Adipose tissue browning in mice and humans Herz, Carsten T; Kiefer, Florian W
Journal of Endocrinology/Journal of endocrinology,
06/2019, Letnik:
241, Številka:
3
Journal Article
Recenzirano
Odprti dostop
In the midst of an obesity epidemic, the promotion of brown adipose tissue (BAT) function and the browning of white adipose tissue (WAT) have emerged as promising therapeutic targets to increase ...energy expenditure and counteract weight gain. Despite the fact that the thermogenic potential of bone fide BAT in rodents is several orders of magnitudes higher than white fat containing brite/beige adipocytes, WAT browning represents a particularly intriguing concept in humans given the extreme amount of excess WAT in obese individuals. In addition, the clear distinction between classic brown and beige fat that has been proposed in mice does not exist in humans. In fact, studies of human BAT biopsies found controversial results suggesting both classic brown and beige characteristics. Irrespective of the true ‘color’, accumulating evidence suggests the induction of thermogenic adipocytes in human WAT depots in response to specific stimuli, highlighting that WAT browning may occur in both, mice and humans. These observations also emphasize the great plasticity of human fat depots and raise important questions about the metabolic properties of thermogenically active adipose tissue in humans and the potential therapeutic implications. We will first review the cellular and molecular aspects of selected adipose tissue browning concepts that have been identified in mouse models with emphasis on neuronal factors, the microbiome, immune cells and several hormones. We will also summarize the evidence for adipose tissue browning in humans including some experimental pharmacologic approaches.
Cellular processes often depend on interactions between proteins and the formation of macromolecular complexes. The impairment of such interactions can lead to deregulation of pathways resulting in ...disease states, and it is hence crucial to gain insights into the nature of macromolecular assemblies. Detailed structural knowledge about complexes and protein-protein interactions is growing, but experimentally determined three-dimensional multimeric assemblies are outnumbered by complexes supported by non-structural experimental evidence. Here, we aim to fill this gap by modeling multimeric structures by homology, only using amino acid sequences to infer the stoichiometry and the overall structure of the assembly. We ask which properties of proteins within a family can assist in the prediction of correct quaternary structure. Specifically, we introduce a description of protein-protein interface conservation as a function of evolutionary distance to reduce the noise in deep multiple sequence alignments. We also define a distance measure to structurally compare homologous multimeric protein complexes. This allows us to hierarchically cluster protein structures and quantify the diversity of alternative biological assemblies known today. We find that a combination of conservation scores, structural clustering, and classical interface descriptors, can improve the selection of homologous protein templates leading to reliable models of protein complexes.
Die Wissenssoziologie von Karl Mannheim wird (nicht nur) in der Medienpädagogik vornehmlich aufgrund der darin ausgearbeiteten Methodologie, die Dokumentarische Methode der Interpretation, zur ...Kenntnis genommen. Wesentlich hierfür sind bspw. die Beiträge zur Theorie der Weltanschauungs-Interpretation (Mannheim 1964a), die Unterscheidung zwischen konjunktivem und kommunikativem Wissen (Mannheim 1980) und der Aufsatz über «Das Problem der Generationen» (Mannheim 1964b). Der Beitrag geht davon aus, dass das Potenzial dieser Theorieschule durch die Reduktion auf ihre methodologischen Implikationen nicht hinreichend ausgeschöpft wird. Deshalb wird vorgeschlagen, die Wissenssoziologie als grundlagentheoretisches Fundament für ein medienpädagogisches Verständnis von professionellem (Denken und) Handeln zu entwickeln. Unter Zuhilfenahme der Medien-Pädagogik als partikulare Einmischung und als akzeptierende Disziplin (Fromme und Meder 2000) einerseits und dem Umgang mit dem Nicht-Wissen (Hugger 2007) andererseits werden die professionstheoretischen Implikationen unter besonderer Berücksichtigung des dynamischen Relationismus als wissenssoziologischen Programmatik reformuliert.
