In these preliminary investigations, the CAARMS displayed good to excellent concurrent, discriminant and predictive validity and excellent inter-rater reliability. The CAARMS instrument provides a useful platform for monitoring subthreshold psychotic symptoms for worsening into full-threshold psychotic disorder.

Cardiac mitochondrial function is altered in a variety of inherited and acquired cardiovascular diseases. Recent studies have identified the transcriptional coactivator peroxisome proliferator-activated receptor γ coactivator-1 (PGC-1) as a regulator of mitochondrial function in tissues specialized for thermogenesis, such as brown adipose. We sought to determine whether PGC-1 controlled mitochondrial biogenesis and energy-producing capacity in the heart, a tissue specialized for high-capacity ATP production. We found that PGC-1 gene expression is induced in the mouse heart after birth and in response to short-term fasting, conditions known to increase cardiac mitochondrial energy production. Forced expression of PGC-1 in cardiac myocytes in culture induced the expression of nuclear and mitochondrial genes involved in multiple mitochondrial energy-transduction/energyproduction pathways, increased cellular mitochondrial number, and stimulated coupled respiration. Cardiac-specific overexpression of PGC-1 in transgenic mice resulted in uncontrolled mitochondrial proliferation in cardiac myocytes leading to loss of sarcomeric structure and a dilated cardiomyopathy. These results identify PGC-1 as a critical regulatory molecule in the control of cardiac mitochondrial number and function in response to energy demands.

Members of the PPARγ coactivator-1 (PGC-1) family of transcriptional coactivators serve as inducible coregulators of nuclear receptors in the control of cellular energy metabolic pathways. This Review focuses on the biologic and physiologic functions of the PGC-1 coactivators, with particular emphasis on striated muscle, liver, and other organ systems relevant to common diseases such as diabetes and heart failure.Members of the nuclear receptor (NR) superfamily relay physiologic and nutritional cues to critical gene regulatory responses. The molecular links between external stimuli, cellular signaling events, and NR-mediated transcriptional control are currently being unraveled. New information emerging over the past decade has demonstrated that NRs receive regulatory input through multiple mechanisms including levels of endogenous ligand, availability of heterodimeric NR partners, and posttranslational modifications. Activating signals trigger the recruitment of coactivator complexes onto the NR platform, leading to enzymatic modification of chromatin, increased access of the RNA polymerase II machinery to RNA, and activation of target gene transcription (Figure 1). Availability of certain coactivator proteins also serves critical regulatory functions linking physiologic stimuli to NR activity. Perhaps the best example of this latter mechanism involves the PPARγ coactivator-1 (PGC-1) family of transcriptional coactivators. PGC-1 coactivators serve as inducible NR "boosters" to equip the organism to meet the energy demands of diverse physiologic and dietary conditions. This Review will focus on the role of this interesting coactivator family in the control of organ-specific biologic responses to the physiologic and pathophysiologic milieu. Emphasis will be given to tissue-specific regulatory features relevant to heart failure and diabetes.The PGC-1 family: inducible transcriptional coactivators orchestrating control of cellular energy metabolism The transcriptional coactivator PGC-1α was identified through its functional interaction with the nuclear receptor PPARγ in brown adipose tissue (BAT), a mitochondria-rich tissue specialized for thermogenesis (1). Thereafter, 2 related coactivators, PGC-1β (also termed PERC) and PGC-1-related coactivator (PRC), were discovered ( Figure 1) (2-4). PGC-1α and PGC-1β are preferentially expressed in tissues with high oxidative capacity, such as heart, slow-twitch skeletal muscle, and BAT, where they serve critical roles in the regulation of mitochondrial functional capacity and cellular energy metabolism (1, 3, 5-7). Less is known about the expression patterns and biologic roles of PRC (2, 8).PGC-1 coactivator docking to specific transcription factors provides a platform for the recruitment of regulatory protein complexes that exert powerful effects on gene transcription ( Figure 1). The amino-terminal region of PGC-1 coactivators interacts with proteins containing histone acetyltransferase (HAT) activity, including CREB-binding protein/p300 and steroid receptor coactivator-...

