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The gene encoding the transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) was targeted in mice. PGC-1alpha null (PGC-1alpha-/-) mice were viable. However, extensive phenotyping revealed multi-system abnormalities indicative of an abnormal energy metabolic phenotype. The postnatal growth of heart and slow-twitch skeletal muscle, organs with high mitochondrial energy demands, is blunted in PGC-1alpha-/- mice. With age, the PGC-1alpha-/- mice develop abnormally increased body fat, a phenotype that is more severe in females. Mitochondrial number and respiratory capacity is diminished in slow-twitch skeletal muscle of PGC-1alpha-/- mice, leading to reduced muscle performance and exercise capacity. PGC-1alpha-/- mice exhibit a modest diminution in cardiac function related largely to abnormal control of heart rate. The PGC-1alpha-/- mice were unable to maintain core body temperature following exposure to cold, consistent with an altered thermogenic response. Following short-term starvation, PGC-1alpha-/- mice develop hepatic steatosis due to a combination of reduced mitochondrial respiratory capacity and an increased expression of lipogenic genes. Surprisingly, PGC-1alpha-/- mice were less susceptible to diet-induced insulin resistance than wild-type controls. Lastly, vacuolar lesions were detected in the central nervous system of PGC-1alpha-/- mice. These results demonstrate that PGC-1alpha is necessary for appropriate adaptation to the metabolic and physiologic stressors of postnatal life.

During the development of heart failure (HF), the capacity for cardiomyocyte (CM) fatty acid oxidation (FAO) and ATP production is progressively diminished, contributing to pathologic cardiac hypertrophy and contractile dysfunction. Receptor-interacting protein 140 (RIP140, encoded by Nrip1) has been shown to function as a transcriptional corepressor of oxidative metabolism. We found that mice with striated muscle deficiency of RIP140 ([strNrip1.sup1.-/-]) exhibited increased expression of a broad array of genes involved in mitochondrial energy metabolism and contractile function in heart and skeletal muscle. [strNrip1.sup.-/-] mice were resistant to the development of pressure overload-induced cardiac hypertrophy, and CM- specific RIP140-deficient ([csNrip1.sup.-/-]) mice were protected against the development of HF caused by pressure overload combined with myocardial infarction. Genomic enhancers activated by RIP140 deficiency in CMs were enriched in binding motifs for transcriptional regulators of mitochondrial function (estrogen-related receptor) and cardiac contractile proteins (myocyte enhancer factor 2). Consistent with a role in the control of cardiac fatty acid oxidation, loss of RIP140 in heart resulted in augmented triacylglyceride turnover and fatty acid utilization. We conclude that RIP140 functions as a suppressor of a transcriptional regulatory network that controls cardiac fuel metabolism and contractile function, representing a potential therapeutic target for the treatment of HF., Introduction The remarkable energy demands of the heart are largely met by the oxidation of fatty acids and glucose in high-capacity mitochondrial networks. Fatty acid oxidation (FAO) is the chief [...]

Intramuscular lipid accumulation is a common manifestation of chronic caloric excess and obesity that is strongly associated with insulin resistance. The mechanistic links between lipid accumulation in myocytes and insulin resistance are not completely understood. In this work, we used a high-throughput chemical biology screen to identify a small-molecule probe, SBI-477, that coordinately inhibited triacylglyceride (TAG) synthesis and enhanced basal glucose uptake in human skeletal myocytes. We then determined that SBI-477 stimulated insulin signaling by deactivating the transcription factor MondoA, leading to reduced expression of the insulin pathway suppressors thioredoxin-interacting protein (TXNIP) and arrestin domain-containing 4 (ARRDC4). Depleting MondoA in myocytes reproduced the effects of SBI-477 on glucose uptake and myocyte lipid accumulation. Furthermore, an analog of SBI-477 suppressed TXNIP expression, reduced muscle and liver TAG levels, enhanced insulin signaling, and improved glucose tolerance in mice fed a high-fat diet. These results identify a key role for MondoA-directed programs in the coordinated control of myocyte lipid balance and insulin signaling and suggest that this pathway may have potential as a therapeutic target for insulin resistance and lipotoxicity., Introduction The rising prevalence of obesity is driving an alarming increase in type 2 diabetes, a global health threat. Comorbidities associated with obesity include insulin resistance and fatty liver disease [...]

