Obesity in the Otsuka Long Evans Tokushima Fatty Rat: Mechanisms and Discoveries

Understanding the neural systems underlying the controls of energy balance has been greatly advanced by identifying the deficits and underlying mechanisms in rodent obesity models. The current review focuses on the Otsuka Long Evans Tokushima Fatty (OLETF) rat obesity model. Since its recognition in the 1990’s significant progress has been made in identifying the causes and consequences of obesity in this model. Fundamental is a deficit in the cholecystokinin (CCK) 1 receptor gene resulting in the absence of CCK 1 receptors in both the gastrointestinal track and the brain. OLETF rats have a deficit in their ability to limit the size of meals and in contrast to CCK1 receptor knock-out mice, do not compensate for this increase in the size of their spontaneous meals, resulting in hyperphagia. Prior to becoming obese and in response to pair feeding, OLETF rats have increased expression of neuropeptide Y (NPY) in the compact region of the dorsomedial hypothalamus (DMH) and this over-expression contributes to their overall hyperphaigia. Study of the OLETF rats has revealed important differences in the organization of the DMH in rats and mice and elucidated previously unappreciated roles for DMH NPY in energy balance and glucose homeostasis

Systematic Revision of Elaphoglossum (Dryopteridaceae) in French Polynesia, with the Description of Three New Species

Species descriptions and a key for the nine species of Elaphoglossum (Dryopteridaceae) in French Polynesia are provided. Three new species are described: E. austromarquesense from the southern Marquesas Islands, E. florencei from Raiatea and Moorea, and E. meyeri from Rapa. Each species is illustrated by a line drawing of the habit, and spore images using a scanning electron microscope. Images of scales, one of the most important diagnostic characters in the genus, are also included. © 2008 The Linnean Society of London

Malonyl-CoA Mediates Leptin Hypothalamic Control of Feeding Independent of Inhibition of CPT-1a

Hypothalamic fatty acid metabolism is involved in central nervous system controls of feeding and energy balance. Malonyl-CoA, an intermediate of fatty acid biosynthesis, is emerging as a significant player in these processes. Notably, hypothalamic malonyl-CoA has been implicated in leptin's feeding effect. Leptin treatment increases malonyl-CoA level in the hypothalamic arcuate nucleus (Arc), and this increase is required for leptin-induced decrease in food intake. However, the intracellular downstream mediators of malonyl-CoA's feeding effect have not been identified. A primary biochemical action of malonyl-CoA is the inhibition of the acyltransferase activity of carnitine palmitoyltransferase-1 (CPT-1). In the hypothalamus, the predominant isoform of CPT-1 that possesses the acyltransferase activity is CPT-1 liver type (CPT-1a). To address the role of CPT-1a in malonyl-CoA's anorectic action, we used a recombinant adenovirus expressing a mutant CPT-1a that is insensitive to malonyl-CoA inhibition. We show that Arc overexpression of the mutant CPT-1a blocked the malonyl-CoA-mediated inhibition of CPT-1 activity. However, the overexpression of this mutant did not affect the anorectic actions of leptin or central cerulenin for which an increase in Arc malonyl-CoA level is also required. Thus, CPT-1a does not appear to be involved in the malonyl-CoA's anorectic actions induced by leptin. Furthermore, long-chain fatty acyl-CoAs, substrates of CPT-1a, dissociate from malonyl-CoA's actions in the Arc under different feeding states. Together, our results suggest that Arc intracellular mechanisms of malonyl-CoA's anorectic actions induced by leptin are independent of CPT-1a. The data suggest that target(s), rather than CPT-1a, mediates malonyl-CoA action on feeding

Partitioning Evapotranspiration in Semiarid Grassland and Shrubland Ecosystems Using Diurnal Surface Temperature Variation

The encroachment of woody plants in grasslands across the Western U.S. will affect soil water availability by altering the contributions of evaporation (E) and transpiration (T) to total evapotranspiration (ET). To study this phenomenon, a network of flux stations is in place to measure ET in grass- and shrub-dominated ecosystems throughout the Western U.S. A method is described and tested here to partition the daily measurements of ET into E and T based on diurnal surface temperature variations of the soil and standard energy balance theory. The difference between the mid-afternoon and pre-dawn soil surface temperature, termed Apparent Thermal Inertia (I(sub A)), was used to identify days when E was negligible, and thus, ET=T. For other days, a three-step procedure based on energy balance equations was used to estimate Qe contributions of daily E and T to total daily ET. The method was tested at Walnut Gulch Experimental Watershed in southeast Arizona based on Bowen ratio estimates of ET and continuous measurements of surface temperature with an infrared thermometer (IRT) from 2004- 2005, and a second dataset of Bowen ratio, IRT and stem-flow gage measurements in 2003. Results showed that reasonable estimates of daily T were obtained for a multi-year period with ease of operation and minimal cost. With known season-long daily T, E and ET, it is possible to determine the soil water availability associated with grass- and shrub-dominated sites and better understand the hydrologic impact of regional woody plant encroachment