Promotion of brown adipose tissue (BAT) activity or browning of white adipose tissue has shown great potential as anti-obesity strategy in numerous preclinical models. The discovery of active BAT in ...humans and the recent advances in the understanding of human BAT biology and function have significantly propelled this field of research. Pharmacological stimulation of energy expenditure to counteract obesity has always been an intriguing therapeutic concept; with the identification of the specific molecular pathways of brown fat function, this idea has now become as realistic as ever. Two distinct strategies are currently being pursued; one is the activation of bone fide BAT, the other is the induction of BAT-like cells or beige adipocytes within white fat depots, a process called browning. Recent evidence suggests that both phenomena can occur in humans. Cold-induced promotion of BAT activity is strongly associated with enhanced thermogenesis and energy expenditure in humans and has beneficial effects on fat mass and glucose metabolism. Despite these encouraging results, a number of issues deserve additional attention including the distinct characteristics of human vs rodent BAT, the heterogeneity of human BAT depots or the identification of the adipocyte precursors that can give rise to thermogenic cells in human adipose tissue. In addition, many pharmaceutical compounds are being tested for their ability to promote a thermogenic program in human adipocytes. This review summarizes the current knowledge about the various cellular and molecular aspects of human BAT as well as the relevance for energy metabolism including its therapeutic potential for obesity.
Brown adipose tissue and thermogenesis Fenzl, Anna; Kiefer, Florian W.
Hormone molecular biology and clinical investigation,
7/2014, Letnik:
19, Številka:
1
Journal Article
Recenzirano
Odprti dostop
The growing understanding of adipose tissue as an important endocrine organ with multiple metabolic functions has directed the attention to the (patho)physiology of distinct fat depots. Brown adipose ...tissue (BAT), in contrast to
white fat, can dissipate significant amounts of chemical energy through uncoupled respiration and heat production (thermogenesis). This process is mediated by the major thermogenic factor uncoupling protein-1 and can be activated by certain stimuli, such as cold exposure, adrenergic compounds or genetic alterations. White adipose tissue (WAT) depots, however, also possess the capacity to acquire brown fat characteristics in response to thermogenic stimuli. The induction of a BAT-like cellular and molecular program in WAT has recently been termed “browning” or “beiging”. Promotion of BAT activity or the browning of WAT is associated with in vivo cold tolerance, increased energy expenditure, and protection against obesity and type 2 diabetes. These preclinical observations have gained additional significance with the recent discovery that active BAT is present in adult humans and can be detected by
fluor-deoxy-glucose positron emission tomography coupled with computed tomography. As in rodents, human BAT can be activated by cold exposure and is associated with increased energy turnover and lower body fat mass. Despite the tremendous progress in brown fat research in recent years, pharmacological concepts to harness BAT function therapeutically are currently still lacking.
Homology modeling aims to build three-dimensional protein structure models using experimentally determined structures of related family members as templates. SWISS-MODEL workspace is an integrated ...Web-based modeling expert system. For a given target protein, a library of experimental protein structures is searched to identify suitable templates. On the basis of a sequence alignment between the target protein and the template structure, a three-dimensional model for the target protein is generated. Model quality assessment tools are used to estimate the reliability of the resulting models. Homology modeling is currently the most accurate computational method to generate reliable structural models and is routinely used in many biological applications. Typically, the computational effort for a modeling project is less than 2 h. However, this does not include the time required for visualization and interpretation of the model, which may vary depending on personal experience working with protein structures.
Abstract The view of adipose tissue as solely a fat storing organ has changed significantly over the past two decades with the discoveries of numerous adipocyte-secreted factors, so called ...adipokines, and their endocrine functions throughout the body. The newest chapter added to this story is the finding that adipose tissue is also a thermogenic organ contributing to energy expenditure through actions of specialized, heat-producing brown or beige adipocytes. In contrast to bone fide brown adipocytes, beige cells develop within white fat depots in response to various stimuli such as prolonged cold exposure, underscoring the great thermogenic plasticity of adipose tissue. The energy dissipating properties of beige and/or brown adipocytes hold great promise as a novel therapeutic concept against obesity and related complications. Hence, identifying the specific thermogenic adipocyte populations in humans and their pathways of activation are key milestones of current metabolism research. Here we will discuss the recent advances in the understanding of the molecular and physiological mechanisms of adipose tissue browning.
Abstract
Background
Accumulating evidence links brown adipose tissue (BAT) to increased cold-induced energy expenditure (CIEE) and regulation of lipid metabolism in humans. BAT has also been proposed ...as a novel source for biologically active lipid mediators including polyunsaturated fatty acids (PUFAs) and oxylipins. However, little is known about cold-mediated differences in energy expenditure and various lipid species between individuals with detectable BAT positive (BATpos) and those without BAT negative (BATneg).
