Brown adipose tissue and glucose homeostasis – the link between climate change and the global rise in obesity and diabetes

There is increasing evidence that the global rise in temperature is contributing to the onset of diabetes, which could be mediated by a concomitant reduction in brown fat activity. Brown (and beige) fat are characterised as possessing a unique mitochondrial protein uncoupling protein (UCP)1 that when activated can rapidly generate large amounts of heat. Primary environmental stimuli of UCP1 include cold-exposure and diet, leading to increased activity of the sympathetic nervous system and large amounts of lipid and glucose being oxidised by brown fat. The exact contribution remains controversial, although recent studies indicate that the amount of brown and beige fat in adult humans has been greatly underestimated. We therefore review the potential mechanisms by which glucose could be utilised within brown and beige fat in adult humans and the extent to which these are sensitive to temperature and diet. This includes the potential contribution from the peridroplet and cytoplasmic mitochondrial sub-fractions recently identified in brown fat, and whether a proportion of glucose oxidation could be UCP1-independent. It is thus predicted that as new methods are developed to assess glucose metabolism by brown fat, a more accurate determination of the thermogenic and non-thermogenic functions could be feasible in humans

The phospholipase A2 family's role in metabolic diseases : Focus on skeletal muscle

ACKNOWLEDGEMENT We would like to thank the Molecular Metabolism Group of the Queen's Medical Research Institute, University of Edinburgh, for useful discussions on the topic of the present review. Research Funding This work was supported by a British Heart Foundation 4Y PhD scholarship (FS/17/692/33477) to Iris Prunonosa Cervera and Nicholas M. Morton; a Wellcome Trust New Investigator Award (100981/Z/13/Z) to Nicholas M. Morton; and a Novo Nordisk Foundation—Postdoc Fellowship for research abroad—Endocrinology & Metabolism (NNF19OC0055072) to Brendan M. Gabriel.Peer reviewedPublisher PD

Beyond obesity - thermogenic adipocytes and cardiometabolic health

The global prevalence of obesity and related cardiometabolic disease continues to increase through the 21st century. Whilst multi-factorial, obesity is ultimately caused by chronic caloric excess. However, despite numerous interventions focussing on reducing caloric intake these either fail or only elicit short-term changes in body mass. There is now a focus on increasing energy expenditure instead which has stemmed from the recent ‘re-discovery’ of cold-activated brown adipose tissue (BAT) in adult humans and inducible ‘beige’ adipocytes. Through the unique mitochondrial uncoupling protein (UCP1), these thermogenic adipocytes are capable of combusting large amounts of chemical energy as heat and in animal models can prevent obesity and cardiometabolic disease. At present, human data does not point to a role for thermogenic adipocytes in regulating body weight or fat mass but points to a pivotal role in regulating metabolic health by improving insulin resistance as well as glucose and lipid homeostasis. This review will therefore focus on the metabolic benefits of BAT activation and the mechanisms and signalling pathways by which these could occur including improvements in insulin signalling in peripheral tissues, systemic lipid and cholesterol metabolism and cardiac and vascular function

Recent advances in our understanding of brown and beige adipose tissue: the good fat that keeps you healthy [version 1; referees: 2 approved]

Brown adipose tissue (BAT) possesses a unique uncoupling protein (UCP1) which, when activated, enables the rapid generation of heat and the oxidation of lipids or glucose or both. It is present in small amounts (~15–350 mL) in adult humans. UCP1 is rapidly activated at birth and is essential in preventing hypothermia in newborns, who rapidly generate large amounts of heat through non-shivering thermogenesis. Since the “re-discovery” of BAT in adult humans about 10 years ago, there has been an exceptional amount of research interest. This has been accompanied by the establishment of beige fat, characterised as discrete areas of UCP1-containing cells dispersed within white adipocytes. Typically, the amount of UCP1 in these depots is around 10% of the amount found in classic BAT. The abundance of brown/beige fat is reduced with obesity, and the challenge is to prevent its loss with ageing or to reactivate existing depots or both. This is difficult, as the current gold standard for assessing BAT function in humans measures radio-labelled glucose uptake in the fasted state and is usually dependent on cold exposure and the same subject can be found to exhibit both positive and negative scans with repeated scanning. Rodent studies have identified multiple pathways that may modulate brown/beige fat function, but their direct relevance to humans is constrained, as these studies typically are undertaken in cool-adapted animals. BAT remains a challenging organ to study in humans and is able to swiftly adapt to changes in the thermal environment and thus enable rapid changes in heat production and glucose oxidation