Activity of dalotuzumab, a selective anti-IGF1R antibody, in combination with erlotinib in unselected patients with Non-small-cell lung cancer: a phase I/II randomized trial

BACKGROUND: We investigated the safety and antitumor activity of dalotuzumab, a selective anti-insulin growth factor 1 receptor monoclonal antibody (IGF1R MoAb), plus erlotinib in a sequential phase I/II trial in unselected patients with refractory advanced non-small-cell lung cancer (NSCLC).The phase I trial determined the recommended dose and safety of erlotinib plus dalotuzumab at 5 mg/kg or 10 mg/kg weekly in 20 patients. The phase II trial compared outcomes to erlotinib alone and erlotinib plus dalotuzumab at the mg/kg established in the phase I trial. RESULTS: Erlotinib at 150 mg plus dalotuzumab at 10 mg/kg was safe. The phase II trial included 37 patients in the erlotinib arm and 38 patients in the erlotinib plus dalotuzumab arm. Progression-free survival was 1.6 versus 2.5 months, overall survival was 10.2 and 6.6 months, and the objective response rate was 7.9% and 2.7%, respectively, with no significant differences between the two arms. Grade 3-5 adverse events occurred in 11 (28.9%) versus 13 (35.1%) patients, respectively. The most frequent adverse events were asthenia (36.8% vs. 37.8%), dehydration (5.3% vs. 2.7%), diarrhea (71% vs. 81.1%), hyperglycemia (13.1% vs.18.9%), and skin-related toxicities (92.1% vs. 86.4%). CONCLUSION: The addition of dalotuzumab to erlotinib did not improve efficacy outcome in patients with refractory advanced NSCLC

TNF is required for TLR ligand–mediated but not protease-mediated allergic airway inflammation

Asthma is associated with exposure to a wide variety of allergens and adjuvants. The extent to which overlap exists between the cellular and molecular mechanisms triggered by these various agents is poorly understood, but it might explain the differential responsiveness of patients to specific therapies. In particular, it is unclear why some, but not all, patients benefit from blockade of TNF. Here, we characterized signaling pathways triggered by distinct types of adjuvants during allergic sensitization. Mice sensitized to an innocuous protein using TLR ligands or house dust extracts as adjuvants developed mixed eosinophilic and neutrophilic airway inflammation and airway hyperresponsiveness (AHR) following allergen challenge, whereas mice sensitized using proteases as adjuvants developed predominantly eosinophilic inflammation and AHR. TLR ligands, but not proteases, induced TNF during allergic sensitization. TNF signaled through airway epithelial cells to reprogram them and promote Th2, but not Th17, development in lymph nodes. TNF was also required during the allergen challenge phase for neutrophilic and eosinophilic inflammation. In contrast, TNF was dispensable for allergic airway disease in a protease-mediated model of asthma. These findings might help to explain why TNF blockade improves lung function in only some patients with asthma

Health Is Still Social: Contemporary Examples in the Age of the Genome

Holtz and colleagues argue that social medicine, including an understanding of the social roots of disease, is as important now as it has ever been

Maternal Environmental Contribution to Adult Sensitivity and Resistance to Obesity in Long Evans Rats

The OLETF rat is an animal model of early onset hyperphagia induced obesity, presenting multiple pre-obese characteristics during the suckling period. In the present study, we used a cross-fostering strategy to assess whether interactions with obese dams in the postnatal environment contributed to the development of obesity.On postnatal Day (PND)-1 OLETF and control LETO pups were cross-fostered to same or opposite strain dams. An independent ingestion test was performed on PND11 and a nursing test on PND18. Rats were sacrificed at weaning or on PND90, and plasma leptin, insulin, cholesterol, triglycerides and alanine aminotransferase (ALT) were assayed. Fat pads were collected and weighed and adipocyte size and number were estimated. Body weight and intake, as well as the estrous cycle of the female offspring were monitored.During the suckling period, the pups' phenotype was almost completely determined by the strain of the mother. However, pups independently ingested food according to their genotype, regardless of their actual phenotype. At adulthood, cross fostered males of both strains and LETO females were affected in regard of their adiposity levels in the direction of the foster dam. On the other hand, OLETF females showed almost no alterations in adiposity but were affected by the strain of the dams in parameters related to the metabolic syndrome. Thus, OLETF females showed reduced liver adiposity and circulating levels of ALT, while LETO females presented a disrupted estrous cycle and increased cholesterol and triglycerides in the long term.The present study provides further support for the early postnatal environment playing a sex-divergent role in programming later life phenotype. In addition, it plays a more central role in determining the functioning of mechanisms involved in energy balance that may provide protection from or sensitivity to later life obesity and pathologies related to the metabolic syndrome