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Experimental Physiology Aug 2020What is the topic of this review? Brown fat's role in meal-associated thermogenesis and the related consequences for energy balance regulation with a focus on the gut... (Review)
Review
NEW FINDINGS
What is the topic of this review? Brown fat's role in meal-associated thermogenesis and the related consequences for energy balance regulation with a focus on the gut hormone secretin, which has been identified as the endocrine molecular mediator of meal-associated brown fat thermogenesis. What advances does it highlight? The finding of the secretin-induced gut-brown fat-brain axis creates new opportunities to manipulate brown fat and thereby energy balance in a natural way while living in a thermoneutral environment. The role of brown fat as a mere catabolic heater organ needs to be revised and more attention should be directed towards the regulatory role of brown fat beyond energy expenditure.
ABSTRACT
Brown fat research concentrates on the energy expenditure function of this heating organ, whereas previous evidence for a role of brown fat in regulating energy intake has been mostly neglected. Ingestion of a single mixed meal activates human brown fat thermogenesis to the same degree as cold. In mice, activation of brown fat thermogenesis with a β -adrenergic receptor agonist inhibits food intake. Pharmacological β-blockade, however, inhibits neither meal-associated thermogenesis nor food intake. We recently identified the gut hormone secretin as a non-adrenergic activator of brown fat. In vivo, secretin treatment acutely increases energy expenditure and inhibits food intake in wild-type, but not in uncoupling protein 1 (UCP1)-knockout (KO) mice, which lack thermogenic brown fat function. Concurrently, secretin alters gene expression of melanocortinergic peptides of hypothalamic neurons in wild-type mice, but not UCP1-KO. Blocking endogenous secretin with a neutralizing antibody attenuates brown fat thermogenesis during refeeding, increases food intake of mice, and alters ad libitum feeding behaviour. Taken together, these findings demonstrate that secretin triggers an endocrine gut-brown adipose tissue-brain axis in the control of satiation. We hypothesize that meal-associated activation of brown adipose tissue thermogenesis induced by secretin results in a rise in brain temperature and increased melanocortinergic signalling. Taken together, brown fat is not a mere heating organ dissipating excess calories but also involved in gut-brain communication in the control of food intake.
Topics: Adipose Tissue, Brown; Animals; Brain; Eating; Energy Intake; Energy Metabolism; Gastrointestinal Tract; Mice; Mice, Knockout; Secretin; Thermogenesis; Uncoupling Protein 1
PubMed: 32271980
DOI: 10.1113/EP087878 -
Current Opinion in Endocrinology,... Apr 2010Human fat consists of white and brown adipose tissue (WAT and BAT). Though most fat is energy-storing WAT, the thermogenic capacity of even small amounts of BAT makes it... (Review)
Review
PURPOSE OF REVIEW
Human fat consists of white and brown adipose tissue (WAT and BAT). Though most fat is energy-storing WAT, the thermogenic capacity of even small amounts of BAT makes it an attractive therapeutic target for inducing weight loss through energy expenditure. This review evaluates the recent discoveries regarding the identification of functional BAT in adult humans and its potential as a therapy for obesity and diabetes.
RECENT FINDINGS
Over the past year, several independent research teams used a combination of positron-emission tomography and computed tomography (PET/CT) imaging, immunohistochemistry, and gene and protein expression assays to prove conclusively that adult humans have functional BAT. This has occurred against a backdrop of basic studies defining the origins of BAT, new components of its transcriptional regulation, and the role of hormones in stimulation of BAT growth and differentiation.
SUMMARY
Adult humans have functional BAT, a new target for antiobesity and antidiabetes therapies focusing on increasing energy expenditure. Future studies will refine the methodologies used to measure BAT mass and activity, expand our knowledge of critical-control points in BAT regulation, and focus on testing pharmacological agents that increase BAT thermogenesis and help achieve long-lasting weight loss and an improved metabolic profile.
Topics: Adipose Tissue, Brown; Animals; Anti-Obesity Agents; Body Fat Distribution; Cell Transdifferentiation; Cell- and Tissue-Based Therapy; Diabetes Mellitus; Humans; Models, Biological; Obesity; Thermogenesis
PubMed: 20160646
DOI: 10.1097/MED.0b013e328337a81f -
Endocrinology, Diabetes & Metabolism Jan 2023Brown adipose tissue (BAT) represents a pivotal scientific renaissance worthy as a strategy for obesity and diabetes since its re-discovery in adults over a decade ago....
Brown adipose tissue (BAT) represents a pivotal scientific renaissance worthy as a strategy for obesity and diabetes since its re-discovery in adults over a decade ago. Equally compelling is the adoption of infrared thermography (IRT) in recent times as a precise and viable alternative methodology over the 'gold standard' PET-CT scan, given constraints of the latter's high ionizing radiation doses and costs. Unravelling BAT metabolic physiology in live humans has been challenging until recent rigorous validation of IRT against PET. Nevertheless, IRT remains a nascent technique with pitfalls unbeknownst to many researchers. Factors impacting its accuracy merit an in-depth scientific scrutiny. This article discusses the strengths and pitfalls of IRT as an emergent BAT detection technique and provides a mathematical proof of its limitations that BAT researchers should be cognizant of. Understanding these limitations of IRT can prompt extra efforts to control these uncertainties with greater rigour. In conclusion, this warrants further investigations of improving IRT quality via advanced auto-segmentation, powerful image processing of thermograms and protocol standardization along the lines of BARCIST 1.0 to minimize errors and enhance the confidence of the global BAT research community in IRT as a robust and reliable BAT research tool.
