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. 2015 May;64(5):1532-43.
doi: 10.2337/db14-0827. Epub 2014 Nov 24.

Muscle-Specific Overexpression of PGC-1α Does Not Augment Metabolic Improvements in Response to Exercise and Caloric Restriction

Kari E Wong  1 , Catherine R Mikus  1 , Dorothy H Slentz  1 , Sarah E Seiler  2 , Karen L DeBalsi  2 , Olga R Ilkayeva  1 , Karen I Crain  3 , Michael T Kinter  4 , C Lawrence Kien  5 , Robert D Stevens  1 , Deborah M Muoio  6
Affiliations

Muscle-Specific Overexpression of PGC-1α Does Not Augment Metabolic Improvements in Response to Exercise and Caloric Restriction

Kari E Wong et al. Diabetes. 2015 May.

Abstract

This study used mice with muscle-specific overexpression of PGC-1α, a transcriptional coactivator that promotes mitochondrial biogenesis, to determine whether increased oxidative potential facilitates metabolic improvements in response to lifestyle modification. MCK-PGC1α mice and nontransgenic (NT) littermates were fed a high-fat diet (HFD) for 10 weeks, followed by stepwise exposures to voluntary wheel running (HFD+Ex) and then 25% caloric restriction with exercise (Ex/CR), each for an additional 10 weeks with continued HFD. Running and CR improved weight and glucose control similarly in MCK-PGC1α and NT mice. Sedentary MCK-PGC1α mice were more susceptible to diet-induced glucose intolerance, and insulin action measured in isolated skeletal muscles remained lower in the transgenic compared with the NT group, even after Ex/CR. Comprehensive profiling of >200 metabolites and lipid intermediates revealed dramatic group-specific responses to the intervention but did not produce a lead candidate that tracked with changes in glucose tolerance irrespective of genotype. Instead, principal components analysis identified a chemically diverse metabolite cluster that correlated with multiple measures of insulin responsiveness. These findings challenge the notion that increased oxidative capacity defends whole-body energy homeostasis and suggest that the interplay between mitochondrial performance, lipotoxicity, and insulin action is more complex than previously proposed.

