Brown and beige fat in humans: thermogenic adipocytes that control energy and glucose homeostasis.
02 Feb 2015-Journal of Clinical Investigation (American Society for Clinical Investigation)-Vol. 125, Iss: 2, pp 478-486
TL;DR: This Review aims to cover recent progress in the understanding of the anatomical, developmental, and functional characteristics of brown and beige adipocytes and discuss emerging questions, with a special emphasis on adult human BAT.
Abstract: Brown adipose tissue (BAT), a specialized fat that dissipates energy to produce heat, plays an important role in the regulation of energy balance. Two types of thermogenic adipocytes with distinct developmental and anatomical features exist in rodents and humans: classical brown adipocytes and beige (also referred to as brite) adipocytes. While classical brown adipocytes are located mainly in dedicated BAT depots of rodents and infants, beige adipocytes sporadically reside with white adipocytes and emerge in response to certain environmental cues, such as chronic cold exposure, a process often referred to as "browning" of white adipose tissue. Recent studies indicate the existence of beige adipocytes in adult humans, making this cell type an attractive therapeutic target for obesity and obesity-related diseases, including type 2 diabetes. This Review aims to cover recent progress in our understanding of the anatomical, developmental, and functional characteristics of brown and beige adipocytes and discuss emerging questions, with a special emphasis on adult human BAT.
Citations
More filters
TL;DR: The connection between adipose tissue inflammation and the development of insulin resistance and catecholamine resistance is examined and the ensuing state of metabolic inflexibility is discussed.
Abstract: Adipose tissue not only has an important role in the storage of excess nutrients but also senses nutrient status and regulates energy mobilization. An overall positive energy balance is associated with overnutrition and leads to excessive accumulation of fat in adipocytes. These cells respond by initiating an inflammatory response that, although maladaptive in the long run, might initially be a physiological response to the stresses obesity places on adipose tissue. In this Review, we characterize adipose tissue inflammation and review the current knowledge of what triggers obesity-associated inflammation in adipose tissue. We examine the connection between adipose tissue inflammation and the development of insulin resistance and catecholamine resistance and discuss the ensuing state of metabolic inflexibility. Finally, we review the current and potential new anti-inflammatory treatments for obesity-associated metabolic disease.
776 citations
TL;DR: This work aims to discuss recent insights regarding the developmental lineages, molecular regulation, and new functions for brown and beige adipocytes.
701 citations
Cites background from "Brown and beige fat in humans: ther..."
...While 18F-FDG-PET-based measurement has recently been substantially improved, the assessment is highly variable depending on the conditions of measurement, such as outside temperature and length of cold exposure (Sidossis and Kajimura, 2015)....
[...]
TL;DR: In this article, the role of inflammation in both type 1 and type 2 diabetes (T1D and T1D) pathophysiology and associated metabolic disorders, has generated increasing interest in targeting inflammation to improve prevention and control of the disease.
Abstract: Diabetes is a complex metabolic disorder affecting the glucose status of the human body. Chronic hyperglycaemia related to diabetes is associated with end organ failure. The clinical relationship between diabetes and atherosclerotic cardiovascular disease is well established. This makes therapeutic approaches that simultaneously target diabetes and atherosclerotic disease an attractive area for research. The majority of people with diabetes fall into two broad pathogenetic categories, type 1 or type 2 diabetes. The role of obesity, adipose tissue, gut microbiota and pancreatic beta cell function in diabetes are under intensive scrutiny with several clinical trials to have been completed while more are in development. The emerging role of inflammation in both type 1 and type 2 diabetes (T1D and T1D) pathophysiology and associated metabolic disorders, has generated increasing interest in targeting inflammation to improve prevention and control of the disease. After an extensive review of the possible mechanisms that drive the metabolic pattern in T1D and T2D and the inflammatory pathways that are involved, it becomes ever clearer that future research should focus on a model of combined suppression for various inflammatory response pathways.