Topics: Adult; Humans; Thermography; Positron Emission Tomography Computed Tomography; Adipose Tissue, Brown; Research Design; Obesity
PubMed: 36379014
DOI: 10.1002/edm2.378 -
Adipocyte 2018Numerous studies have shown that feeding rodents n-3 polyunsaturated fatty acids attenuates adiposity. Moreover, meta-analyses of human dietary intervention studies... (Review)
Review
Numerous studies have shown that feeding rodents n-3 polyunsaturated fatty acids attenuates adiposity. Moreover, meta-analyses of human dietary intervention studies indicate that fish oil (eicosapentaenoic and docosahexaenoic acid) supplementation might reduce waist circumference. A recent line of research suggests that browning of white adipose depots and activation of uncoupled respiration in brown fat contributes to these effects. This mini-review summarizes the observations in rodents, highlights several mechanisms that might explain these observations and discusses the translational potential. Given the available in vivo evidence and the ability of human adipocytes to aquire a beige phenotype in response to eicosapentaenoic acid incubation, future studies should test the hypothesis that fish oil activates thermogenic brown and beige adipose tissue in humans.
Topics: Adipocytes; Adipose Tissue, Beige; Adipose Tissue, Brown; Fish Oils; Humans; Thermogenesis
PubMed: 29521565
DOI: 10.1080/21623945.2018.1442980 -
Biochimica Et Biophysica Acta Mar 2010The role of white and brown adipose tissues in energy metabolism is well established. However, the existence of brown fat in adult humans was until very recently a... (Review)
Review
The role of white and brown adipose tissues in energy metabolism is well established. However, the existence of brown fat in adult humans was until very recently a matter of debate, and the molecular mechanisms underlying brown adipocyte development remained largely unknown. In 2009, several studies brought direct evidence for functional brown adipose tissue in adults. New factors involved in brown fat cell differentiation have been identified. Moreover, work on the origin of fat cells took an unexpected path with the recognition of different populations of brown fat cell precursors according to the anatomical location of the fat depots: a precursor common to skeletal muscle cells and brown adipocytes from brown fat depots, and a progenitor cell common to white adipocytes and brown adipocytes that appear in certain conditions in white fat depots. There is also mounting evidence that mature white adipocytes, including human fat cells, can be converted into brown fat-like adipocytes, and that the typical fatty acid storage phenotype of white adipocyte can be altered towards a fat utilization phenotype. These data open up new opportunities for the development of drugs for obesity and its metabolic and cardiovascular complications.
Topics: Adipocytes, Brown; Adipocytes, White; Adipose Tissue, Brown; Animals; Cell Differentiation; Humans; Models, Biological; Obesity
PubMed: 19782764
DOI: 10.1016/j.bbalip.2009.09.008 -
Discovery Medicine Mar 2011Caloric restriction is associated with a reduction in body weight and temperature, as well as a reduction in trabecular bone volume and paradoxically an increase in... (Review)
Review
Caloric restriction is associated with a reduction in body weight and temperature, as well as a reduction in trabecular bone volume and paradoxically an increase in adipocytes within the bone marrow. The nature of these adipocytes is uncertain, although there is emerging evidence of a direct relationship between bone remodeling and brown adipocytes. For example, in heterotrophic ossification, brown adipocytes set up a hypoxic gradient that leads to vascular invasion, chondrocyte differentiation, and subsequent bone formation. Additionally, deletion of retinoblastoma protein in an osteosarcoma model leads to increased hibernoma (brown fat tumor). Brown adipose tissue (BAT) becomes senescent with age at a time when thermoregulation is altered, bone loss becomes apparent, and sympathetic activity increases. Interestingly, heart rate is an unexpected but good predictor of fracture risk in elderly individuals, pointing to a key role for the sympathetic nervous system in senile osteoporosis. Hence the possibility exists that BAT could play an indirect role in age-related bone loss. However, evidence of an indirect effect from thermogenic dysfunction on bone loss is currently limited. Here, we present current evidence for a relationship between brown adipose tissue and bone as well as provide novel insights into the effects of thermoregulation on bone mineral density.
