Whole body overexpression of PGC-1alpha has opposite effects on hepatic and muscle insulin sensitivity - PubMed (original) (raw)

Whole body overexpression of PGC-1alpha has opposite effects on hepatic and muscle insulin sensitivity

Huiyun Liang et al. Am J Physiol Endocrinol Metab. 2009 Apr.

Abstract

Type 2 diabetes is characterized by fasting hyperglycemia, secondary to hepatic insulin resistance and increased glucose production. Peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) is a transcriptional coactivator that is thought to control adaptive responses to physiological stimuli. In liver, PGC-1alpha expression is induced by fasting, and this effect promotes gluconeogenesis. To examine whether PGC-1alpha is involved in the pathogenesis of hepatic insulin resistance, we generated transgenic (TG) mice with whole body overexpression of human PGC-1alpha and evaluated glucose homeostasis with a euglycemic-hyperinsulinemic clamp. PGC-1alpha was moderately (approximately 2-fold) overexpressed in liver, skeletal muscle, brain, and heart of TG mice. In liver, PGC-1alpha overexpression resulted in increased expression of hepatocyte nuclear factor-4alpha and the gluconeogenic enzymes phosphoenolpyruvate carboxykinase and glucose-6-phosphatase. PGC-1alpha overexpression caused hepatic insulin resistance, manifested by higher glucose production and diminished insulin suppression of gluconeogenesis. Paradoxically, PGC-1alpha overexpression improved muscle insulin sensitivity, as evidenced by elevated insulin-stimulated Akt phosphorylation and peripheral glucose disposal. Content of myoglobin and troponin I slow protein was increased in muscle of TG mice, indicating fiber-type switching. PGC-1alpha overexpression also led to lower reactive oxygen species production by mitochondria and reduced IKK/IkappaB signaling in muscle. Feeding a high-fat diet to TG mice eliminated the increased muscle insulin sensitivity. The dichotomous effect of PGC-1alpha overexpression in liver and muscle suggests that PGC-1alpha is a fuel gauge that couples energy demands (muscle) with the corresponding fuel supply (liver). Thus, under conditions of physiological stress (i.e., prolonged fast and exercise training), increased hepatic glucose production may help sustain glucose utilization in peripheral tissues.

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Figures

Fig. 1.

A: structure of the human peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) gene (gray area) and its endogenous regulatory sequences in the bacterial artificial chromosome (CTD2238L2) utilized for generation of the transgenic (TG) animal. B: regions where PCR amplifications were carried out for identification of the human PGC-1α gene in the TG animal (P1–P5). C: identification of the human PGC-1α (hPGC-1α) transgene in the TG founders by PCR. RT-PCR demonstrates ubiquitous expression of hPGC-1α in white and brown adipose tissue (WAT and BAT), heart, brain, muscle, kidney, lung, and liver. WT, wild type.

Fig. 2.

A: PGC-1α mRNA expression in heart, brain, liver, gastrocnemius (Gastroc), BAT, and WAT from TG and WT mice. B: Western blot analysis of PGC-1α protein in liver and muscle from WT and TG animals. AU, arbitrary units. C: PGC-1α mRNA expression in liver after 18 h of fasting in 2- to 4-mo-old male and female animals. AL, ad libitum. Values are means ± SE in 4–6 mice per group. *P < 0.05 vs. WT.

Fig. 3.

A: increased basal endogenous (primarily hepatic) glucose production (EGP) in 6-mo-old female TG mice. B: impaired suppression of hepatic glucose production during the clamp in 6-mo-old female TG mice. Values are means ± SE in 5 TG and 7 WT mice. *P < 0.05 vs. WT.

Fig. 4.

Whole body glucose disposal is increased in 6-mo-old female TG mice. Values are means ± SE in 5 TG and 7 WT mice. *P < 0.05 vs. WT.

Fig. 5.

Glucose tolerance was improved after intraperitoneal injection of glucose in 6-mo-old female TG mice. Values are means ± SE in 8 mice per group. *P < 0.05 vs. WT.

Fig. 6.

A–C: increased gene expression of hepatic nuclear receptor (HNF)-4α and the gluconeogenic enzymes phospho_enol_pyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) in liver of 4- to 6-mo-old male and female ad libitum-fed PGC-1α TG mice. D: higher levels of mRNA for proteins involved in oxidative phosphorylation, such as cyclooxygenase (COX) subunits II and IV and cytochrome c (Cyt.c), in liver of 4- to 6-mo-old male and female ad libitum-fed PGC-1α TG mice. Values are means ± SE in 6–9 mice per group. *P < 0.05 vs. WT.

Fig. 7.

A and B: Western blot analysis of myoglobin and troponin I slow protein content in quadriceps muscle of 4- to 6-mo-old male and female mice in the basal state. *P < 0.05 vs. WT. C: higher levels of mRNA for COX subunits II and IV in muscle of 4- to 6-mo-old male and female TG compared with WT mice. D: Akt-Ser476 phosphorylation (p-Akt) in quadriceps muscle in the basal state (non-insulin-infused animals) and at the end of the insulin clamp in 4- to 6-mo-old male and female mice. *P < 0.05 vs. basal. †P < 0.05 vs. WT during clamp. E–G: basal Akt, GLUT4, and GLUT1 content in quadriceps muscle of 4- to 6-mo-old male and female mice. Values are means ± SE in 6–8 mice per group.

Fig. 8.

Basal p38 MAPK phosphorylation (A), JNK phosphorylation (B), and IκBα abundance (C) in quadriceps muscle of 6-mo-old female mice. Values are means ± SE in 6 mice per group. *P < 0.05 vs. WT.

Fig. 9.

Diacylglycerol (DAG) and ceramide content in liver (A) and quadriceps muscle (B) from standard chow-fed animals. C: carnitine palmitoyltransferase (CPT-1A) and medium-chain acyl CoA dehydrogenase (MCAD) as measured by real-time PCR in liver and muscle. D: H2O2 production by mitochondria isolated from muscle. Succinate (succ), malate (mal), and glutamate (Glu) were used as substrates for respiration. Rote, rotenone. Values are means ± SE in 6 (4- to 6-mo-old male and female) mice per group. *P < 0.05 vs. WT.

Fig. 10.

Under high-fat diet (HFD) conditions, insulin suppression of endogenous glucose production (A) and peripheral insulin sensitivity (B) during clamp are similar in TG and WT mice. DAG and ceramide levels in liver (C) and muscle (D) are similar in HFD-fed TG and WT animals. Values are means ± SE in 6 (6-mo-old male and female) mice per group.

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Whole body overexpression of PGC-1alpha has opposite effects on hepatic and muscle insulin sensitivity - PubMed (original) (raw)