Total daily energy expenditure has declined over the past three decades due to declining basal expenditure, not reduced activity expenditure.

Obesity is caused by a prolonged positive energy balance1,2. Whether reduced energy expenditure stemming from reduced activity levels contributes is debated3,4. Here we show that in both sexes, total energy expenditure (TEE) adjusted for body composition and age declined since the late 1980s, while adjusted activity energy expenditure increased over time. We use the International Atomic Energy Agency Doubly Labelled Water database on energy expenditure of adults in the United States and Europe (n = 4,799) to explore patterns in total (TEE: n = 4,799), basal (BEE: n = 1,432) and physical activity energy expenditure (n = 1,432) over time. In males, adjusted BEE decreased significantly, but in females this did not reach significance. A larger dataset of basal metabolic rate (equivalent to BEE) measurements of 9,912 adults across 163 studies spanning 100 years replicates the decline in BEE in both sexes. We conclude that increasing obesity in the United States/Europe has probably not been fuelled by reduced physical activity leading to lowered TEE. We identify here a decline in adjusted BEE as a previously unrecognized factor.

Thermoneutrality-Induced Macrophage Accumulation in Brown Adipose Tissue Does Not Impair the Tissue's Competence for Cold-Induced Thermogenic Recruitment.

Brown adipose tissue from mice living under conditions approaching human thermal and nutritional conditions (prolonged exposure to thermoneutral temperature and to an energy-rich (high-fat, high-sugar) diet) - referred to as "physiologically humanized" mice, displays morphological and molecular characteristics significantly different from those observed in young, chow-fed mice maintained at room temperature - referred to as "standard" mice. Here, we further examined brown fat from physiologically humanized and standard mice, as well as from mice exposed to thermoneutrality for a long time but not to an energy-rich diet - referred to here as "long-term thermoneutral" mice. Global transcriptome analysis of brown fat revealed that genes that were the most upregulated in brown fat of thermoneutral mice (both physiologically humanized and long-term thermoneutral) were those related to inflammatory processes, including genes expressed selectively in macrophages. Cellular and molecular analyses confirmed that brown fat from thermoneutral mice was heavily infiltrated by macrophages, predominantly organized into crown-like structures. However, despite this, the brown fat of thermoneutral mice retained full competence to attain the greatest possible recruitment state and became macrophage-depleted during the process of cold acclimation. Thus, profound macrophage accumulation does not influence the thermogenic recruitment competence of brown fat.

Human brown adipose tissue: Classical brown rather than brite/beige?

NEW FINDINGS: What is the topic of this review? It has been suggested that human brown adipose tissue (BAT) is more similar to the brite/beige adipose tissue of mice than to classical BAT of mice. The basis of this is discussed in relationship to the physiological conditions of standard experimental mice. What advances does it highlight? We highlight that, provided mouse adipose tissues are examined under physiological conditions closer to those prevalent for most humans, the gene expression profile of mouse classical BAT is more similar to that of human BAT than is the profile of mouse brite/beige adipose tissue. Human BAT is therefore not different in nature from classical mouse BAT. ABSTRACT: Since the presence of brown adipose tissue (BAT) was established in adult humans some 13 years ago, its physiological significance and molecular characteristics have been discussed. In particular, it has been proposed that the mouse adipose tissue depot most closely resembling and molecularly parallel to human BAT is not classical mouse BAT. Instead, so-called brite or beige adipose tissue, which is characteristically observed in the inguinal 'white' adipose tissue depot of mice, has been proposed to be the closest mouse equivalent of human BAT. We summarize here the published evidence examining this question. We emphasize the differences in tissue appearance and tissue transcriptomes from 'standard' mice [young, chow fed and, in effect semi-cold exposed (20°C)] versus 'physiologically humanized' mice [middle-aged, high-fat diet-fed mice living at thermoneutrality (30°C)]. We find that in the physiologically humanized mice, classical BAT displays molecular and cellular characteristics that are more akin to human BAT than are those of brite/beige adipose tissues from either standard or physiologically humanized mice. We suggest, therefore, that mouse BAT is the more relevant tissue for translational studies. This is an invited summary of a presentation given at Physiology 2019 (Aberdeen).

