It is clear that the PGC-1 coactivators play important roles in various aspects of energy homeostasis. Using gain-of-function and complete-loss-of-function studies, these proteins were shown to be dominant regulators of oxidative metabolism, particularly mitochondrial biogenesis, skeletal muscle biology, brown fat thermogenesis, and the hepatic fasting response (4
). However, what remained unclear from these studies were the metabolic consequences of modulating PGC-1α within physiological levels.
Importantly, the expression of PGC-1α is quantitatively dysregulated in a variety of disease states. Increased PGC-1α expression has been shown in livers of diabetic mice (7
), reduced levels are found in the muscle of insulin-resistant humans (33
), and hepatic PGC-1α levels are inversely correlated with insulin resistance in humans (34
). We show here that hepatic heterozygosity for PGC-1α, leading to a corresponding reduction in PGC-1α mRNA and protein, caused a substantial change in hepatic metabolism that is manifested primarily as hepatic steatosis and insulin resistance.
Our data demonstrate for the first time that chronically and mildly reduced hepatic PGC-1α causes hepatic insulin resistance. Primary LH hepatocytes and high-fat–fed LH livers exhibited decreased insulin-stimulated Akt activation ( and ). Moreover, LH mice on a high-fat diet had increased fed gluconeogenic gene expression that could not be efficiently reduced after fasting/refeeding (). Interestingly, the decrease in hepatic insulin sensitivity shown here is in contrast to results from Koo et al. (11
), who demonstrated that a sharp, adenoviral-mediated reduction of hepatic PGC-1α reduced TRB-3 mRNA expression and increased insulin sensitivity in vivo. In contrast, we observed no differences in TRB-3 mRNA expression in fed or fasted LH mice (F
, supplementary Table A1). These differences may be attributable to the degree of PGC-1α loss in these two sets of experiments, the method of knockdown, or the differential effects of chronic versus transient decreases in PGC-1α expression.
Chronic reductions in hepatic PGC-1α affected triglyceride assembly and/or production (), which can also be attributed to hepatic insulin resistance. Insulin reduces the amount of circulating VLDL particles by directly suppressing hepatic VLDL production (2
), and hepatic insulin resistance contributes to both increased hepatic VLDL production and decreased VLDL uptake in patients with type 2 diabetes (rev. in (35
). Insulin has been shown to inhibit the expression of MTP, a protein that initiates the production of VLDL (36
). Consistent with decreased insulin action, we observed increased expression of MTP in LH mice (B
). We also detected increased expression of apoB, the major protein constituent of VLDL, which, along with high serum triglycerides, is associated with coronary artery disease (35
). Thus, it is likely that hepatic insulin resistance contributed to the hypertriglyceridemia in fed LH mice. However, there remains the possibility that long-term reduction of hepatic PGC-1α has extrahepatic effects on triglyceride lipolysis or absorption.
Interestingly, we observed increased circulating insulin levels in LH mice after refeeding. In contrast to the muscle-specific PGC-1α knockout mice, we observed no difference in gross islet morphology (38
) (data not shown). Thus, it is likely that chronically reduced hepatic PGC-1α has effects on peripheral tissue metabolism through currently unidentified mechanisms.
The most striking and clear-cut consequence of quantitatively decreasing hepatic PGC-1α was impairment of the fatty acid oxidation gene program. Decreased hepatic fatty acid oxidation and concomitant lipid accumulation have been shown to negatively affect insulin signaling (39
). Our study showed that the fatty acid oxidation genes VLCAD, LCAD, and SCAD are highly sensitive to changes in PGC-1α expression levels. Other studies have shown that mice deficient in these fatty acid oxidation genes show marked hepatosteatosis and hepatic insulin resistance (30
). Studies also suggest there is a synergistic effect of having reduced function in two or more of the acyl-CoA dehydrogenases (40
). Given that PGC-1α is crucial for maintaining the expression levels of multiple enzymes within this family, it is likely that long-term dysregulation of lipid metabolism in LH mice contributes to the development of hepatic insulin resistance, particularly under the challenge of a high-fat diet. Interestingly, hepatic steatosis was not significantly worse in high-fat–fed LH mice. However, because insulin directly downregulates fatty acid oxidation (41
), insulin resistance may mask the effects of reduced PGC-1α on fatty acid oxidation in these mice.
Our study clearly demonstrates that modest changes in hepatic PGC-1α expression can have significant effects on energy homeostasis. Furthermore, although chronic reduction of hepatic PGC-1α had only a modest effect on reducing gluconeogenesis, multiple aspects of hepatic metabolism were significantly disrupted by loss of the transcriptional coactivator. Because there is growing interest in the therapeutic potential of targeting this transcriptional coactivator during the development of metabolic diseases, it will be of interest to investigate how chemical modulators of PGC-1α activity affect liver function in diabetic and obese patients.