Mild cold effects on hunger, food intake, satiety and skin temperature in humans.

BACKGROUND: Mild cold exposure increases energy expenditure and can influence energy balance, but at the same time it does not increase appetite and energy intake. OBJECTIVE: To quantify dermal insulative cold response, we assessed thermal comfort and skin temperatures changes by infrared thermography. METHODS: We exposed healthy volunteers to either a single episode of environmental mild cold or thermoneutrality. We measured hunger sensation and actual free food intake. After a thermoneutral overnight stay, five males and five females were exposed to either 18°C (mild cold) or 24°C (thermoneutrality) for 2.5 h. Metabolic rate, vital signs, skin temperature, blood biochemistry, cold and hunger scores were measured at baseline and for every 30 min during the temperature intervention. This was followed by an ad libitum meal to obtain the actual desired energy intake after cold exposure. RESULTS: We could replicate the cold-induced increase in REE. But no differences were detected in hunger, food intake, or satiety after mild cold exposure compared with thermoneutrality. After long-term cold exposure, high cold sensation scores were reported, which were negatively correlated with thermogenesis. Skin temperature in the sternal area was tightly correlated with the increase in energy expenditure. CONCLUSIONS: It is concluded that short-term mild cold exposure increases energy expenditure without changes in food intake. Mild cold exposure resulted in significant thermal discomfort, which was negatively correlated with the increase in energy expenditure. Moreover, there is a great between-subject variability in cold response. These data provide further insights on cold exposure as an anti-obesity measure.The study was funded by NIHR, BRC Seed Fund, individual grants: ML and MS: Marie Curie Fellowship, CYT: Welcome Trust Fellowship, SV: MRC, BHF and BBSRC, AVP: BBSRC.This is the final version of the article. It first appeared from Bioscientifica via https://doi.org/ 10.1530/EC-16-000

Sphingolipids and glycerophospholipids - The "ying and yang" of lipotoxicity in metabolic diseases

Sphingolipids in general and ceramides in particular, contribute to pathophysiological mechanisms by modifying signalling and metabolic pathways. Here, we present the available evidence for a bidirectional homeostatic crosstalk between sphingolipids and glycerophospholipids, whose dysregulation contributes to lipotoxicity induced metabolic stress. The initial evidence for this crosstalk originates from simulated models designed to investigate the biophysical properties of sphingolipids in plasma membrane representations. In this review, we reinterpret some of the original findings and conceptualise them as a sort of "$\textit{ying/yang}$" interaction model of opposed/complementary forces, which is consistent with the current knowledge of lipid homeostasis and pathophysiology. We also propose that the dysregulation of the balance between sphingolipids and glycerophospholipids results in a lipotoxic insult relevant in the pathophysiology of common metabolic diseases, typically characterised by their increased ceramide/sphingosine pools.This work was funded by the Medical Research Council Programme grants (MC_UU_12012/2) “Lipotoxicity and obesity-associated metabolic complications”. FP7-ETHERPATHS (KBBE-2007-2A-222639-2), FP7-MITIN (223450), BBSRC (BB/H002731/1)

The stem/progenitor landscape is reshaped in a mouse model of essential thrombocythemia and causes excess megakaryocyte production

Frameshift mutations in CALR (calreticulin) are associated with essential thrombocythemia (ET), but the stages at and mechanisms by which mutant CALR drives transformation remain incompletely defined. Here, we use single-cell approaches to examine the hematopoietic stem/progenitor cell landscape in a mouse model of mutant CALR-driven ET. We identify a trajectory linking hematopoietic stem cells (HSCs) with megakaryocytes and prospectively identify a previously unknown intermediate population that is overrepresented in the disease state. We also show that mutant CALR drives transformation primarily from the earliest stem cell compartment, with some contribution from megakaryocyte progenitors. Last, relative to wild-type HSCs, mutant CALR HSCs show increases in JAK-STAT signaling, the unfolded protein response, cell cycle, and a previously undescribed up-regulation of cholesterol biosynthesis. Overall, we have identified a novel megakaryocyte-biased cell population that is increased in a mouse model of ET and described transcriptomic changes linking CALR mutations to increased HSC proliferation and megakaryopoiesis