Human brown adipose tissue is phenocopied by classical brown adipose tissue in physiologically humanized mice.

Human and rodent brown adipose tissues (BAT) appear morphologically and molecularly different. Here we compare human BAT with both classical brown and brite/beige adipose tissues of 'physiologically humanized' mice: middle-aged mice living under conditions approaching human thermal and nutritional conditions, that is, prolonged exposure to thermoneutral temperature (approximately 30 °C) and to an energy-rich (high-fat, high-sugar) diet. We find that the morphological, cellular and molecular characteristics (both marker and adipose-selective gene expression) of classical brown fat, but not of brite/beige fat, of these physiologically humanized mice are notably similar to human BAT. We also demonstrate, both in silico and experimentally, that in physiologically humanized mice only classical BAT possesses a high thermogenic potential. These observations suggest that classical rodent BAT is the tissue of choice for translational studies aimed at recruiting human BAT to counteract the development of obesity and its comorbidities.

Author Correction: Human brown adipose tissue is phenocopied by classical brown adipose tissue in physiologically humanized mice.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Promotion of lipid storage rather than of thermogenic competence by fetal versus newborn calf serum in primary cultures of brown adipocytes.

Much current understanding of brown adipocyte development comes from in-vitro cell models. Serum type may affect the behavior of cultured cells and thus conclusions drawn. Here, we investigate effects of serum type ("fetal bovine" versus "newborn calf") on responses to differentiation inducers (the PPARγ agonist rosiglitazone or the neurotransmitter norepinephrine) in cultured primary brown adipocytes. Lipid storage was enhanced by fetal versus newborn serum. However, molecular adipose conversion (Pparg2 and Fabp4 expression) was not affected by serum type. Rosiglitazone-induced (7-days) expression of thermogenic genes (i.e. Ucp1, Pgc1a, Dio2 and Elovl3) was not systematically affected by serum type. However, importantly, acute (2 h) norepinephrine-induced thermogenic gene expression was overall markedly higher (and adipose genes somewhat lower) in cells cultured in newborn serum. Thus, newborn serum promotes thermogenic competence, and the use of fetal serum in brown adipocyte cultures (as is often routine) counteracts adequate differentiation. Agents that counteract this inhibition may therefore confoundingly be ascribed genuine thermogenic competence-inducing properties.

The ß3-adrenergic receptor is dispensable for browning of adipose tissues.

Brown and brite/beige adipocytes are attractive therapeutic targets to treat metabolic diseases. To maximally utilize their functional potential, further understanding is required about their identities and their functional differences. Recent studies with ß3-adrenergic receptor knockout mice reported that brite/beige adipocytes, but not classical brown adipocytes, require the ß3-adrenergic receptor for cold-induced transcriptional activation of thermogenic genes. We aimed to further characterize this requirement of the ß3-adrenergic receptor as a functional distinction between classical brown and brite/beige adipocytes. However, when comparing wild-type and ß3-adrenergic receptor knockout mice, we observed no differences in cold-induced thermogenic gene expression (Ucp1, Pgc1a, Dio2, and Cidea) in brown or white (brite/beige) adipose tissues. Irrespective of the duration of the cold exposure or the sex of the mice, we observed no effect of the absence of the ß3-adrenergic receptor. Experiments with the ß3-adrenergic receptor agonist CL-316,243 verified the functional absence of ß3-adrenergic signaling in these knockout mice. The ß3-adrenergic receptor knockout model in the present study was maintained on a FVB/N background, whereas earlier reports used C57BL/6 and 129Sv mice. Thus our data imply background-dependent differences in adrenergic signaling mechanisms in response to cold exposure. Nonetheless, the present data indicate that the ß3-adrenergic receptor is dispensable for cold-induced transcriptional activation in both classical brown and, as opposed to earlier studies, brite/beige cells.

UCP1 in adipose tissues: two steps to full browning.

