Turning up the heat : role of brown adipose tissue in metabolic disease

In 1551, the Swiss naturalist Konrad Gessner first described brown adipose tissue (BAT) as being __neither fat, nor flesh (nec pinguitudo, nec caro), but something in between__. Now, some 460 years later, we know that Gessner had guessed the origin of brown adipocytes correctly. A unique property of the brown adipocyte is its capacity to dissipate energy stored in triglycerides (TG) as heat, which is mediated via the uncoupling protein UCP1. The recent discovery that active BAT is present in human adults meant the beginning of an exciting new area in metabolic research. BAT is currently regarded as a potential target to combat obesity and related diseases by inducing a sustained increase in energy expenditure. Interestingly, South Asians have lower energy expenditure, which may thus theoretically be caused by a reduction in BAT activity. The studies of which the results are described in this thesis were aimed at 1) gaining more insight into the physiology of BAT, 2) identifying novel tools and targets that may activate BAT, and 3) investigating the involvement of BAT in metabolism in humans with a focus on potential differences between South Asians and white Caucasians.Sanofi, TSE systems, Novo Nordisk B.V.UBL - phd migration 201

Fracture toughness measurements on igneous rocks using a high-pressure, high-temperature rock fracture mechanics cell

A sound knowledge of mechanical properties of rocks at high temperatures and pressures is essential for modelling volcanological problems such as fracture of lava flows and dike emplacement. In particular, fracture toughness is a scale-invariant material property of a rock that describes its resistance to tensile failure. A new fracture mechanics apparatus has been constructed enabling fracture toughness measurements on large (60 mm diameter) rock core samples at temperatures up to 750–C and pressures up to 50 MPa. We present a full description of this apparatus and, by plotting fracture resistance as a function of crack length, show that the size of the samples is sufficient for reliable fracture toughness measurements. A series of tests on Icelandic, Vesuvian and Etnean basalts at temperatures from 30 to 600–C and confining pressures up to 30 MPa gave fracture toughness values between 1.4 and 3.8 MPa m1=2. The Icelandic basalt is the strongest material and the Etnean material sampled from the surface crust of a lava flow the weakest. Increasing temperature does not greatly affect the fracture toughness of the Etnean or Vesuvian material but the Icelandic samples showed a marked increase in toughness at around 150–C, followed by a return to ambient toughness levels. This material also became tougher under moderate confining pressure but the other two materials showed little change in toughness. We describe in terms of fracture mechanics probable causes for the changes in fracture toughness and compare our experimental results with values obtained from dike propagation modelling found in the literature

The role of AMPK signaling in brown adipose tissue activation

Obesity is becoming a pandemic, and its prevalence is still increasing. Considering that obesity increases the risk of developing cardiometabolic diseases, research efforts are focusing on new ways to combat obesity. Brown adipose tissue (BAT) has emerged as a possible target to achieve this for its functional role in energy expenditure by means of increasing thermogenesis. An important metabolic sensor and regulator of whole-body energy balance is AMP-activated protein kinase (AMPK), and its role in energy metabolism is evident. This review highlights the mechanisms of BAT activation and investigates how AMPK can be used as a target for BAT activation. We review compounds and other factors that are able to activate AMPK and further discuss the therapeutic use of AMPK in BAT activation. Extensive research shows that AMPK can be activated by a number of different kinases, such as LKB1, CaMKK, but also small molecules, hormones, and metabolic stresses. AMPK is able to activate BAT by inducing adipogenesis, maintaining mitochondrial homeostasis and inducing browning in white adipose tissue. We conclude that, despite encouraging results, many uncertainties should be clarified before AMPK can be posed as a target for anti-obesity treatment via BAT activation.Diabetes mellitus: pathophysiological changes and therap

A simplified procedure to trace triglyceride-rich lipoprotein metabolism in vivo

Glycerol tri[H-3]oleate and [C-14]cholesteryl oleate double-labeled triglyceride-rich lipoprotein (TRL)-like particles are a well-established tool to trace the effect of lipid-modulating interventions on TRL metabolism. The routine generation of these particles involves sonication of a lipid mixture and subsequent fractionation of resulting particles into populations of different average size through density gradient ultracentrifugation. Here, we describe a simplified and more time-efficient procedure for preparing TRL-like particles without the need of fractionation. The simplified procedure shortened the preparation of particles from over 4 h to less than 2 h and generated particles with a higher yield, although with a smaller average size and more heterogeneous size distribution. In C57Bl/6J mice housed at thermoneutrality (30 degrees C), the two preparations showed highly comparable plasma clearance and organ distribution of glycerol tri[H-3]oleate-derived [H-3]oleate and [C-14]cholesteryl oleate, as measures of lipolysis and core remnant uptake, respectively. Upon a cold challenge (14 degrees C), plasma clearance was accelerated due to enhanced uptake of glycerol tri[H-3]oleate-derived [H-3]oleate by brown adipose tissue. The simplified procedure resulted in a modestly increased particle uptake by the spleen, while uptake by other organs was comparable between the two preparations. In conclusion, the simplified procedure accelerates the preparation of TRL-like particles for tracing in vivo TRL metabolism. We anticipate that this time-efficient procedure will be useful for incorporation of PET-traceable lipids to obtain more insight into human lipoprotein metabolism.Diabetes mellitus: pathophysiological changes and therap

