Recruiting brown adipose tissue in human obesity

Obesity remains a major biomedical challenge with the associated diseases, particularly insulin resistance and type 2 diabetes, imposing a substantial and increasing burden on healthcare systems. In the US, one-third of adults are classed as obese (BMI >30), while in the UK, which has one of the highest incidence rates in Europe, 25% are obese. Conceptually, the treatment of obesity is simple: energy expenditure must exceed energy intake. In the late 1970’s it was proposed, primarily from studies on rats and mice, that reduced expenditure on adaptive heat production (thermogenesis) associated with a specialised fat tissue – brown adipose tissue (BAT) – is central to the development of obesity. Correspondingly, for a period stimulation of heat production in BAT was seen as a potential therapeutic route for reversing obesity and there was a search for agents that would stimulate the activity of the tissue

Oxygen — A Critical, but Overlooked, Nutrient

Gaseous oxygen is essential for all aerobic animals, without which mitochondrial respiration and oxidative phosphorylation cannot take place. It is not, however, regarded as a “nutrient” by nutritionists and does not feature as such within the discipline of nutritional science. This is primarily a consequence of the route by which O2 enters the body, which is via the nose and lungs in terrestrial animals as opposed to the mouth and gastrointestinal tract for what are customarily considered as nutrients. It is argued that the route of entry should not be the critical factor in defining whether a substance is, or is not, a nutrient. Indeed, O2 unambiguously meets the standard dictionary definitions of a nutrient, such as “a substance that provides nourishment for the maintenance of life and for growth” (Oxford English Dictionary). O2 is generally available in abundance, but deficiency occurs at high altitude and during deep sea dives, as well as in lung diseases. These impact on the provision at a whole-body level, but a low pO2 is characteristic of specific tissues includings the retina and brain, while deficiency, or overt hypoxia, is evident in certain conditions such as ischaemic disease and in tumours - and in white adipose tissue in obesity. Hypoxia results in a switch from oxidative metabolism to increased glucose utilisation through anaerobic glycolysis, and there are extensive changes in the expression of multiple genes in O2-deficient cells. These changes are driven by hypoxia-sensitive transcription factors, particularly hypoxia-inducible factor-1 (HIF-1). O2 deficiency at a whole-body level can be treated by therapy or supplementation, but O2 is also toxic through the generation of reactive oxygen species. It is concluded that O2 is a critical, but overlooked, nutrient which should be considered as part of the landscape of nutritional science

Open Access publishing: the continuing development of the Journal of Nutritional Science

The Journal of Nutritional Science (JNS) was established in the early part of this decade as an initiative between the Nutrition Society and Cambridge University Press(1), with the first volume appearing in 2012. The founding Editor-in-Chief, Professor Philip Calder, was at the time also Editor-in-Chief of the British Journal of Nutrition (BJN). This reflected the original concept that the JNS would be closely allied to the BJN, with the same Editor-in-Chief and a common Editorial Board. The new journal was in part intended to provide a vehicle for articles that while scientifically sound were not able to be published by the BJN, because of the pressures on space in the Society’s flagship journal. A close association between the JNS and the BJN continued when Professor Graham Burdge took over as Editor-in-Chief of both journals in 2013

Through fat and thin - A journey with the adipose tissues. The Gowland Hopkins Award Lecture 2019

The present paper is based on the lecture that I gave on receiving the Nutrition Society’s inaugural Gowland Hopkins Award for contributions to Cellular and Molecular Nutrition. It reviews studies on the adipose tissues – brown and white – conducted by the groups that I have led since entering nutrition research in 1975. The initial focus was on exploring metabolic factors that underpin the development of obesity using animal models. This resulted in an interest in non-shivering thermogenesis with brown adipose tissue being identified as the key effector of facultative heat production. Brown fat is less thermogenically active in various obese rodents, and major changes in activity are exhibited in physiological conditions such as lactation and fasting consistent with a general role for the tissue in nutritional energetics. My interests moved to white adipose tissue following the cloning of the Ob gene. Our initial contributions in this area included demonstrating nutritional regulation of Ob gene expression and circulating leptin levels, as well as a regulatory role for the sympathetic nervous system operating through β3-adrenoceptors. My interests subsequently evolved to a wider concern with the endocrine/signalling role of adipose tissue. Inflammation is a characteristic of white fat in obesity with the release of inflammation-related adipokines, and we proposed that hypoxia underlies this inflammatory state. O2-deprivation was shown to have substantial effects on gene expression and cellular function in white adipocytes. The hypoxia studies led to the proposition that O2 should be considered as a critical – essential - macronutrient

A basic scientist’s odyssey in nutrition

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Lactate and the GPR81 receptor in metabolic regulation: implications for adipose tissue function and fatty acid utilisation by muscle during exercise

Lactate is increasingly recognised to be more than a simple end product of anaerobic glycolysis. Skeletal muscle and white adipose tissue are considered to be the main sites of lactate production and release. Recent studies have demonstrated that there is a specific G-protein coupled receptor for lactate, GPR81, which is expressed primarily in adipose tissue, and also in muscle. Lactate inhibits lipolysis in adipose tissue by mediating, through GPR81, the anti-lipolytic action of insulin. A high proportion (50% or more) of the glucose utilised by white adipose tissue is converted to lactate and lactate production by the tissue increases markedly in obesity; this is likely to reflect a switch towards anaerobic metabolism with the development of hypoxia in the tissue. During exercise, there is a shift in fuel utilisation by muscle from lipid to carbohydrate, but this does not appear to be a result of the inhibition of lipolysis in the main adipose tissue depots by muscle-derived lactate. It is suggested instead that a putative autocrine lactate loop in myocytes may regulate fuel utilisation by muscle during exercise, operating via a muscle GPR81 receptor. In addition to being an important substrate, lactate is a key signal in metabolic regulation