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Figures

Figure 1
Figure 1
Muscle-specific overexpression of PGC-1α increased mitochondrial preference for lipid substrate. MCK-PGC1α transgenic mice and NT littermates were fed an HFD for 6 weeks prior to experiments. Mitochondria isolated from gastrocnemius muscles were used to assess oxidation of 200 μmol/L [14C]palmitate to CO2 (A) and ASM (B), measured in the absence (FA) or presence (FA+Pyr) of 1 mmol/L pyruvate. Whole-body energy metabolism and exercise performance were assessed during a graded treadmill test during which oxygen consumption (C), distance to exhaustion (D), RER (E), and average RER (F) were evaluated. Values are means ± SEM for 6–9 mice per group. *P < 0.05 between genotypes, **P < 0.005 between genotypes. FA, fatty acid; Pyr, pyruvate.
Figure 2
Figure 2
Muscle-specific overexpression of PGC-1α does not defend against diet-induced obesity or promote weight loss in response to exercise and caloric restriction. A: NT and MCK-PGC1α mice were fed a 45% HFD for 10 weeks prior to 10 weeks of voluntary wheel running (HFD+Ex) followed by an additional 10 weeks of wheel running combined with 25% caloric restriction (Ex/CR) with continued high-fat feeding. B: Body weight measurements taken throughout the course of this study for both sedentary (Sed) and Ex/CR groups. Rates of weight change per week during the three phases of the study for the sedentary (C) and Ex/CR (D) group. E: Caloric intake measured every 2 days during the HFD+Ex phase. F: Food efficiency, an estimate of how much food ingested is converted to body mass (weight gain [g] per week/food ingested [g] per week) during the HFD+Ex phase of the study. G: Average daily running distance during HFD+Ex and Ex/CR. The relationships between running distance and weight gain (H) or weight loss (I) during HFD+Ex and Ex/CR, respectively. Values are means ± SEM for 6–8 mice per group. *P < 0.05 between genotypes. Wgt, weight.
Figure 3
Figure 3
Muscle-specific overexpression of PGC-1α does not defend against glucose intolerance or enhance glucose control in response to exercise and caloric restriction. Mice were fed an HFD for 26 weeks, and measures of insulin action were made at the designated time points. Intraperitoneal glucose tolerance tests (1.5 mg/kg lean body wt) were performed on age-matched cohorts of NT and MCK-PGC1α mice that remained sedentary for the duration of the HFD (A) or were given access to running wheels (HFD+Ex) (B) during weeks 11–20, followed by an additional 10 weeks of exercise combined with 25% caloric restriction (Ex/CR). Blood and tissues were harvested at 30 weeks and used for analysis of fasting insulin levels (C) and glycogen content (D) in gastrocnemius muscles. Insulin-stimulated glycogen synthesis, expressed as fold change relative to basal rates assessed in the contralateral muscles, was measured in isolated soleus (E) and isolated EDL (F). Data were analyzed by two-way ANOVA. A main effect of Ex/CR on insulin, glycogen, and insulin-stimulated glycogen synthesis in the soleus was detected, but symbols were excluded for simplicity. Data represent means ± SEM for 6–8 mice per group. *P < 0.05 between genotypes. #P < 0.05 within a genotype between treatment conditions (sedentary versus Ex/CR). Sed, sedentary; wk, week.
Figure 4
Figure 4
Effects of exercise and caloric restriction on muscle content of TAG, DAG, and ceramides in NT and MCK-PGC1α mice fed an HFD. Lipid metabolites were measured in gastrocnemius muscles of NT and MCK-PGC1α mice after 30 weeks of high-fat feeding without or with exercise and caloric restriction (Ex/CR). Total TAG (A) and individual TAG species (B). Total DAG (C) and individual DAG species (D). Total ceramides (E) and individual ceramide species (F). Two-way ANOVA revealed an interaction between genotype and TAG and DAG levels. Data represent means ± SEM for 6–8 mice per group. Statistical differences were analyzed by two-way ANOVA. *P < 0.05 between genotypes, **P < 0.01 between genotypes, #P < 0.05 within a genotype between treatment conditions (sedentary [Sed] versus Ex/CR).
Figure 5
Figure 5
Effects of exercise and caloric restriction on lipid-derived acylcarnitine and acyl-CoA metabolites in NT and MCK-PGC1α mice fed an HFD. Lipid metabolites were measured by tandem mass spectrometry using gastrocnemius muscles from NT and MCK-PGC1α mice after 30 weeks of high-fat feeding without or with exercise and caloric restriction (Ex/CR). A: Free carnitine and acetylcarnitine. B: Even-chain acylcarnitines. C: Free CoA and acetyl-CoA. D: Even-chain acyl-CoAs. Data represent means ± SEM for 6–8 mice per group. Statistical differences were analyzed by two-way ANOVA. There was an effect of treatment group on free carnitine, acylcarnitine, and acyl-CoA levels. *P < 0.05 between genotypes, #P < 0.05 within a genotype between treatment conditions (sedentary [Sed] versus Ex/CR).
Figure 6
Figure 6
Effects of exercise and caloric restriction on muscle organic and amino acid and plasma acylcarnitine metabolites in NT and MCK-PGC1α mice fed an HFD. Metabolites were measured by tandem mass spectrometry using gastrocnemius muscles from NT and MCK-PGC1α mice after 30 weeks of high-fat feeding without or with exercise and caloric restriction (Ex/CR). A: Organic acids. B: Amino acids. Acylcarnitine (C) and acyl-CoA intermediates (D) of amino acid catabolism. E: Plasma acetylcarnitine (C2). F: Plasma short-chain acylcarnitines. Data represent means ± SEM for 6–8 mice per group. Statistical differences were analyzed by two-way ANOVA. There was an effect of treatment group on organic acid, amino acid, and their acylcarnitine and acyl-CoA metabolites. *P < 0.05 between genotypes, #P < 0.05 within a genotype between treatment conditions (sedentary [Sed] versus Ex/CR).
Figure 7
Figure 7
PCA and factor associations with functional outcomes. PCA was used as a data reduction strategy for exploratory purposes. Factors comprised of strongly corrected metabolites were surveyed for potential relationships with measures of energy and glucose homeostasis (see research design and methods). A: Key metabolites in PCA factors 1–7 and the effect of genotype and treatment (Ex/CR) on each factor. Key metabolites within each retained factor (i.e., metabolites with factor load ≥|0.4|) and an overall description of each factor are presented. Underlined metabolites had a negative load score. *P > 0.05. DC, dicarboxylic, OH, hydroxyl. B: Heat map illustrating the positive (red) and negative (blue) associations between factors 1–7 and physiologic outcome measures. Glucose tolerance test (GTT) (26 weeks [wks]): blood glucose levels measured 120 min after an intraperitoneal glucose injection. ISGS, insulin-stimulated glycogen synthesis.
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