Exercise-induced ‘browning’ of adipose tissues

Global rates of obesity continue to rise and are necessarily the consequence of a long-term imbalance between energy intake and energy expenditure. This is the result of an expansion of adipose tissue due to both the hypertrophy of existing adipocytes and hyperplasia of adipocyte precursors. Exercise elicits numerous physiological benefits on adipose tissue, which are likely to contribute to the associated cardiometabolic benefits. More recently it has been demonstrated that exercise, through a range of mechanisms, induces a phenotypic switch in adipose tissue from energy storing white adipocytes to thermogenic beige adipocytes. This has generated the hypothesis that the process of adipocyte ‘browning’ may partially underlie the improved cardiometabolic health in physically active populations. Interestingly, ‘browning’ also occurs in response to various stressors and could represent an adaptive response. In the context of exercise, it is not clear whether the appearance of beige adipocytes is metabolically beneficial or whether they occur as a transient adaptive process to exercise-induced stresses. The present review discusses the various mechanisms (e.g. fatty acid oxidation during exercise, decreased thermal insulation, stressors and angiogenesis) by which the exercise-induced ‘browning’ process may occur

Housing temperature modulates the impact of diet-induced rise in fat mass on adipose tissue before and during pregnancy in rats

Aim: To investigate whether housing temperature influences rat adiposity, and the extent it is modified by diet and/or pregnancy. Housing temperature impacts on brown adipose tissue, that possess a unique uncoupling protein (UCP) 1, which, when activated by reduced ambient temperature, enables rapid heat generation. Methods: We, therefore, examined whether the effects of dietary induced rise in fat mass on interscapular brown fat in female rats were dependent on housing temperature, and whether pregnancy further modulates the response. Four week old rats were either maintained at thermoneutrality (27°C) or at a “standard” cool temperature (20°C), and fed either a control or obesogenic (high in fat and sugar) diet until 10 weeks old. They were then either tissue sampled or mated with a male maintained under the same conditions. The remaining dams were tissue sampled at either 10 or 19 days gestation. Results: Diet had the greatest effect on fat mass at thermoneutrality although, by 19 days gestation, fat weight was similar between groups. Prior to mating, the abundance of UCP1 was higher at 20°C, but was similar between groups during pregnancy. UCP1 mRNA followed a similar pattern, with expression declining to a greater extent in the animals maintained at 20°C. Conclusion: Housing temperature has a marked influence on the effect of dietary induced rise in fat deposition that was modified through gestation. This maybe mediated by the reduction in UCP1 with housing at thermoneutrality prior to pregnancy and could subsequently impact on growth and development of the offspring

Interscapular and perivascular brown adipose tissue respond differently to a short-term high-fat diet

Brown adipose tissue (BAT) function may depend on its anatomical location and developmental origin. Interscapular BAT (iBAT) regulates acute macronutrient metabolism, whilst perivascular BAT (PVAT) regulates vascular function. Although phenotypically similar, whether these depots respond differently to acute nutrient excess is unclear. Given their distinct anatomical locations and developmental origins and we hypothesised that iBAT and PVAT would respond differently to brief period of nutrient excess. Sprague-Dawley rats aged 12 weeks (n=12) were fed either a standard (10% fat, n=6) or high fat diet (HFD: 45% fat, n=6) for 72h and housed at thermoneutrality. Following an assessment of whole body physiology, fat was collected from both depots for analysis of gene expression and the proteome. HFD consumption for 72h induced rapid weight gain (c. 2.6%) and reduced serum non-esterified fatty acids (NEFA) with no change in either total adipose or depot mass. In iBAT, an upregulation of genes involved in insulin signalling and lipid metabolism was accompanied by enrichment of lipid-related processes and functions, plus glucagon and peroxisome proliferator-activated receptor (PPAR) signalling pathways. In PVAT, HFD induced a pronounced down-regulation of multiple metabolic pathways which was accompanied with increased abundance of proteins involved in apoptosis (e.g. Hdgf and Ywaq) and toll-like receptor signalling (Ube2n). There was also an enrichment of DNA-related processes and functions (e.g. nucleosome assembly and histone exchange) and RNA degradation and cell adhesion pathways. In conclusion, we show that iBAT and PVAT elicit divergent responses to short-term nutrient excess highlighting early adaptations in these depots before changes in fat mass