Mining microarray datasets in nutrition: expression of the GPR120 (n-3 fatty acid receptor/sensor) gene is down-regulated in human adipocytes by macrophage secretions

Microarray datasets are a rich source of information in nutritional investigation. Targeted mining of microarray data following initial, non-biased bioinformatic analysis can provide key insight into specific genes and metabolic processes of interest. Microarrays from human adipocytes were examined to explore the effects of macrophage secretions on the expression of the G-protein-coupled receptor (GPR) genes that encode fatty acid receptors/sensors. Exposure of the adipocytes to macrophage-conditioned medium for 4 or 24 h had no effect on GPR40 and GPR43 expression, but there was a marked stimulation of GPR84 expression (receptor for medium-chain fatty acids), the mRNA level increasing 13·5-fold at 24 h relative to unconditioned medium. Importantly,expression of GPR120, which encodes an n-3 PUFA receptor/sensor, was strongly inhibited by the conditioned medium (15-fold decrease in mRNA at 24h). Macrophage secretions have major effects on the expression of fatty acid receptor/sensor genes in human adipocytes, which may lead to an augmentation of the inflammatory response in adipose tissue in obesity

Oxygen deprivation and the cellular response to hypoxia in adipocytes – perspectives on white and brown adipose tissues in obesity

Relative hypoxia has been shown to develop in white adipose tissue depots of different types of obese mouse (genetic, dietary), and this leads to substantial changes in white adipocyte function. These changes include increased production of inflammation-related adipokines (such as IL-6, leptin, Angptl4, and VEGF), an increase in glucose utilization and lactate production, and the induction of fibrosis and insulin resistance. Whether hypoxia also occurs in brown adipose tissue depots in obesity has been little considered. However, a recent study has reported low pO2 in brown fat of obese mice, this involving mitochondrial loss and dysfunction.We suggest that obesity-linked hypoxia may lead to similar alterations in brown adipocytes as in white fat cells – particularly changes in adipokine production, increased glucose uptake and lactate release, and insulin resistance. This would be expected to compromise thermogenic activity and the role of brown fat in glucose homeostasis and triglyceride clearance, underpinning the development of the metabolic syndrome. Hypoxia-induced augmentation of lactate production may also stimulate the “browning” of white fat depots through recruitment of UCP1 and the development of brite adipocytes

Detection of thermogenesis in rodents in response to anti-obesity drugs and genetic modification

Many compounds and genetic manipulations are claimed to confer resistance to obesity in rodents by raising energy expenditure. Examples taken from recent and older literature, demonstrate that such claims are often based on measurements of energy expenditure after body composition has changed, and depend on comparisons of energy expenditure divided by body weight. This is misleading because white adipose tissue has less influence than lean tissue on energy expenditure. Application of this approach to human data would suggest that human obesity is usually due to a low metabolic rate, which is not an accepted view. Increased energy expenditure per animal is a surer way of demonstrating thermogenesis, but even then it is important to know whether this is due to altered body composition (repartitioning), or increased locomotor activity rather than thermogenesis per se. Regression analysis offers other approaches. The thermogenic response to some compounds has a rapid onset and so cannot be due to altered body composition. These compounds usually mimic or activate the sympathetic nervous system. Thermogenesis occurs in, but may not be confined to, brown adipose tissue. It should not be assumed that weight loss in response to these treatments is due to thermogenesis unless there is a sustained increase in 24-h energy expenditure. Thyroid hormones and fibroblast growth factor 21 also raise energy expenditure before they affect body composition. Some treatments and genetic modifications alter the diurnal rhythm of energy expenditure. It is important to establish whether this is due to altered locomotor activity or efficiency of locomotion. There are no good examples of compounds that do not affect short-term energy expenditure but have a delayed effect. How and under what conditions a genetic modification or compound increases energy expenditure influences the decision on whether to seek drugs for the target or take a candidate drug into clinical studie

Oxygen—A Critical, but Overlooked, Nutrient

Gaseous oxygen is essential for all aerobic animals, without which mitochondrial respiration and oxidative phosphorylation cannot take place. It is not, however, regarded as a “nutrient” by nutritionists and does not feature as such within the discipline of nutritional science. This is primarily a consequence of the route by which O2 enters the body, which is via the nose and lungs in terrestrial animals as opposed to the mouth and gastrointestinal tract for what are customarily considered as nutrients. It is argued that the route of entry should not be the critical factor in defining whether a substance is, or is not, a nutrient. Indeed, O2 unambiguously meets the standard dictionary definitions of a nutrient, such as “a substance that provides nourishment for the maintenance of life and for growth” (Oxford English Dictionary). O2 is generally available in abundance, but deficiency occurs at high altitude and during deep sea dives, as well as in lung diseases. These impact on the provision at a whole-body level, but a low pO2 is characteristic of specific tissues includings the retina and brain, while deficiency, or overt hypoxia, is evident in certain conditions such as ischaemic disease and in tumours - and in white adipose tissue in obesity. Hypoxia results in a switch from oxidative metabolism to increased glucose utilisation through anaerobic glycolysis, and there are extensive changes in the expression of multiple genes in O2-deficient cells. These changes are driven by hypoxia-sensitive transcription factors, particularly hypoxia-inducible factor-1 (HIF-1). O2 deficiency at a whole-body level can be treated by therapy or supplementation, but O2 is also toxic through the generation of reactive oxygen species. It is concluded that O2 is a critical, but overlooked, nutrient which should be considered as part of the landscape of nutritional science