We are witnessing a period of renewed interest in the biology of the mitochondrion. The mitochondrion serves a critical function in the maintenance of cellular energy stores, thermogenesis, and apoptosis. Moreover, alterations in mitochondrial function contribute to several inherited and acquired human diseases and the aging process. This review summarizes our understanding of the transcriptional regulatory mechanisms involved in the biogenesis and energy metabolic function of mitochondria in higher organisms.

The gene encoding the transcriptional coactivator peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) was targeted in mice. PGC-1α null (PGC-1α−/−) 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-1α−/− mice. With age, the PGC-1α−/− 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-1α−/− mice, leading to reduced muscle performance and exercise capacity. PGC-1α−/− mice exhibit a modest diminution in cardiac function related largely to abnormal control of heart rate. The PGC-1α−/− mice were unable to maintain core body temperature following exposure to cold, consistent with an altered thermogenic response. Following short-term starvation, PGC-1α−/− mice develop hepatic steatosis due to a combination of reduced mitochondrial respiratory capacity and an increased expression of lipogenic genes. Surprisingly, PGC-1α−/− 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-1α−/− mice. These results demonstrate that PGC-1α is necessary for appropriate adaptation to the metabolic and physiologic stressors of postnatal life.

The peroxisome proliferator-activated receptor ␣ (PPAR␣) is a fatty acid-activated nuclear receptor that plays a key role in the transcriptional regulation of genes involved in cellular lipid and energy metabolism. PPAR␣ together with PPAR␦ and PPAR␥ form a subgroup within the nuclear receptor superfamily (12, 17). In contrast to PPAR␣ which is involved in the control of cellular lipid utilization, PPAR␥ has been shown to be a necessary component of the adipocyte differentiation program (22,36). The biological function of PPAR␦ is unknown. A diverse group of compounds can act as activating ligands for PPAR␣ including several prostaglandin derivatives, eicosanoids, and long-chain unsaturated fatty acids (8,18,39). To date, the majority of PPAR␣ target genes identified are involved in cellular fatty acid oxidation (FAO) (22). We and others have previously demonstrated that PPAR␣ mediates fatty acid-induced transcriptional control of several nuclear genes encoding mitochondrial FAO enzymes, including mediumchain acyl coenzyme A (acyl-CoA) dehydrogenase (MCAD) (9) and muscle carnitine palmitoyltransferase I (M-CPT I or CPT I␤) (2, 9, 26, 41). PPAR␣ is enriched in tissues with high oxidative energy demands that depend on mitochondrial FAO as a primary energy source such as heart and liver (17). PPAR␣ is also expressed at high levels in brown adipose tissue (BAT), a specialized tissue in which mitochondrial FAO provides the reducing equivalents necessary for the generation of heat via the uncoupling of oxidative phosphorylation. Consistent with its regulatory role in mitochondrial FAO, the expression of PPAR␣ is much higher in BAT than in white adipose tissue, which is a lipid storage tissue (15,36). Recent studies of PPAR␣-null mice have confirmed that PPAR␣ is necessary in vivo for high-level expression of mitochondrial and peroxisomal FAO enzyme genes in heart and liver under basal and stimulated conditions (1,7,24).Evidence has emerged that nuclear receptors regulate transcription, in large part, via interactions with coactivator (e.g., CBP/p300, SRC-1, GRIP1, pCIP) or corepressor (e.g., N-CoR, SMRT) molecules (4,5,10,11,14,20). Nuclear receptor interacting proteins regulate transcriptional activity by affecting chromatin structure through changes in the acetylation status of histones. Most coactivators are recruited to nuclear receptors upon ligand binding. Several coactivators such as SRC-1, which possesses intrinsic histone acetylase activity, also serve as adaptor molecules to link nuclear receptors to multiprotein complexes containing larger pleiotropic activator proteins such as CBP or p300 (35,37,40). The ligand-mediated activation of PPARs also involves coactivator networks (28, 44). Crystallographic studies have demonstrated that the binding of ligand to PPAR stabilizes the position of an alpha-helical domain (the AF2 helix) forming a "charge clamp" that interacts with an LXXLL motif within coactivator molecules (28). Indeed, SRC-1 has been shown to interact with the PPARs upon ligand binding leading to t...