Methods
Here we investigated a unique cohort of matched BATpos and BATneg individuals identified by 18F-fluorodeoxyglucose positron emission tomography combined with computed tomography (18F-FDG PET/CT). BAT function, CIEE, and circulating oxylipins, were analyzed before and after short-term cold exposure using 18F-FDG PET/CT, indirect calorimetry, and high-resolution mass spectrometry, respectively.
Results
We found that active BAT is the major determinant of CIEE since only BATpos individuals experienced significantly increased energy expenditure in response to cold. A single bout of moderate cold exposure resulted in the dissipation of an additional 20 kcal excess energy in BATpos but not in BATneg individuals. The presence of BAT was associated with a unique systemic PUFA and oxylipin profile characterized by increased levels of anti-inflammatory omega-3 fatty acids as well as cytochrome P450 products but decreased concentrations of some proinflammatory hydroxyeicosatetraenoic acids when compared with BATneg individuals. Notably, cold exposure raised circulating levels of various lipids, including the recently identified BAT-derived circulating factors (BATokines) DiHOME and 12-HEPE, only in BATpos individuals.
Conclusions
In summary, our data emphasize that BAT in humans is a major contributor toward cold-mediated energy dissipation and a critical organ in the regulation of the systemic lipid pool.
Aims/hypothesis
The newly identified liver- and fat-derived hormone, betatrophin, has recently been linked to insulin resistance and pancreatic beta cell growth in mice. These preclinical findings ...have suggested betatrophin as a potential candidate for novel glucose-lowering treatment concepts involving beta cell regeneration. However, the role of betatrophin in human insulin resistance and type 2 diabetes is currently unknown. Hence, the aim of this study was to investigate circulating betatrophin concentrations in two distinct cohorts with insulin resistance.
Methods
Betatrophin concentrations were analysed in (1) age- and sex-matched lean (
n
= 20) and morbidly obese individuals (
n
= 19), and (2) age-, sex- and BMI-matched non-diabetic (
n
= 19) and type 2 diabetic individuals (
n
= 18).
Results
Betatrophin concentrations did not differ between lean and morbidly obese or between non-diabetic and type 2 diabetic participants. No association was found with variables of beta cell function and glucose homeostasis. However, betatrophin did correlate significantly with plasma atherogenic lipids including total cholesterol, LDL-cholesterol and apolipoprotein B in morbidly obese and type 2 diabetic patients but not in controls. Insulin-resistant individuals with hypercholesterolaemia (≥5.2 mmol/l) had significantly higher betatrophin concentrations than those with normal cholesterol (<5.2 mmol/l).
Conclusions/interpretation
Betatrophin is a recently identified hormone, the circulating concentrations of which are unaltered in human insulin resistance but correlate significantly with atherogenic lipid profiles in high-risk cohorts with morbid obesity or type 2 diabetes. Betatrophin could therefore be a novel pathomechanistic player in dysfunctional lipid metabolism associated with high cardiovascular risk.
Betatrophin has recently been introduced as a novel hormone and promotor of beta cell proliferation and improved glucose tolerance in mouse models of insulin resistance. In obese and diabetic humans ...altered levels were reported and a role in pathophysiology of metabolic diseases was therefore hypothesized. However its release and regulation in women with gestational diabetes mellitus (GDM), as well as its associations with markers of obesity, glucose and lipid metabolism during pregnancy still remain unclear.
Circulating betatrophin was quantified in 21 women with GDM and 19 pregnant body mass index-matched women with normal glucose tolerance (NGT) as well as 10 healthy age-matched non-pregnant women by enzyme-linked immunosorbent assay. Additionally we performed radioimmunassay (RIA) to confirm the results.
Betatrophin concentrations measured by ELISA were significantly higher in GDM than in NGT (29.3±4.4 ng/ml vs. 18.1±8.7 ng/ml, p<0.001) which was confirmed by RIA. Betatrophin did not correlate with BMI or insulin resistance but showed a weak association with leptin levels in pregnancy and negative relationship with fasting C-peptide levels in all women. Moreover it correlated significantly with lipid parameters including triglycerides and total cholesterol in pregnancy, as well as estrogen, progesteron and birth weight.
Circulating betatrophin concentrations are dramatically increased in pregnancy and are significantly higher in GDM versus pregnant NGT. In the light of the previously reported role in lipid metabolism, betatrophin may represent a novel endocrine regulator of lipid alterations in pregnancy. However additional studies are needed to elucidate whether hormonal factors, such as estrogen, control the production of betatrophin and if targeting betatrophin could hold promise in the fight against metabolic disease.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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