The possibility that brown adipose tissue thermogenesis can be recruited in order to combat the development of obesity has led to a high interest in the identification of "browning agents", i.e. agents that increase the amount and activity of UCP1 in brown and brite/beige adipose tissues. However, functional analysis of the browning process yields confusingly different results when the analysis is performed in one of two alternative steps. Thus, in one of the steps, using cold acclimation as a potent model browning agent, we find that if the browning process is followed in mice initially housed at 21 °C (the most common procedure), there is only weak molecular evidence for increases in UCP1 gene expression or UCP1 protein abundance in classical brown adipose tissue; however, in brite/beige adipose depots, there are large increases, apparently associating functional browning with events only in the brite/beige tissues. Contrastingly, in another step, if the process is followed starting with mice initially housed at 30 °C (thermoneutrality for mice, thus similar to normal human conditions), large increases in UCP1 gene expression and UCP1 protein abundance are observed in the classical brown adipose tissue depots; there is then practically no observable UCP1 gene expression in brite/beige tissues. This apparent conundrum can be resolved when it is realized that the classical brown adipose tissue at 21 °C is already essentially fully differentiated and thus expands extensively through proliferation upon further browning induction, rather than by further enhancing cellular differentiation. When the limiting factor for thermogenesis, i.e. the total amount of UCP1 protein per depot, is analyzed, classical brown adipose tissue is by far the predominant site for the browning process, irrespective of which of the two steps is analyzed. There are to date no published data demonstrating that alternative browning agents would selectively promote brite/beige tissues versus classical brown tissue to a higher degree than does cold acclimation. Thus, to restrict investigations to examine adipose tissue depots where only a limited part of the adaptation process occurs (i.e. the brite/beige tissues) and to use initial conditions different from the thermoneutrality normally experienced by adult humans may seriously hamper the identification of therapeutically valid browning agents. The data presented here have therefore important implications for the analysis of the potential of browning agents and the nature of human brown adipose tissue.

Leptin Raises Defended Body Temperature without Activating Thermogenesis.

Leptin has been believed to exert its weight-reducing action not only by inducing hypophagia but also by increasing energy expenditure/thermogenesis. Leptin-deficient ob/ob mice have correspondingly been thought to be thermogenically limited and to show hypothermia, mainly due to atrophied brown adipose tissue (BAT). In contrast to these established views, we found that BAT is fully functional and that leptin treatment did not increase thermogenesis in wild-type or in ob/ob mice. Rather, ob/ob mice showed a decreased but defended body temperature (i.e., were anapyrexic, not hypothermic) that was normalized to wild-type levels after leptin treatment. This was not accompanied by increased energy expenditure or BAT recruitment but, instead, was mediated by decreased tail heat loss. The weight-reducing hypophagic effects of leptin are, therefore, not augmented through a thermogenic effect of leptin; leptin is, however, pyrexic, i.e., it alters centrally regulated thresholds of thermoregulatory mechanisms, in parallel to effects of other cytokines.

Cidea improves the metabolic profile through expansion of adipose tissue.

In humans, Cidea (cell death-inducing DNA fragmentation factor alpha-like effector A) is highly but variably expressed in white fat, and expression correlates with metabolic health. Here we generate transgenic mice expressing human Cidea in adipose tissues (aP2-hCidea mice) and show that Cidea is mechanistically associated with a robust increase in adipose tissue expandability. Under humanized conditions (thermoneutrality, mature age and prolonged exposure to high-fat diet), aP2-hCidea mice develop a much more pronounced obesity than their wild-type littermates. Remarkably, the malfunctioning of visceral fat normally caused by massive obesity is fully overcome-perilipin 1 and Akt expression are preserved, tissue degradation is prevented, macrophage accumulation is decreased and adiponectin expression remains high. Importantly, the aP2-hCidea mice display enhanced insulin sensitivity. Our data establish a functional role for Cidea and suggest that, in humans, the association between Cidea levels in white fat and metabolic health is not only correlative but also causative.

A stringent validation of mouse adipose tissue identity markers.

