursors. Indeed, prior work has demonstrated considerable redundancy in the regulation of metabolic processes by the MPC (Gray et al, 2015; McCommis et al, 2015; Yiew et al, 2023). For example, cytosolic conversion of pyruvate to alanine circumvents mitochondrial pyruvate transport to support hepatic gluconeogenesis (McCommis et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

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Sex-dependent adipose glucose partitioning by the mitochondrial pyruvate carrier

Shannon,

Bakewell,

Fourcaudot

et al. 2024

Preprint

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ObjectiveThe mitochondrial pyruvate carrier (MPC) occupies a critical node in intermediary metabolism, prompting interest in its utility as a therapeutic target for the treatment of obesity and cardiometabolic disease. Dysregulated nutrient metabolism in adipose tissue is a prominent feature of obesity pathophysiology, yet the functional role of adipose MPC has not been explored. We investigated whether the MPC shapes the adaptation of adipose tissue to dietary stress in female and male mice.MethodsThe impact of pharmacological and genetic disruption of the MPC on mitochondrial pathways of triglyceride assembly (lipogenesis and glyceroneogenesis) was assessed in 3T3L1 adipocytes and murine adipose explants, combined with analyses of adipose MPC expression in metabolically compromised humans. Whole-body and adipose-specific glucose metabolism were subsequently investigated in male and female mice lacking adipocyte MPC1 (Mpc1AD-/-) and fed either standard chow, high-fat western style, or high-sucrose lipid restricted diets for 24 weeks, using a combination of radiolabeled tracers and GC/MS metabolomics.ResultsTreatment with UK5099 or siMPC1 impaired the synthesis of lipids and glycerol-3-phosphate from pyruvate and blunted triglyceride accumulation in 3T3L1 adipocytes, whilst MPC expression in human adipose tissue was negatively correlated with indices of whole-body and adipose tissue metabolic dysfunction. Mature adipose explants fromMpc1AD-/-mice were intrinsically incapable of incorporating pyruvate into triglycerides.In vivo, MPC deletion restricted the incorporation of circulating glucose into adipose triglycerides, but only in female mice fed a zero fat diet, and this associated with sex-specific reductions in tricarboxylic acid cycle pool sizes and compensatory transcriptional changes in lipogenic and glycerol metabolism pathways. However, whole-body adiposity and metabolic health were preserved inMpc1AD-/-mice regardless of sex, even under conditions of zero dietary fat.ConclusionThese findings highlight the greater capacity for mitochondrially driven triglyceride assembly in adipose from female versus male mice and expose a reliance upon MPC-gated metabolism for glucose partitioning in female adipose under conditions of dietary lipid restriction.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 61%

Section: Discussionsupporting

confidence: 58%

Section: Discussionmentioning

confidence: 99%

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Sex-dependent adipose glucose partitioning by the mitochondrial pyruvate carrier

Shannon,

Bakewell,

Fourcaudot

et al. 2024

Preprint

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“…The generation of LS- Mpc2 − /− and LS- Gpt2 − /− mice has been described previously ( 18 , 24 ). Gpt2 fl/fl mice were mated with LS- Mpc2 − /− mice to generate LS- Gpt2/Mpc2 −/− (DKO) mice ( 26 , 27 ). Littermate mice not expressing Cre (fl/fl mice or double Mpc2 / Gpt2 fl/fl mice) were used as control mice in all experiments.…”

Section: Methodsmentioning

confidence: 99%

Disruption of hepatic mitochondrial pyruvate and amino acid metabolism impairs gluconeogenesis and endurance exercise capacity in mice

Martino,

Habibi,

Ferguson

et al. 2024

American Journal of Physiology-Endocrinology and Metabolism

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Exercise robustly increases the glucose demands of skeletal muscle. This demand is met not only by muscle glycogenolysis, but also by accelerated liver glucose production from hepatic glycogenolysis and gluconeogenesis to fuel mechanical work and prevent hypoglycemia during exercise. Hepatic gluconeogenesis during exercise is dependent on highly coordinated responses within and between muscle and liver. Specifically, exercise increases the rate at which gluconeogenic precursors such as pyruvate/lactate or amino acids are delivered from muscle to the liver, extracted by the liver, and channeled into glucose. Herein, we examined the effects of interrupting gluconeogenic efficiency and capacity on exercise performance by deleting hepatic mitochondrial pyruvate carrier 2 (MPC2) and/or alanine transaminase 2 (ALT2) in mice. We found that deletion of MPC2 or ALT2 alone did not significantly affect time to exhaustion or post-exercise glucose concentrations in treadmill exercise tests, but mice lacking both MPC2 and ALT2 in liver (DKO) reached exhaustion faster and exhibited lower circulating glucose during and after exercise. Use of ²H/¹³C metabolic flux analyses demonstrated that DKO mice exhibited lower endogenous glucose production owing to decreased glycogenolysis and gluconeogenesis at rest and during exercise. The decreased gluconeogenesis was accompanied by lower anaplerotic, cataplerotic, and TCA cycle fluxes. Collectively, these findings demonstrate that the transition of the liver to the gluconeogenic mode is critical for preventing hypoglycemia and sustaining performance during exercise. The results also illustrate the need for interorgan crosstalk during exercise as described by the Cahill and Cori cycles.

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The mitochondrial pyruvate carrier regulates adipose glucose partitioning in female mice

Shannon,

Bakewell,

Fourcaudot

et al. 2024

Molecular Metabolism

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Effects of hepatic mitochondrial pyruvate carrier deficiency on de novo lipogenesis and gluconeogenesis in mice

Cited by 3 publications

References 46 publications

Sex-dependent adipose glucose partitioning by the mitochondrial pyruvate carrier

Sex-dependent adipose glucose partitioning by the mitochondrial pyruvate carrier

Disruption of hepatic mitochondrial pyruvate and amino acid metabolism impairs gluconeogenesis and endurance exercise capacity in mice

The mitochondrial pyruvate carrier regulates adipose glucose partitioning in female mice

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