A Comparative Study of Different Methodologies for Fault Diagnosis in Multivariate Quality Control

Different methodologies for fault diagnosis in multivariate quality control have been proposed in recent years. These methods work in the space of the original measured variables and have performed reasonably well when there is a reduced number of mildly correlated quality and/or process variables with a well-conditioned covariance matrix. These approaches have been introduced by emphasizing their positive or negative virtues, generally on an individual basis, so it is not clear for the practitioner the best method to be used. This paper provides a comprehensive study of the performance of diverse methodological approaches when tested on a large number of distinct simulated scenarios. Our primary aim is to highlight key weaknesses and strengths in these methods as well as clarifying their relationships and the requirements for their implementation in practice.Vidal Puig, S.; Ferrer, A. (2014). A Comparative Study of Different Methodologies for Fault Diagnosis in Multivariate Quality Control. Communications in Statistics - Simulation and Computation. 43(5):986-1005. doi:10.1080/03610918.2012.720745S9861005435Arteaga, F., & Ferrer, A. (2010). How to simulate normal data sets with the desired correlation structure. Chemometrics and Intelligent Laboratory Systems, 101(1), 38-42. doi:10.1016/j.chemolab.2009.12.003Doganaksoy, N., Faltin, F. W., & Tucker, W. T. (1991). Identification of out of control quality characteristics in a multivariate manufacturing environment. Communications in Statistics - Theory and Methods, 20(9), 2775-2790. doi:10.1080/03610929108830667Fuchs, C., & Benjamini, Y. (1994). Multivariate Profile Charts for Statistical Process Control. Technometrics, 36(2), 182-195. doi:10.1080/00401706.1994.10485765Hawkins, D. M. (1991). Multivariate Quality Control Based on Regression-Adiusted Variables. Technometrics, 33(1), 61-75. doi:10.1080/00401706.1991.10484770Editorial Board. (2007). Computational Statistics & Data Analysis, 51(8), iii-v. doi:10.1016/s0167-9473(07)00125-9Hayter, A. J., & Tsui, K.-L. (1994). Identification and Quantification in Multivariate Quality Control Problems. Journal of Quality Technology, 26(3), 197-208. doi:10.1080/00224065.1994.11979526HOCHBERG, Y. (1988). A sharper Bonferroni procedure for multiple tests of significance. Biometrika, 75(4), 800-802. doi:10.1093/biomet/75.4.800HOMMEL, G. (1988). A stagewise rejective multiple test procedure based on a modified Bonferroni test. Biometrika, 75(2), 383-386. doi:10.1093/biomet/75.2.383Kourti, T., & MacGregor, J. F. (1996). Multivariate SPC Methods for Process and Product Monitoring. Journal of Quality Technology, 28(4), 409-428. doi:10.1080/00224065.1996.11979699Li, J., Jin, J., & Shi, J. (2008). Causation-BasedT2Decomposition for Multivariate Process Monitoring and Diagnosis. Journal of Quality Technology, 40(1), 46-58. doi:10.1080/00224065.2008.11917712Mason, R. L., Tracy, N. D., & Young, J. C. (1995). Decomposition ofT2 for Multivariate Control Chart Interpretation. Journal of Quality Technology, 27(2), 99-108. doi:10.1080/00224065.1995.11979573Mason, R. L., Tracy, N. D., & Young, J. C. (1997). A Practical Approach for Interpreting Multivariate T2 Control Chart Signals. Journal of Quality Technology, 29(4), 396-406. doi:10.1080/00224065.1997.11979791Murphy, B. J. (1987). Selecting Out of Control Variables With the T 2 Multivariate Quality Control Procedure. The Statistician, 36(5), 571. doi:10.2307/2348668Rencher, A. C. (1993). The Contribution of Individual Variables to Hotelling’s T 2 , Wilks’ Λ, and R 2. Biometrics, 49(2), 479. doi:10.2307/2532560Roy, J. (1958). Step-Down Procedure in Multivariate Analysis. The Annals of Mathematical Statistics, 29(4), 1177-1187. doi:10.1214/aoms/1177706449Runger, G. C., Alt, F. B., & Montgomery, D. C. (1996). Contributors to a multivariate statistical process control chart signal. Communications in Statistics - Theory and Methods, 25(10), 2203-2213. doi:10.1080/03610929608831832Sankoh, A. J., Huque, M. F., & Dubey, S. D. (1997). Some comments on frequently used multiple endpoint adjustment methods in clinical trials. Statistics in Medicine, 16(22), 2529-2542. doi:10.1002/(sici)1097-0258(19971130)16:223.0.co;2-jTukey, J. W., Ciminera, J. L., & Heyse, J. F. (1985). Testing the Statistical Certainty of a Response to Increasing Doses of a Drug. Biometrics, 41(1), 295. doi:10.2307/253066