The nature of brown adipose tissue in humans is presently debated: whether it is classical brown or of brite/beige nature. The dissimilar developmental origins and proposed distinct functions of the brown and brite/beige tissues make it essential to ascertain the identity of human depots with the perspective of recruiting and activating them for the treatment of obesity and type 2 diabetes. For identification of the tissues, a number of marker genes have been proposed, but the validity of the markers has not been well documented. We used established brown (interscapular), brite (inguinal), and white (epididymal) mouse adipose tissues and corresponding primary cell cultures as validators and examined the informative value of a series of suggested markers earlier used in the discussion considering the nature of human brown adipose tissue. Most of these markers unexpectedly turned out to be noninformative concerning tissue classification (Car4, Cited1, Ebf3, Eva1, Fbxo31, Fgf21, Lhx8, Hoxc8, and Hoxc9). Only Zic1 (brown), Cd137, Epsti1, Tbx1, Tmem26 (brite), and Tcf21 (white) proved to be informative in these three tissues. However, the expression of the brite markers was not maintained in cell culture. In a more extensive set of adipose depots, these validated markers provide new information about depot identity. Principal component analysis supported our single-gene conclusions. Furthermore, Zic1, Hoxc8, Hoxc9, and Tcf21 displayed anteroposterior expression patterns, indicating a relationship between anatomic localization and adipose tissue identity (and possibly function). Together, the observed expression patterns of these validated marker genes necessitates reconsideration of adipose depot identity in mice and humans.

UCP1 in brite/beige adipose tissue mitochondria is functionally thermogenic.

The phenomenon of white fat "browning," in which certain white adipose tissue depots significantly increase gene expression for the uncoupling protein UCP1 and thus supposedly acquire thermogenic, fat-burning properties, has attracted considerable attention. Because the mRNA increases are from very low initial levels, the metabolic relevance of the change is unclear: is the UCP1 protein thermogenically competent in these brite/beige-fat mitochondria? We found that, in mitochondria isolated from the inguinal "white" adipose depot of cold-acclimated mice, UCP1 protein levels almost reached those in brown-fat mitochondria. The UCP1 was thermogenically functional, in that these mitochondria exhibited UCP1-dependent thermogenesis with lipid or carbohydrate substrates with canonical guanosine diphosphate (GDP) sensitivity and loss of thermogenesis in UCP1 knockout (KO) mice. Obesogenic mouse strains had a lower thermogenic potential than obesity-resistant strains. The thermogenic density (UCP1-dependent oxygen consumption per g tissue) of inguinal white adipose tissue was maximally one-fifth of interscapular brown adipose tissue, and the total quantitative contribution of all inguinal mitochondria was maximally one-third of all interscapular brown-fat mitochondria, indicating that the classical brown adipose tissue depots would still predominate in thermogenesis.

Concentrations of salivary testosterone, cortisol, and immunoglobulin A after supra-maximal exercise in female adolescents.

The aim of this study was to examine the effect of supra-maximal exercise on circulating concentrations of salivary testosterone, salivary cortisol, and salivary immunoglobulin A in female adolescents. Nineteen apparently healthy females aged 15-16 years participated in this study. All participants completed 668 s sprints, interspersed with 30 s recovery intervals on a cycle ergometer. Salivary testosterone, cortisol, and immunoglobulin A samples were taken before and 5 min after exercise. Experimental procedures continued over two mornings, at least 3 h after a light breakfast. Participants refrained from performing any strenuous physical activity for at least 24 h prior to the exercise test. None of the participants were engaged in a structured training programme. The group mean (± s) for peak power output was 562 ± 113.0 W. Female adolescents recruited for this study showed no changes in salivary testosterone, cortisol or immunoglobulin A following repeated bouts of supra-maximal cycling (P > 0.05). To date, there has been a paucity of information concerning adolescents' hormonal and mucosal immune function responses to supra-maximal exercise. Our data provide further guidance with regard to physical activities and sports prescription for female adolescents. Further research, on a larger sample of females, is required to elucidate the physiological significance of these findings.

Nurses' perceptions of the value of written reflection.

Reflective writing is increasingly becoming a feature of professional practice as nurses seek to provide evidence of their continuing development and competence. This study reports the process and findings of a study using grounded theory to explore how nurses are using and developing writing techniques as a tool for facilitating and supporting their development in practice. Two focus group interviews were conducted with 12 experienced nurses completing a professional course which involved reflective writing as the assessment component over a calendar year. These interviews generated the broad base of concepts and categories which direct the later stages of a grounded theory study. These preliminary categories suggest that firstly, the skills of reflective writing need to be learnt rather than being assumed as a natural capacity; secondly, that this leads to the acceptance of writing as a learning strategy in its own right; thirdly, reflective writing is considered to be a tool which helps the practitioner to develop analytical and critical abilities; finally, the nurses identified their own personal, as well as professional growth as being facilitated by reflective writing. Lincoln and Guba's (1985) criteria for establishing rigour in qualitative studies, and Strauss and Corbin's (1990) criteria for judging a grounded theory study are used as benchmarks throughout the paper.