Mitochondrial homeostasis is critical for tissue health, and mitochondrial dysfunction contributes to numerous diseases, including heart failure. Here, we have shown that the transcription factor Kruppel-like factor 4 (KLF4) governs mitochondrial biogenesis, metabolic function, dynamics, and autophagic clearance. Adult mice with cardiac-specific Klf4 deficiency developed cardiac dysfunction with aging or in response to pressure overload that was characterized by reduced myocardial ATP levels, elevated ROS, and marked alterations in mitochondrial shape, size, ultrastructure, and alignment. Evaluation of mitochondria isolated from KLF4-deficient hearts revealed a reduced respiration rate that is likely due to defects in electron transport chain complex I. Further, cardiac- specific, embryonic Klf4 deletion resulted in postnatal premature mortality, impaired mitochondrial biogenesis, and altered mitochondrial maturation. We determined that KLF4 binds to, cooperates with, and is requisite for optimal function of the estrogen-related receptor/PPARγ coactivator 1 (ERR/PGC-1) transcriptional regulatory module on metabolic and mitochondrial targets. Finally, we found that KLF4 regulates autophagy flux through transcriptional regulation of a broad array of autophagy genes in cardiomyocytes. Collectively, these findings identify KLF4 as a nodal transcriptional regulator of mitochondrial homeostasis., Introduction The heart has an unrelenting need for energy throughout life to sustain contractile function. Despite its high-energy demand, the heart contains relatively low ATP reserves, and thus, a continual [...]

The mechanisms involved in the coordinate regulation of the metabolic and structural programs controlling muscle fitness and endurance are unknown. Recently, the nuclear receptor PPAR β/δ was shown to activate [...]

Cellular reprogramming of somatic cells to patient-specific induced pluripotent stem cells (iPSCs) enables in vitro modelling of human genetic disorders for pathogenic investigations and therapeutic screens (1-7). However, using iPSC-derived [...]

To define the necessity of calcineurin (Cn) signaling for cardiac maturation and function, the postnatal phenotype of mice with cardiac-specific targeted ablation of the Cn B1 regulatory subunit (Ppp3rl) gene ([csCnbl.sup.-/-] mice) was characterized, [csCnbl.sup.-/-] mice develop a lethal cardiomyopathy, characterized by impaired postnatal growth of the heart and combined systolic and diastolic relaxation abnormalities, despite a lack of structural derangements. Notably, the [csCnbl.sup.-/-] hearts did not exhibit diastolic dilatation, despite the severe functional phenotype. Myocytes isolated from the mutant mice exhibited reduced rates of contraction/relaxation and abnormalities in calcium transients, consistent with altered sarcoplasmic reticulum loading. Levels of sarco(endo) plasmic mticulum Ca-ATPase 2a (Atp2a2) and phospholamban were normal, but phospholamban phosphorylation was markedly reduced at [Ser.sup.16] and [Thr.sup.17]. In addition, levels of the Na/Ca exchanger (Slc8a1) were modestly reduced. These results define a novel mouse model of cardiac-specific Cn deficiency and demonstrate novel links between Cn signaling, postnatal growth of the heart, pathological ventricular remodeling, and excitation-contraction coupling. calcium signaling; restrictive cardiomyopathy; cardiac hypertrophy; excitation-contraction coupling; cardiac mitochondria doi: 10.1152/ajpheart.00152.2009

