Summary Tumors are largely classified by histological appearance, yet morphological features do not necessarily predict cellular origin. To determine the origin of pancreatic ductal adenocarcinoma (PDA), we labeled and traced pancreatic cell populations after induction of a PDA-initiating Kras mutation. Our studies reveal that ductal and stem-like centroacinar cells are surprisingly refractory to oncogenic transformation, whereas acinar cells readily form PDA precursor lesions with ductal features. We show that formation of acinar-derived premalignant lesions depends on ectopic induction of the ductal gene Sox9. Moreover, when concomitantly expressed with oncogenic Kras, Sox9 accelerates formation of premalignant lesions. These results provide insight into the cellular origin of PDA and suggest that its precursors arise via induction of a duct-like state in acinar cells.

The transcriptional coactivator peroxisome proliferator-activated receptor ␥ coactivator 1␣ (PGC-1␣) is a key integrator of neuromuscular activity in skeletal muscle. Ectopic expression of PGC-1␣ in muscle results in increased mitochondrial number and function as well as an increase in oxidative, fatigue-resistant muscle fibers. Whole body PGC-1␣ knock-out mice have a very complex phenotype but do not have a marked skeletal muscle phenotype. We thus analyzed skeletal muscle-specific PGC-1␣ knock-out mice to identify a specific role for PGC-1␣ in skeletal muscle function. These mice exhibit a shift from oxidative type I and IIa toward type IIx and IIb muscle fibers. Moreover, skeletal muscle-specific PGC-1␣ knock-out animals have reduced endurance capacity and exhibit fiber damage and elevated markers of inflammation following treadmill running. Our data demonstrate a critical role for PGC-1␣ in maintenance of normal fiber type composition and of muscle fiber integrity following exertion.Skeletal muscle has an enormous capacity to adapt to motor neuron activity. Many changes in gene expression are controlled by motor neuron-induced calcium signaling (1-3). The transcriptional coactivator peroxisome proliferator-activated receptor ␥ coactivator 1␣ 3 is at the nexus of this signaling and subsequently regulates the expression of gene programs needed for skeletal muscle adaptations to increased work load (4, 5). By coactivating the myocyte enhancer factor 2 members MEF2C and MEF2D, PGC-1␣ potently drives transcription of myofibrillar genes typical of oxidative muscle fibers (6). Interestingly, MEF2 and PGC-1␣ also control PGC-1␣ gene transcription in an autoregulatory loop (7,8). Metabolic genes, including those responsible for mitochondrial oxidative phosphorylation, are induced by a transcriptional cascade with coactivation of the estrogen-related receptor ␣ (ERR␣, official nomenclature NR3B1), the nuclear respiratory factor 2 (NRF-2, alternatively called GA-binding protein, GABP), and the nuclear respiratory factor 1 (NRF-1) by PGC-1␣ and subsequent increase in the levels of mitochondrial transcription factor A (TFAM) and mitochondrial transcription specificity factors TFB1M and TFB2M (9 -13). Recently, we have found that activity-induced remodeling of the postsynaptic side of neuromuscular junctions involves a complex between PGC-1␣, GABP, and host cell factor that assembles upon phosphorylation of PGC-1␣ and GABP in post-synaptic nuclei (14).Data obtained from muscle-specific PGC-1␣ transgenic animals underline the importance of PGC-1␣ in skeletal muscle in vivo (6). These mice have increased number and function of mitochondria accompanied by a higher number of type IIa and type I oxidative, slow twitch, high endurance muscle fibers (6). Furthermore, even in the absence of functional motor nerve signaling following hind leg denervation, ectopically expressed PGC-1␣ maintains skeletal muscle function and blunts skeletal muscle atrophy that normally occurs in the absence of motor neuron signaling (15). Thus, PGC-...

A high-fat, ketogenic diet induces a unique metabolic state in mice. Am J Physiol Endocrinol Metab 292: E1724 -E1739, 2007. First published February 13, 2007; doi:10.1152/ajpendo.00717.2006.-Ketogenic diets have been used as an approach to weight loss on the basis of the theoretical advantage of a low-carbohydrate, high-fat diet. To evaluate the physiological and metabolic effects of such diets on weight we studied mice consuming a very-low-carbohydrate, ketogenic diet (KD). This diet had profound effects on energy balance and gene expression. C57BL/6 mice animals were fed one of four diets: KD; a commonly used obesogenic high-fat, high-sucrose diet (HF); 66% caloric restriction (CR); and control chow (C). Mice on KD ate the same calories as mice on C and HF, but weight dropped and stabilized at 85% initial weight, similar to CR. This was consistent with increased energy expenditure seen in animals fed KD vs. those on C and CR. Microarray analysis of liver showed a unique pattern of gene expression in KD, with increased expression of genes in fatty acid oxidation pathways and reduction in lipid synthesis pathways. Animals made obese on HF and transitioned to KD lost all excess body weight, improved glucose tolerance, and increased energy expenditure. Analysis of key genes showed similar changes as those seen in lean animals placed directly on KD. Additionally, AMP kinase activity was increased, with a corresponding decrease in ACC activity. These data indicate that KD induces a unique metabolic state congruous with weight loss.liver; gene expression OVER THE PAST FEW DECADES the rates of obesity have risen substantially worldwide. Paradoxically, the increases in body weight, particularly in Western countries, occurred during a period of emphasis on diets low in fat as a means for avoiding weight gain. These dietary recommendations were based largely on the concept that high-fat diets were less satiating (39) and that reducing dietary fat reduced risk for cardiovascular disease by lowering circulating fat and cholesterol (5). As a result of the perceived failure of traditional dietary advice, attention shifted to alternative dietary regimes, including lowglycemic-index diets and very-low-carbohydrate ketogenic diets. Interest in these diets derives in part from the theoretical effects of dietary composition on energy expenditure. Although a small number of human studies have found such diets to be more effective in short-term weight loss and without adverse effects on glucose, insulin, lipids, or blood pressure (7,14,42,49,51), reports on metabolic effects remain inconclusive (8,38). Thus the precise effects of macronutrient diet composition on energy balance remain controversial.Studies of the physiological effects of dietary composition are intrinsically difficult in human populations because of problems achieving both compliance and accurate dietary reporting. Therefore, we developed a mouse model to examine the effect of diet composition on physiology, with particular reference to energy expenditure and metab...

Summary Recently, loss of beta cell-specific traits has been proposed as an early cause of beta cell failure in diabetes. However, the molecular mechanisms that underlie this loss of beta cell features remain unclear. Here, we identify an Nkx6.1-controlled gene regulatory network as essential for maintaining the functional and molecular traits of mature beta cells. Conditional Nkx6.1 inactivation in adult mice caused rapid-onset diabetes and hypoinsulinemia. Genome-wide analysis of Nkx6.1-regulated genes and functional assays further revealed a critical role for Nkx6.1 in the control of insulin biosynthesis, insulin secretion and beta cell proliferation. Over time, Nkx6.1-deficient beta cells acquired molecular characteristics of delta cells, revealing a molecular link between impaired beta cell functional properties and loss of cell identity. Given that Nkx6.1 levels are reduced in human type 2-diabetic beta cells, our study lends support to the concept that loss of beta cell features could contribute to the pathogenesis of diabetes.