511 citations
TL;DR: The metabolic phenotypes of transgenic mouse models in which AMPK expression and function have been manipulated are evaluated, and the impact this has on controlling lipid metabolism, glucose homeostasis, and inflammation is evaluated.
Abstract: The AMP-activated protein kinase (AMPK) is a central regulator of multiple metabolic pathways and may have therapeutic importance for treating obesity, insulin resistance, type 2 diabetes (T2D), non-alcoholic fatty liver disease (NAFLD), and cardiovascular disease (CVD). Given the ubiquitous expression of AMPK, it has been a challenge to evaluate which tissue types may be most beneficially poised for mediating the positive metabolic effects of AMPK-centered treatments. In this review we evaluate the metabolic phenotypes of transgenic mouse models in which AMPK expression and function have been manipulated, and the impact this has on controlling lipid metabolism, glucose homeostasis, and inflammation. This information may be useful for guiding the development of AMPK-targeted therapeutics to treat chronic metabolic diseases.
404 citations
TL;DR: Treatment of mice with glycine-β-muricholic acid (Gly-MCA) inhibits FXR signalling exclusively in intestine, and improves metabolic parameters in mouse models of obesity, suggesting that Gly-M CA may be a candidate for the treatment of metabolic disorders.
Abstract: The farnesoid X receptor (FXR) regulates bile acid, lipid and glucose metabolism. Here we show that treatment of mice with glycine-β-muricholic acid (Gly-MCA) inhibits FXR signalling exclusively in intestine, and improves metabolic parameters in mouse models of obesity. Gly-MCA is a selective high-affinity FXR inhibitor that can be administered orally and prevents, or reverses, high-fat diet-induced and genetic obesity, insulin resistance and hepatic steatosis in mice. The high-affinity FXR agonist GW4064 blocks Gly-MCA action in the gut, and intestine-specific Fxr-null mice are unresponsive to the beneficial effects of Gly-MCA. Mechanistically, the metabolic improvements with Gly-MCA depend on reduced biosynthesis of intestinal-derived ceramides, which directly compromise beige fat thermogenic function. Consequently, ceramide treatment reverses the action of Gly-MCA in high-fat diet-induced obese mice. We further show that FXR signalling in ileum biopsies of humans positively correlates with body mass index. These data suggest that Gly-MCA may be a candidate for the treatment of metabolic disorders. The nuclear farnesoid X receptor (FXR) is activated by bile acids and influences energy metabolism. Here, the authors report a small molecule inhibitor of FXR, glycine-s-muricholic acid, which inhibits FXR in the intestine and improves metabolic homeostasis by repressing intestinal ceramide synthesis.
391 citations
References
More filters
TL;DR: Defined regions of functionally active brown adipose tissue are present in adult humans, are more frequent in women than in men, and may be quantified noninvasively with the use of (18)F-FDG PET-CT.
Abstract: Background Obesity results from an imbalance between energy intake and expenditure. In rodents and newborn humans, brown adipose tissue helps regulate energy expenditure by thermogenesis mediated by the expression of uncoupling protein 1 (UCP1), but brown adipose tissue has been considered to have no physiologic relevance in adult humans. Methods We analyzed 3640 consecutive 18F-fluorodeoxyglucose (18F-FDG) positron-emission tomographic and computed tomographic (PET–CT) scans performed for various diagnostic reasons in 1972 patients for the presence of substantial depots of putative brown adipose tissue. Such depots were defined as collections of tissue that were more than 4 mm in diameter, had the density of adipose tissue according to CT, and had maximal standardized uptake values of 18F-FDG of at least 2.0 g per milliliter, indicating high metabolic activity. Clinical indexes were recorded and compared with those of date-matched controls. Immunostaining for UCP1 was performed on biopsy specimens from t...
3,805 citations
TL;DR: This article showed that PGC1α expression in muscle stimulates an increase in expression of FNDC5, a membrane protein that is cleaved and secreted as a newly identified hormone, irisin.