Unraveling the developmental roadmap toward human brown adipose tissue

Increasing brown adipose tissue (BAT) mass and activation is a therapeutic strategy to treat obesity and complications. Obese and diabetic patients possess low amounts of BAT, so an efficient way to expand their mass is necessary. There is limited knowledge about how human BAT develops, differentiates, and is optimally activated. Accessing human BAT is challenging, given its low volume and anatomical dispersion. These constraints make detailed BAT-related developmental and functional mechanistic studies in humans virtually impossible. We have developed and characterized functionally and molecularly a new chemically defined protocol for the differentiation of human pluripotent stem cells (hPSCs) into brown adipocytes (BAs) that overcomes current limitations. This protocol recapitulates step by step the physiological developmental path of human BAT. The BAs obtained express BA and thermogenic markers, are insulin sensitive, and responsive to β-adrenergic stimuli. This new protocol is scalable, enabling the study of human BAs at early stages of development

Calcium Channel CaV2.3 Subunits Regulate Hepatic Glucose Production by Modulating Leptin-Induced Excitation of Arcuate Pro-opiomelanocortin Neurons

Leptin acts on hypothalamic pro-opiomelanocortin (POMC) neurons to regulate glucose homeostasis, but the precise mechanisms remain unclear. Here, we demonstrate that leptin-induced depolarization of POMC neurons is associated with the augmentation of a voltage-gated calcium (CaV) conductance with the properties of the “R-type” channel. Knockdown of the pore-forming subunit of the R-type (CaV2.3 or Cacna1e) conductance in hypothalamic POMC neurons prevented sustained leptin-induced depolarization. In vivo POMC-specific Cacna1e knockdown increased hepatic glucose production and insulin resistance, while body weight, feeding, or leptin-induced suppression of food intake were not changed. These findings link Cacna1e function to leptin-mediated POMC neuron excitability and glucose homeostasis and may provide a target for the treatment of diabetes

Defective extracellular matrix remodeling in brown adipose tissue is associated with fibro-inflammation and reduced diet-induced thermogenesis.

The relevance of extracellular matrix (ECM) remodeling is reported in white adipose tissue (AT) and obesity-related dysfunctions, but little is known about the importance of ECM remodeling in brown AT (BAT) function. Here, we show that a time course of high-fat diet (HFD) feeding progressively impairs diet-induced thermogenesis concomitantly with the development of fibro-inflammation in BAT. Higher markers of fibro-inflammation are associated with lower cold-induced BAT activity in humans. Similarly, when mice are housed at thermoneutrality, inactivated BAT features fibro-inflammation. We validate the pathophysiological relevance of BAT ECM remodeling in response to temperature challenges and HFD using a model of a primary defect in the collagen turnover mediated by partial ablation of the Pepd prolidase. Pepd-heterozygous mice display exacerbated dysfunction and BAT fibro-inflammation at thermoneutrality and in HFD. Our findings show the relevance of ECM remodeling in BAT activation and provide a mechanism for BAT dysfunction in obesity