Circadian control of brown adipose tissue

Disruption of circadian (similar to 24 h) rhythms is associated with an increased risk of cardiometabolic diseases. Therefore, unravelling how circadian rhythms are regulated in different metabolic tissues has become a prominent research focus. Of particular interest is brown adipose tissue (BAT), which combusts triglyceride-derived fatty acids and glucose into heat and displays a circannual and diurnal rhythm in its thermogenic activity. In this review, the genetic, neuronal and endocrine generation of these rhythms in BAT is discussed. In addition, the potential risks of disruption or attenuation of these rhythms in BAT, and possible factors influencing these rhythms, are addressed.Diabetes mellitus: pathophysiological changes and therap

Segmenting Critical Factors for Enhancing the use of IT in Humanitarian Supply Chain Management

AbstractThis study intends to explore and segment the critical factors (CFs) to enhance the use of Information Technology (IT) in Humanitarian Supply Chain (HSC), particularly in the Indian context. In this study, ten influencing factors has been identified through an extensive literature review and expert opinion. A structural model and cause–effect relationship diagram was developed using decision-making trial and evaluation laboratory (DEMATEL) method for the identification of CFs. The present study adopt a comprehensive and rigorous procedure to identify six CFs namely, top management support, Government support, feedback mechanism to facilitate learning from prior experiences, transparent and accountable supply chain, strategic planning, and mutual learning with other commercial organizations (COs). The developed framework provides a simple, effective and efficient way to enhance the utilization of IT in HSC and in large to improve the competencies and performance of HSC

Absence of Self-Averaging and Universal Fluctuations in Random Systems Near Critical Points

The distributions P(X) of singular thermodynamic quantities, on an ensemble of d-dimensional quenched random samples of linear size L near a critical point, are analyzed using the renormalization group. For L much larger than the correlation length ξ, we recover strong self-averaging (SA): P(X) approaches a Gaussian with relative squared width RX~(L/ξ)−d. For L≪ξ we show weak SA (RX decays with a small power of L) or no SA [P(X) approaches a non-Gaussian, with universal L-independent relative cumulants], when the randomness is irrelevant or relevant, respectively

Targeting white, brown and perivascular adipose tissue in atherosclerosis development

Functional Genomics of Systemic Disorder

Distribution of brown adipose tissue radiodensity in young adults: implications for cold [F-18]FDG-PET/CT analyses

Purpose Nowadays, 2-deoxy-2-[F-18]fluoro-D-glucose ([F-18]FDG) positron emission tomography (PET)/X-ray computed tomography (CT) is considered the best available technique to in vivo determination of human BAT volume. The most used Hounsfield unit (HU) threshold for BAT quantification is from - 250 to - 50 HU. Therefore, the main objective of the present study is (i) to examine the influence of SUV and HU thresholds on BAT quantification by [F-18]FDG-PET/CT scan, (ii) to identify the proportion of BAT which is not detected by [F-18]FDG-PET/CT scan when limiting the range between - 10 and - 50 HU, and (iii) to describe the distribution of BAT radiodensity by weight status and sex in young healthy individuals. Procedures We measured 125 individuals after a personalized cooling protocol with a static [F-18]FDG-PET/CT scan. We quantified BAT using different combination of threshold in every single HU for all participants. Results We observed that the SUV threshold influences BAT quantification by [F-18]FDG-PET/CT scans more than the HU range. We found that the range from - 50 to - 10 HU had the highest proportion of total BAT volume (43.2 %), which represents 41.4 % of the total BAT metabolic activity in our cohort. We also observed that BAT volume was not different between categories of body mass index, as well as BAT activity (SUVmean). In addition, BAT was less dense in women than in men, although the BAT activity (SUVmean) was higher in all ranges of HU. We also observed that the radiodensity of BAT located in the cervical area was mainly in the range from - 50 to - 10 HU. Conclusion Therefore, all future human studies using static [F-18]FDG-PET/CT scans should include BAT in the radiodensity range from - 50 to - 10 HU.Diabetes mellitus: pathophysiological changes and therap

Differences between the most used equations in BAT-human studies to estimate parameters of skin temperature in young lean men

Diabetes mellitus: pathophysiological changes and therap