Abstract: Exercise benefits a variety of organ systems in mammals, and some of the best-recognized effects of exercise on muscle are mediated by the transcriptional co-activator PPAR-γ co-activator-1 α (PGC1-α). Here we show in mouse that PGC1-α expression in muscle stimulates an increase in expression of FNDC5, a membrane protein that is cleaved and secreted as a newly identified hormone, irisin. Irisin acts on white adipose cells in culture and in vivo to stimulate UCP1 expression and a broad program of brown-fat-like development. Irisin is induced with exercise in mice and humans, and mildly increased irisin levels in the blood cause an increase in energy expenditure in mice with no changes in movement or food intake. This results in improvements in obesity and glucose homeostasis. Irisin could be therapeutic for human metabolic disease and other disorders that are improved with exercise.
3,338 citations
TL;DR: Brown adipose tissue may be metabolically important in men, and the fact that it is reduced yet present in most overweight or obese subjects may make it a target for the treatment of obesity.
Abstract: Background Studies in animals indicate that brown adipose tissue is important in the regulation of body weight, and it is possible that individual variation in adaptive thermogenesis can be attributed to variations in the amount or activity of brown adipose tissue. Until recently, the presence of brown adipose tissue was thought to be relevant only in small mammals and infants, with negligible physiologic relevance in adult humans. We performed a systematic examination of the presence, distribution, and activity of brown adipose tissue in lean and obese men during exposure to cold temperature. Brown-adipose-tissue activity was studied in relation to body composition and energy metabolism. Methods We studied 24 healthy men — 10 who were lean (body-mass index [BMI] [the weight in kilograms divided by the square of the height in meters], <25) and 14 who were overweight or obese (BMI, ≥25) — under thermoneutral conditions (22°C) and during mild cold exposure (16°C). Putative brown-adipose-tissue activity was ...
3,114 citations
"Brown and beige fat in humans: ther..." refers background in this paper
...For example, cold-induced thermogenesis was reported to be proportional to BAT perfusion (110) and activity (15, 49), even after adjusting for potential confounding factors (111)....
[...]
TL;DR: These findings document the presence of substantial amounts of metabolically active brown adipose tissue in healthy adult humans.
Abstract: Using positron-emission tomography (PET), we found that cold-induced glucose uptake was increased by a factor of 15 in paracervical and supraclavicular adipose tissue in five healthy subjects. We obtained biopsy specimens of this tissue from the first three consecutive subjects and documented messenger RNA (mRNA) and protein levels of the brown-adipocyte marker, uncoupling protein 1 (UCP1). Together with morphologic assessment, which showed numerous multilocular, intracellular lipid droplets, and with the results of biochemical analysis, these findings document the presence of substantial amounts of metabolically active brown adipose tissue in healthy adult humans.
2,790 citations
TL;DR: Beige cells have a gene expression pattern distinct from either white or brown fat and are preferentially sensitive to the polypeptide hormone irisin, providing evidence that previously identified brown fat deposits in adult humans are composed of beige adipocytes.
2,767 citations
"Brown and beige fat in humans: ther..." refers background in this paper
...When stimulated by such external cues, beige adipocytes express UCP1 protein at a similar level to classical brown adipocytes and exhibit UCP1-dependent thermogenic capacity (25, 26)....
[...]
...On the other hand, BAT in the supraclavicular regions of infants and in adult humans expresses high levels of beige adipocyte-enriched genes, including Tbx1, Cd137, Tmem26, and Cited1 (26, 27, 45)....
[...]
...Beige adipocytes express several markers, including Ucp1, Pgc1a, and Cidea, and beige-selective markers, such as Cd137, Tbx1, Tmed26, and Cited1....
[...]
...Cellular identity of adult human BAT — is human BAT recruitable? Recent studies have identified several genes that are preferentially expressed either in classical brown adipocytes or in beige adipocytes in rodents (26, 39, 45, 46)....
[...]