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The peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) is a transcriptional coactivator that controls expression of metabolic/energetic genes, programming cellular responses to nutrient and environmental adaptations such as fasting, cold, or exercise. Unlike other coactivators, PGC-1α contains protein domains involved in RNA regulation such as serine/arginine (SR) and RNA recognition motifs (RRMs). However, the RNA targets of PGC-1α and how they pertain to metabolism are unknown. To address this, we performed enhanced ultraviolet (UV) cross-linking and immunoprecipitation followed by sequencing (eCLIP-seq) in primary hepatocytes induced with glucagon. A large fraction of RNAs bound to PGC-1α were intronic sequences of genes involved in transcriptional, signaling, or metabolic function linked to glucagon and fasting responses, but were not the canonical direct transcriptional PGC-1α targets such as OXPHOS or gluconeogenic genes. Among the top-scoring RNA sequences bound to PGC-1α were Foxo1, Camk1δ, Per1, Klf15, Pln4, Cluh, Trpc5, Gfra1, and Slc25a25 PGC-1α depletion decreased a fraction of these glucagon-induced messenger RNA (mRNA) transcript levels. Importantly, knockdown of several of these genes affected glucagon-dependent glucose production, a PGC-1α-regulated metabolic pathway. These studies show that PGC-1α binds to intronic RNA sequences, some of them controlling transcript levels associated with glucagon action.

Oncogene-targeted and immune checkpoint the rapies have revolutionized the clinical management of malignant melanoma and now offer hope to patients with advanced disease. Intimately connected to patients' overall clinical risk is whether the initial primary melanoma lesion will metastasize and cause advanced disease, but underlying mechanisms are not entirely understood. A subset of melanomas display heightened peroxisome proliferator-activated receptor y coactivator 1-a (PGC1[alpha]) expression that maintains cell survival cues by promoting mitochondrial function, but also suppresses metastatic spread. Here, we show that PGC1[alpha] expression in melanoma cells was silenced by chromatin modifications that involve promoter H3K27 trimethylation. Pharmacological EZH2 inhibition diminished H3K27me3 histone markers, increased PGC1[alpha] expression, and functionally suppressed invasion within PGC1[alpha]-silenced melanoma cells. Mechanistically, PGC1[alpha] silencing activated transcription factor 12 (TCF12), to increase expression of WNT5A, which in turn stabilized YAP protein levels to promote melanoma migration and metastasis. Accordingly, inhibition of components of this transcription-signaling axis, including TCF12, WNT5A, or YAP, blocked melanoma migration in vitro and metastasis in vivo. These results indicate that epigenetic control of melanoma metastasis involved altered expression of PGC1[alpha] and an association with the inherent metabolic state of the tumor., Introduction Recent breakthroughs in the clinical management of malignant melanoma, which include treatment using BRAF(V600E)-targeted drugs and immune checkpoint-blocking antibodies, now improve survival for patients with advanced stage disease (1). [...]

In obesity and type 2 diabetes, Glut4 glucose transporter expression is decreased selectively in adipocytes. Adipose-specific knockout or overexpression of Glut4 alters systemic insulin sensitivity. Here we show, using DNA array analyses, that nicotinamide N-methyltransferase (Nnmt) is the most strongly reciprocally regulated gene when comparing gene expression in white adipose tissue (WAT) from adipose-specific Glut4-knockout or adipose-specific Glut4-overexpressing mice with their respective controls. NNMT methylates nicotinamide (vitamin B3) using S-adenosylmethionine (SAM) as a methyl donor. Nicotinamide is a precursor of NAD(+), an important cofactor linking cellular redox states with energy metabolism. SAM provides propylamine for polyamine biosynthesis and donates a methyl group for histone methylation. Polyamine flux including synthesis, catabolism and excretion, is controlled by the rate-limiting enzymes ornithine decarboxylase (ODC) and spermidine-spermine N(1)-acetyltransferase (SSAT; encoded by Sat1) and by polyamine oxidase (PAO), and has a major role in energy metabolism. We report that NNMT expression is increased in WAT and liver of obese and diabetic mice. Nnmt knockdown in WAT and liver protects against diet-induced obesity by augmenting cellular energy expenditure. NNMT inhibition increases adipose SAM and NAD(+) levels and upregulates ODC and SSAT activity as well as expression, owing to the effects of NNMT on histone H3 lysine 4 methylation in adipose tissue. Direct evidence for increased polyamine flux resulting from NNMT inhibition includes elevated urinary excretion and adipocyte secretion of diacetylspermine, a product of polyamine metabolism. NNMT inhibition in adipocytes increases oxygen consumption in an ODC-, SSAT- and PAO-dependent manner. Thus, NNMT is a novel regulator of histone methylation, polyamine flux and NAD(+)-dependent SIRT1 signalling, and is a unique and attractive target for treating obesity and type 2 diabetes.

Cannabinoid receptor 1 (CB-1) antagonists are potential candidates for treating obesity and metabolic complications. Despite clear metabolic benefits, unwanted side effects in the brain pose issues for patients. With the hope of overcoming this obstacle, CB-1 in peripheral tissues has become a potential drug target. Previous studies had suggested that liver CB-1 would be an excellent target to prevent development of nonalcoholic steatohepatitis (NAFLD). However, in this issue of the JCI, Wang et al. showed that CB-1 was barely detectable in the liver and deletion of CB-1 in hepatocytes provided no metabolic benefits against NAFLD. These contradictory results raise substantial concerns about the potential benefits of peripheral CB-1 blockers against NAFLD., Sources of liver fat in metabolic diseases NAFLD is a continuum of liver pathologies, usually seen in overweight or obese people, that can be described in three progressive stages: (a) [...]

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Mitochondria provide essential metabolites and adenosine triphosphate (ATP) for the regulation of energy homeostasis. For instance, liver mitochondria are a vital source of gluconeogenic precursors under a fasted state. However, the regulatory mechanisms at the level of mitochondrial membrane transport are not fully understood. Here, we report that a liver-specific mitochondrial inner-membrane carrier SLC25A47 is required for hepatic gluconeogenesis and energy homeostasis. Genome-wide association studies found significant associations between SLC25A47 and fasting glucose, HbA1c, and cholesterol levels in humans. In mice, we demonstrated that liver-specific depletion of SLC25A47 impaired hepatic gluconeogenesis selectively from lactate, while significantly enhancing whole-body energy expenditure and the hepatic expression of FGF21. These metabolic changes were not a consequence of general liver dysfunction because acute SLC25A47 depletion in adult mice was sufficient to enhance hepatic FGF21 production, pyruvate tolerance, and insulin tolerance independent of liver damage and mitochondrial dysfunction. Mechanistically, SLC25A47 depletion leads to impaired hepatic pyruvate flux and malate accumulation in the mitochondria, thereby restricting hepatic gluconeogenesis. Together, the present study identified a crucial node in the liver mitochondria that regulates fasting-induced gluconeogenesis and energy homeostasis. [ABSTRACT FROM AUTHOR]