We hypothesized that the lipid-activated transcription factor, the peroxisome proliferator-activated receptor ␣ (PPAR␣), 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␣ (PPAR␣ ؊͞؊ ), a phenotype that bears remarkable similarity to that of humans with genetic defects in mitochondrial fatty acid oxidation enzymes. In PPAR␣ ؉͞؉ mice, fasting induced the hepatic and cardiac expression of PPAR␣ target genes encoding key mitochondrial (mediumchain 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␣ target genes was not induced by fasting in PPAR␣ ؊͞؊ mice. These results define a critical role for PPAR␣ in a transcriptional regulatory response to fasting and identify the PPAR␣ ؊͞؊ mouse as a potentially useful murine model of inborn and acquired abnormalities of human fatty acid utilization.Starvation triggers a complex array of adaptive metabolic responses. A prominent feature of the energy-metabolic response to fasting includes a switch to reliance on fatty acids and ketones for energy production (1-4) and an augmentation in the capacity for mitochondrial fatty acid oxidation (FAO) in tissues with high oxidative energy demands such as heart and liver (5). The importance of the fasting-inducible capacity for cellular lipid utilization is underscored by the dramatic phenotype of human inborn errors in mitochondrial FAO enzymes (6). Children afflicted with genetically determined enzymatic defects in the FAO pathway typically are asymptomatic under normal feeding conditions. However, short-term fasting, such as that associated with an infectious illness, precipitates a dramatic and often fatal clinical picture characterized by hypoketotic hypoglycemia, liver dysfunction, and cardiomyopathy (6-8). Postmortem studies of FAO enzyme-deficient patients have demonstrated marked intracellular accumulation of neutral lipid in liver and heart. The capacity to oxidize fats is also diminished in several common acquired cardiac diseases including cardiac hypertrophy and myocardial ischemia (9-17). The molecular pathogenesis of target organ dysfunction from inherited and acquired alterations in cellular FAO has not been elucidated.A previous study in rodents demonstrated that the hepatic expression of genes encoding mitochondrial FAO enzymes is induced, at the transcriptional level, in response to fasting (5). This transcriptional regulatory response likely plays a key role in the fasting-induced augmentation of FAO capacity in liver and other oxidative tissues. The mechanisms involved in the fasting-induced transcriptional activation of FAO enzyme genes are unknown. However, recent studies have identified a role for a nuclear receptor, the peroxisome proliferatoractivated receptor ␣ (PPAR␣), in the ...

Endurance exercise induces increases in mitochondria and the GLUT4 isoform of the glucose transporter in muscle. Although little is known about the mechanisms underlying these adaptations, new information has accumulated regarding how mitochondrial biogenesis and GLUT4 expression are regulated. This includes the findings that the transcriptional coactivator PGC-1 promotes mitochondrial biogenesis and that NRF-1 and NRF-2 act as transcriptional activators of genes encoding mitochondrial enzymes. We tested the hypothesis that increases in PGC-1, NRF-1, and NRF-2 are involved in the initial adaptive response of muscle to exercise. Five daily bouts of swimming induced increases in mitochondrial enzymes and GLUT4 in skeletal muscle in rats. One exercise bout resulted in approximately twofold increases in full-length muscle PGC-1 mRNA and PGC-1 protein, which were evident 18 h after exercise. A smaller form of PGC-1 increased after exercise. The exercise induced increases in muscle NRF-1 and NRF-2 that were evident 12 to 18 h after one exercise bout. These findings suggest that increases in PGC-1, NRF-1, and NRF-2 represent key regulatory components of the stimulation of mitochondrial biogenesis by exercise and that PGC-1 mediates the coordinated increases in GLUT4 and mitochondria.