Topics: Adipose Tissue, Brown; Animals; Body Temperature Regulation; Bone and Bones; Homeostasis; Humans
PubMed: 21447277
DOI: No ID Found -
Annual Review of Pharmacology and... 2015Brown adipose tissue (BAT) was previously regarded as a special type of fat relevant only for defending hibernating animals and newborns against a cold environment.... (Review)
Review
Brown adipose tissue (BAT) was previously regarded as a special type of fat relevant only for defending hibernating animals and newborns against a cold environment. Recently, BAT has received considerable attention following its (re)discovery in humans. Using glucose tracers, multiple laboratories independently found metabolically active BAT in adults. The enormous metabolic powers of BAT in animal models could make it an attractive target for antiobesity therapies in humans. Here, we review the present knowledge on the role of BAT in energy homeostasis and metabolism, focusing on signaling pathways and potential targets for novel therapeutics. We also shine light on ongoing debates, including those about the true color of brown fat in adults, as well as on the requirements for translation of basic research on BAT into clinical medicine.
Topics: Adipocytes, Brown; Adipocytes, White; Adipose Tissue, Brown; Adipose Tissue, White; Animals; Anti-Obesity Agents; Drug Discovery; Energy Metabolism; Humans; MicroRNAs; Molecular Targeted Therapy; Obesity; Phenotype; Signal Transduction; Transcription Factors
PubMed: 25149919
DOI: 10.1146/annurev-pharmtox-010814-124346 -
The Journal of Pharmacology and... Jun 2018Indomethacin, a nonsteroidal anti-inflammatory drug, has been shown to induce white adipocyte differentiation; however, its roles in brown adipocyte differentiation and...
Indomethacin, a nonsteroidal anti-inflammatory drug, has been shown to induce white adipocyte differentiation; however, its roles in brown adipocyte differentiation and activation in brown adipose tissue (BAT) and obesity are unknown. To address this issue, we treated mouse brown preadipocytes with different doses of indomethacin, and delivered indomethacin to interscapular BAT (iBAT) of obese mice using implanted osmotic pumps. Indomethacin dose dependently increased brown preadipocyte differentiation and upregulated both mRNA and protein expression of uncoupling protein 1 (UCP1) and peroxisome proliferator-activated receptor (PPAR) coactivator 1-alpha. The mechanistic study showed that indomethacin significantly activated the reporter driven by the PPAR response element, indicating that indomethacin may work as a PPAR agonist in this cell line. Consistently, indomethacin significantly decreased iBAT mass and fasting blood glucose levels in high-fat diet-induced obesity (DIO) mice. Histologic analysis showed that brown adipocytes of indomethacin-treated mice contained smaller lipid droplets compared with control mice, suggesting that indomethacin alleviated the whitening of BAT induced by the high-fat diet. Moreover, indomethacin significantly increased UCP1 mRNA expression in iBAT. Taken together, this study indicates that indomethacin can promote mouse brown adipocyte differentiation, and might increase brown fat and glucose oxidation capacity in DIO mice.
Topics: Adipocytes; Adipose Tissue, Brown; Adipose Tissue, White; Animals; Cell Differentiation; Cell Line; Indomethacin; Mice; Obesity
PubMed: 29567865
DOI: 10.1124/jpet.117.246256 -
Journal of Cancer Research and Clinical... Jul 2023The purpose of this study was to compare the survival of patients with and without BAT activity on FDG PET/CT.
PURPOSE
The purpose of this study was to compare the survival of patients with and without BAT activity on FDG PET/CT.
METHODS
PET/CT exams from 3937 breast cancer patients were retrospectively reviewed for bilateral symmetric elongated FDG activity in the neck and chest, typical of BAT activation. A control group of age-matched (± 1 year) breast cancer patients who underwent PET/CT the same week was also enrolled for comparison. Kaplan-Meier curves of progression-free survival (PFS) and overall survival (OS) for BAT positive patients and the control group were calculated. Further sub-analysis was performed to account for the hormonal changes associated with menopause.
RESULTS
2.0% (80/3937) of the breast cancer patients who underwent PET/CT demonstrated BAT activation, and 80 additional patients were analyzed for comparison as the group without BAT activity. Mean follow-up was 76 months (range 1-225 months). There were 4 recurrences in the BAT group, compared to 12 in the control. The mean PFS for the BAT group was 127 months, which was significantly lower than the mean PFS of 180 months in the control (p = 0.047). Sub-analysis of premenopausal women again showed longer PFS for the BAT group (129 vs. 196 months, p = 0.095) while no difference was found in postmenopausal women (mean 102 vs. 135 months, p = 0.360). Presence of BAT activity was also a significant predictor variable for PFS on Cox regression.
CONCLUSION
Patients with BAT activity showed longer progression-free survival than those without, emphasizing the need for further evaluation of its role in metabolism, treatment response, tumor microenvironment and long-term prognosis.
Topics: Humans; Female; Positron Emission Tomography Computed Tomography; Fluorodeoxyglucose F18; Adipose Tissue, Brown; Retrospective Studies; Positron-Emission Tomography; Breast Neoplasms; Radiopharmaceuticals; Tumor Microenvironment
PubMed: 36266524
DOI: 10.1007/s00432-022-04390-7 -
The Journal of Clinical Investigation Dec 2023
Topics: Humans; Adipose Tissue, Brown; Adipocytes, Brown; Hot Temperature; Metabolic Diseases
PubMed: 38038128
DOI: 10.1172/JCI176678