High-capacity mitochondrial ATP production is essential for normal function of the adult heart, and evidence is emerging that mitochondrial derangements occur in common myocardial diseases. Previous overexpression studies have shown that the inducible transcriptional coactivator peroxisome proliferator-activated receptor-[gamma] coactivator (PGC)-l[alpha] is capable of activating postnatal cardiac myocyte mitochondrial biogenesis. Recently, we generated mice deficient in PGC-1[alpha] ([PGC-1[alpha].sup.-/-] mice), which survive with modestly blunted postnatal cardiac growth. To determine if PGC-1[alpha] is essential for normal cardiac energy metabolic capacity, mitochondrial function experiments were performed on saponin-permeabilized myocardial fibers from PGC-l[[alpha].sup.-/-] mice. These experiments demonstrated reduced maximal (state 3) palmitoyl-L-carnitine respiration and increased maximal (state 3) pyruvate respiration in [PGC-l[alpha].sup.-/-] mice compared with PGC-1[[alpha].sup.+/+] controls. ATP synthesis rates obtained during maximal (state 3) respiration in permeabilized myocardial fibers were reduced for PGC-1[[alpha].sup.-/-] mice, whereas ATP produced per oxygen consumed (ATP/O), a measure of metabolic efficiency, was decreased by 58% for PGC-l[[alpha].sup.-/-] fibers. Ex vivo isolated working heart experiments demonstrated that PGC-l[[alpha].sup.-/-] mice exhibited lower cardiac power, reduced palmitate oxidation, and increased reliance on glucose oxidation, with the latter likely a compensatory response. [sup.13]C NMR revealed that hearts from PGC-l[[alpha].sup.-/-] mice exhibited a limited capacity to recruit triglyceride as a source for lipid oxidation during [beta]-adrenergic challenge. Consistent with reduced mitochondrial fatty acid oxidative enzyme gene expression, the total triglyceride content was greater in hearts of PGC-1[[alpha].sup.-/-] mice relative to PGC-l[[alpha].sup.+/+] following a fast. Overall, these results demonstrate that PGC-l[alpha] is essential for the maintenance of maximal, efficient cardiac mitochondrial fatty acid oxidation, ATP synthesis, and myocardial lipid homeostasis. nuclear receptors; ATP; cardiac energetics; heart failure; left ventricular hypertrophy; peroxisome proliferator-activated receptor-[gamma] coactivator-1[alpha]

Hypertension and diabetes are common side effects of glucocorticoid treatment. To determine whether peroxisome proliferator-activated receptor-[alpha] (PPAR-[alpha]) mediates these sequelae, mice deficient in low-density lipoprotein receptor (Ldlr[sup.-/-]), with (Ppara[sup.+/+]) or without (Ppara[sup.-/-]) PPAR-[alpha], were treated chronically with dexamethasone. Ppara[sup.+/+], but not Ppara[sup.-/-], mice developed hyperglycemia, hyperinsulinemia and hypertension. Similar effects on glucose metabolism were seen in a different model using C57BL/6 mice. Hepatic gluconeogenic gene expression was increased and insulin-mediated suppression of endogenous glucose production was less effective in dexamethasone-treated Ppara[sup.+/+] mice. Adenoviral reconstitution of PPAR-[alpha] in the livers of nondiabetic, normotensive, dexamethasone-treated Ppara[sup.-/-] mice induced hyperglycemia, hyperinsulinemia and increased gluconeogenic gene expression. It also increased blood pressure, renin activity, sympathetic nervous activity and renal sodium retention. Human hepatocytes treated with dexamethasone and the PPAR-[alpha] agonist Wy14,643 induced PPARA and gluconeogenic gene expression. These results identify hepatic activation of PPAR-[alpha] as a mechanism underlying glucocorticoid-induced insulin resistance., Author(s): Carlos Bernal-Mizrachi [1, 2]; Sherry Weng [1, 2]; Chu Feng [1, 2]; Brian N Finck [1, 5]; Russell H Knutsen [3]; Teresa C Leone [1, 5]; Trey Coleman [1, [...]

We hypothesized that the lipid-activated transcription factor, the peroxisome proliferator-activated receptor [Alpha] (PPAR[Alpha]), plays a pivotal role in the cellular metabolic response to fasting. Short-term starvation caused hepatic steatosis, myocardial lipid accumulation, and hypoglycemia, with an inadequate ketogenic response in adult mice lacking PPAR[Alpha] (PPAR[[Alpha].sup.-/-]), a phenotype that bears remarkable similarity to that of humans with genetic defects in mitochondrial fatty acid oxidation enzymes. In PPAR[[Alpha].sup.+/+] mice, fasting induced the hepatic and cardiac expression of PPAR[Alpha] target genes encoding key mitochondrial (medium-chain acyl-CoA dehydrogenase, carnitine palmitoyltransferase I) and extramitochondrial (acyl-CoA oxidase, cytochrome P450 4A3) enzymes. In striking contrast, the hepatic and cardiac expression of most PPAR[Alpha] target genes was not induced by fasting in PPAR[[Alpha].sup.-/-] mice. These results define a critical role for PPAR[Alpha] in a transcriptional regulatory response to fasting and identify the PPAR[[Alpha].sup.-/-] mouse as a potentially useful murine model of inborn and acquired abnormalities of human fatty acid utilization.