The potential of the professional portfolio for nursing.

Professional profiles and portfolios have recently been identified by nursing's regulatory bodies in the UK as ways of recording each nurse's career and professional development. Although the use of portfolios is widespread in education, the concept of a developmental portfolio to support continuing professional development on an individual basis is recent. As an innovation in nursing the portfolio is to be used for periodic registration with the UK Central Council (UKCC), for the on-going recording of learning, both formal and experiential, and as a way of accrediting prior learning for academic purposes. This paper argues that the potential of the portfolio is wider than the purposes already identified in that the knowledge generated from experiential learning and identified by reflective practice is of specific interest and value to the nursing profession as a whole. In particular portfolios are likely to record the knowledge embedded in practice, which is often hard to describe, yet represents nursing's expertise. For this potential to be realized pragmatic issues such as finance, time and verification of experiences need to be addressed, and an infrastructure created to support the nurse compiling the profile.

Expert: a discussion of the implications of the concept as used in nursing.

The concept 'expert' has become common in the nursing literature since Benner's (1984) work more than a decade ago. Whilst the term has a common meaning, it is apparent that when used in nursing it refers to a multitude of attributes and lacks clear definition. This paper uses the strategy for concept analysis developed by Walker & Avant (1988) to seek an operational definition for the concept of 'expert', and suggests the defining attributes of: possession of a specialized body of knowledge and skill; extensive experience in a field of practice; highly developed levels of pattern recognition, and acknowledgement by others. These are discussed in relation to nursing practice and the circumstances under which the concept is used. Development of cases is carried out to exemplify the concept, and the antecedents and consequences of the attributes are discussed, suggesting that the concept lacks clarity, both in conceptualization, and in use. A first definition of the concept is posed to open debate concerning the relevance of the term for the future. The conclusions reached suggest that whilst an operational definition is unlikely to be found, because of the problems of definition and measurement, it is possible, through various strategies, to recognize expert practice and use it to further develop nursing. Furthermore, it is likely to become increasingly important to recognize and reward expert practitioners, given the political and economic constraints in health care today.

A shortened common foundation programme for graduates--the students' experience of student-centred learning.

This paper examines the students' experience of student-centred teaching and learning strategies within a shortened Common Foundation Programme (CFP) for Graduates. The perceptions of 'student-centreness' and its use as experienced by the students is addressed using material generated from on-going research using new-paradigm methodology within an action research framework. Graduates enter nurse training from the background of a subject area and possessing the academic skills required to access and assimilate knowledge effectively. These qualities underpin the design of this course, which concentrates on enabling the students to achieve the learning outcomes of the CFP within a flexible structure concentrating on skill acquisition and reflective practice according to the needs of the individual. The differing expectations of the course, the need for clear, externally set objectives, and the question of the ability of the students to self-motivate arise as the pertinent issues from the evaluation. These are discussed with reference to the students perceived needs, levels of achievement and differing learning styles. The author concludes that student-centred methods are appropriate for nurse education, but that these have significant implications for course design, course content and staff development, if the course is to satisfy both students and teachers.

Issues in phenomenology for researchers of nursing.

Nursing today, with its individualistic approach to care, shares many of its underlying beliefs and values with the school of philosophical thought known as phenomenology. The research method derived from phenomenology considers that the true meaning of phenomena can only be explored through the experience of them as described by the individual. This paper explores the features of phenomenology as a research method in relation to its relevance for nursing by first discussing the philosophical underpinnings of the method, and then proceeding to an examination of the features of the method with relation to research design, and data analysis. The specific issues of validity and generalizability are developed further, with reference to the criticisms levelled at the phenomenological method from the alternative quantitative paradigm. Finally, the author discusses the relevance of phenomenology for nursing, and concludes that, as a research method within the qualitative paradigm, it has a great deal to offer nursing as a humanistic discipline.