Lipid zonation and phospholipid remodeling in nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) can progress from simple steatosis (i.e., nonalcoholic fatty liver [NAFL]) to nonalcoholic steatohepatitis (NASH), cirrhosis, and cancer. Currently, the driver for this progression is not fully understood; in particular, it is not known how NAFLD and its early progression affects the distribution of lipids in the liver, producing lipotoxicity and inflammation. In this study, we used dietary and genetic mouse models of NAFL and NASH and translated the results to humans by correlating the spatial distribution of lipids in liver tissue with disease progression using advanced mass spectrometry imaging technology. We identified several lipids with distinct zonal distributions in control and NAFL samples and observed partial to complete loss of lipid zonation in NASH. In addition, we found increased hepatic expression of genes associated with remodeling the phospholipid membrane, release of arachidonic acid (AA) from the membrane, and production of eicosanoid species that promote inflammation and cell injury. The results of our immunohistochemistry analyses suggest that the zonal location of remodeling enzyme LPCAT2 plays a role in the change in spatial distribution for AA-containing lipids. This results in a cycle of AA-enrichment in pericentral hepatocytes, membrane release of AA, and generation of proinflammatory eicosanoids and may account for increased oxidative damage in pericentral regions in NASH. Conclusion: NAFLD is associated not only with lipid enrichment, but also with zonal changes of specific lipids and their associated metabolic pathways. This may play a role in the heterogeneous development of NAFLD. (Hepatology 2017;65:1165-1180)

SREBP1-induced fatty acid synthesis depletes macrophages antioxidant defences to promote their alternative activation

Macrophages exhibit a spectrum of activation states ranging from classical to alternative activation1. Alternatively, activated macrophages are involved in diverse pathophysiological processes such as confining tissue parasites2, improving insulin sensitivity3 or promoting an immune tolerant microenvironment that facilitates tumour growth and metastasis4. Recently, the role of metabolism regulating macrophage function has come into focus as both the classical and alternative activation programmes require specific regulated metabolic reprogramming5. While most of the studies regarding immunometabolism have focussed on the catabolic pathways activated to provide energy, little is known about the anabolic pathways mediating macrophage alternative activation. In this study, we show that the anabolic transcription factor sterol regulatory element binding protein 1 (SREBP1) is activated in response to the canonical Th2 cytokine interleukin 4 (IL-4) to trigger the de novo lipogenesis (DNL) programme, as a necessary step for macrophage alternative activation. Mechanistically, DNL consumes NADPH, partitioning it away from cellular antioxidant defences and raising ROS levels. ROS serves as a second messenger, signalling sufficient DNL, and promoting macrophage alternative activation. The pathophysiological relevance of this mechanism is validated by showing that SREBP1/DNL is essential for macrophage alternative activation in vivo in a helminth infection model.This work was supported by the British Heart Foundation (RG/18/7/33636), the MRC (MC_UU_00014/2) and the FP7 MITIN (223450). K.P. was a recipient of a fellowship from the Wellcome Trust. A.N.J.M. and E.J. are supported by the Wellcome Trust (100963/Z/13/Z) and the MRC (U105178805). J.L. is a recipient fellowship of the British Heart Foundation. A.D. was a Marie-Curie Early-Stage Researcher supported by the European Union’s Horizon 2020 research and innovation programme (675585 Marie-Curie ITN ‘SymBioSys’) to J.S.-R. A.K. is supported by the Wellcome Trust (106260/Z/14/Z) and an ERC award (648889). P.F. is supported by the Science Foundation Ireland (10/IN.1/B3004). The IMS Genomics and Transcriptomics and Histology cores (B.M.-A., B.Y.H.L. and M.K.M.) are funded by the UK MRC Metabolic Disease Unit (MRC_MC_UU_12012/5) and a Wellcome Trust Strategic Award (100574/Z/12/Z). The Disease Model Core is part of the MRC Metabolic Diseases Unit (MRC_MC_UU_12012/5) and Wellcome Trust Strategic Award (100574/Z/12/Z)