The mechanism(s) by which impaired mitochondrial respiratory function and the accumulation of lipid droplets and mitochondria in hearts of copper-deficient rats occur remains unclear. It is not known whether specific components of the regulatory pathway involved in mitochondrial biogenesis, such as mitochondrial transcription factor A (mtTFA) and nuclear respiratory factors 1 and 2 (NRF-1 and NRF-2), are activated in copper deficiency. Little is known about gene expression of enzymes involved in fatty acid oxidation (FAO) in hearts of copper-deficient rats. Male weanling rats were fed copper-adequate (CuA), copper-deficient (CUD) or pair-fed (CUP) diets for 5 wk. Mitochondria and lipid droplet volume densities from electron micrographs were greater and there was an elevation in the mtTFA protein level in hearts of copper-deficient rats. DNA binding activities of NRF-1 and NRF-2 did not differ among the groups. Northern blot analysis of cardiac tissue revealed that transcripts of [F.sub.1][F.sub.0]-ATP synthase subunit c were greater, but mRNA levels of ATP synthase [Beta] subunit and the FAO enzyme, medium-chain acyl-CoA dehydrogenase (MCAD), were lower in hearts of copper-deficient rats. Long-chain acyl-CoA dehydrogenase (LCAD) mRNA levels did not differ among treatment groups. These results suggest that certain components of the mitochondrial biogenesis program are activated in hearts of copper-deficient rats. [F.sub.1][F.sub.0]-ATP synthase [Beta] subunit and MCAD transcript levels remain low, which may contribute to impaired mitochondrial respiratory function, decreased fatty acid utilization and lipid droplet accumulation in hearts of copper-deficient rats. J. Nutr. 130: 2143-2150, 2000. KEY WORDS: * rats * mitochondrial transcription factor A * ATP synthase * copper deficiency * medium-chain acyl-CoA dehydrogenase

Horowitz, Jeffrey F., Teresa C. Leone, Weqing Feng, Daniel P. Kelly, and Samuel Klein. Effect of endurance training on lipid metabolism in women: a potential role for PPAR[Alpha] in the metabolic response to training. Am J Physiol Endocrinol Metab 279: E348-E355, 2000.--Endurance training increases fatty acid oxidation (FAO) and skeletal muscle oxidative capacity. However, the source of the additional fat and the mechanisms for increasing FAO capacity in muscle are not clear. We measured whole body and regional lipolytic activity and whole body and plasma FAO in six lean women during 90 min of bicycling exercise (50% pretraining peak [O.sub.2] consumption) before and after 12 wk of endurance training. We also assessed skeletal muscle content of peroxisome proliferator-activated receptor-[Alpha] (PPAR[Alpha]) and its target proteins that regulate FAO [medium-chain and very long chain acyl-CoA dehydrogenase (MCAD and VLCAD)]. Despite a 25% increase in whole body FAO during exercise after training (P [is less than] 0.05), training did not alter regional adipose tissue lipolysis (abdominal: 0.56 [+ or -] 0.26 and 0.57 [+ or -] 0.10 [micro]mol [multiplied by] 100 [g.sup.-1] [multiplied by] [min.sup.-1]; femoral: 0.13 [+ or -] 0.07 and 0.09 [+ or -] 0.02 [micro]mol [multiplied by] 100 [g.sup.-1] [multiplied by] [min.sup.-1]), whole body palmitate rate of appearance in plasma (168 [+ or -] 18 and 150 [+ or -] 25 [micro]mol/min), and plasma FAO (554 [+ or -] 61 and 601 [+ or -] 45 [micro]mol/min). However, training doubled the levels of muscle PPAR[Alpha], MCAD, and VLCAD. We conclude that training increases the use of nonplasma fatty acids and may enhance skeletal muscle oxidative capacity by PPAR[Alpha] regulation of gene expression. exercise; lipolysis; fatty acid; intramuscular triglyceride; stable isotopes