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Article ; Online: Human brown adipose tissue function: insights from current in vivo techniques.

Kwok, T'ng Choong / Stimson, Roland H

2023 Volume 259, Issue 1

Abstract: The identification of brown adipose tissue (BAT) as a thermogenic organ in human adults approximately 20 years ago raised the exciting possibility of activating this tissue as a new treatment for obesity and cardiometabolic disease. [18F]Fluoro-2- ... ...

Abstract	The identification of brown adipose tissue (BAT) as a thermogenic organ in human adults approximately 20 years ago raised the exciting possibility of activating this tissue as a new treatment for obesity and cardiometabolic disease. [18F]Fluoro-2-deoxyglucose (18F-FDG) combined positron emission tomography and computed tomography (PET/CT) scanning is the most commonly used imaging modality to detect and quantify human BAT activity in vivo. This technique exploits the substantial glucose uptake by BAT during thermogenesis as a marker for BAT metabolism. 18F-FDG PET has provided substantial insights into human BAT physiology, including its regulatory pathways and the effect of obesity and cardiometabolic disease on BAT function. The use of alternative PET tracers and the development of novel techniques such as magnetic resonance imaging, supraclavicular skin temperature measurements, contrast-enhanced ultrasound, near-infrared spectroscopy and microdialysis have all added complementary information to improve our understanding of human BAT. However, many questions surrounding BAT physiology remain unanswered, highlighting the need for further research and novel approaches to investigate this tissue. This review critically discusses current techniques to assess human BAT function in vivo, the insights gained from these modalities and their limitations. We also discuss other promising techniques in development that will help dissect the pathways regulating human thermogenesis and determine the therapeutic potential of BAT activation.
MeSH term(s)	Adult ; Humans ; Adipose Tissue, Brown/diagnostic imaging ; Fluorodeoxyglucose F18 ; Positron Emission Tomography Computed Tomography ; Obesity ; Cardiovascular Diseases
Chemical Substances	Fluorodeoxyglucose F18 (0Z5B2CJX4D)
Language	English
Publishing date	2023-08-18
Publishing country	England
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	3028-4
ISSN	1479-6805 ; 0022-0795
ISSN (online)	1479-6805
ISSN	0022-0795
DOI	10.1530/JOE-23-0017
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Article ; Online: Nutritional Regulation of Human Brown Adipose Tissue.

Suchacki, Karla J / Stimson, Roland H

Nutrients

2021 Volume 13, Issue 6

Abstract: The recent identification of brown adipose tissue in adult humans offers a new strategy to increase energy expenditure to treat obesity and associated metabolic disease. While white adipose tissue (WAT) is primarily for energy storage, brown adipose ... ...

Abstract	The recent identification of brown adipose tissue in adult humans offers a new strategy to increase energy expenditure to treat obesity and associated metabolic disease. While white adipose tissue (WAT) is primarily for energy storage, brown adipose tissue (BAT) is a thermogenic organ that increases energy expenditure to generate heat. BAT is activated upon cold exposure and improves insulin sensitivity and lipid clearance, highlighting its beneficial role in metabolic health in humans. This review provides an overview of BAT physiology in conditions of overnutrition (obesity and associated metabolic disease), undernutrition and in conditions of altered fat distribution such as lipodystrophy. We review the impact of exercise, dietary macronutrients and bioactive compounds on BAT activity. Finally, we discuss the therapeutic potential of dietary manipulations or supplementation to increase energy expenditure and BAT thermogenesis. We conclude that chronic nutritional interventions may represent a useful nonpharmacological means to enhance BAT mass and activity to aid weight loss and/or improve metabolic health.
MeSH term(s)	Adipose Tissue, Brown/physiopathology ; Energy Metabolism/physiology ; Exercise/physiology ; Humans ; Insulin Resistance/physiology ; Malnutrition/physiopathology ; Nutritional Status/physiology ; Overnutrition/physiopathology ; Thermogenesis/physiology ; Weight Loss/physiology
Language	English
Publishing date	2021-05-21
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2518386-2
ISSN	2072-6643 ; 2072-6643
ISSN (online)	2072-6643
ISSN	2072-6643
DOI	10.3390/nu13061748
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Article ; Online: MECHANISMS IN ENDOCRINOLOGY: Human brown adipose tissue as a therapeutic target: warming up or cooling down?

McNeill, Ben T / Suchacki, Karla J / Stimson, Roland H

European journal of endocrinology

2021 Volume 184, Issue 6, Page(s) R243–R259

Abstract: Excessive accumulation of white adipose tissue leads to obesity and its associated metabolic health consequences such as type 2 diabetes and cardiovascular disease. Several approaches to treat or prevent obesity including public health interventions, ... ...

Abstract	Excessive accumulation of white adipose tissue leads to obesity and its associated metabolic health consequences such as type 2 diabetes and cardiovascular disease. Several approaches to treat or prevent obesity including public health interventions, surgical weight loss, and pharmacological approaches to reduce caloric intake have failed to substantially modify the increasing prevalence of obesity. The (re-)discovery of active brown adipose tissue (BAT) in adult humans approximately 15 years ago led to a resurgence in research into whether BAT activation could be a novel therapy for the treatment of obesity. Upon cold stimulus, BAT activates and generates heat to maintain body temperature, thus increasing energy expenditure. Activation of BAT may provide a unique opportunity to increase energy expenditure without the need for exercise. However, much of the underlying mechanisms surrounding BAT activation are still being elucidated and the effectiveness of BAT as a therapeutic target has not been realised. Research is ongoing to determine how best to expand BAT mass and activate existing BAT; approaches include cold exposure, pharmacological stimulation using sympathomimetics, browning agents that induce formation of thermogenic beige adipocytes in white adipose depots, and the identification of factors secreted by BAT with therapeutic potential. In this review, we discuss the caloric capacity and other metabolic benefits from BAT activation in humans and the role of metabolic tissues such as skeletal muscle in increasing energy expenditure. We discuss the potential of current approaches and the challenges of BAT activation as a novel strategy to treat obesity and metabolic disorders.
MeSH term(s)	Adipose Tissue, Brown/physiology ; Body Temperature Regulation ; Energy Metabolism ; Humans ; Obesity/physiopathology ; Obesity/therapy
Language	English
Publishing date	2021-05-04
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1183856-5
ISSN	1479-683X ; 0804-4643
ISSN (online)	1479-683X
ISSN	0804-4643
DOI	10.1530/EJE-20-1439
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Associations between glucagon prescribing, hospital admissions for hypoglycaemia and continuous glucose monitoring metrics in adults with type 1 diabetes.

Stimson, Roland H / Dover, Anna R / Strachan, Mark W J / Wright, Rohana J / Lyall, Marcus J / Jeeyavudeen, Mohammad S / Forbes, Shareen / Gibb, Fraser W

Journal of diabetes and its complications

2023 Volume 37, Issue 9, Page(s) 108561

Abstract: Aims: To assess features associated with glucagon prescribing and hospital admissions with hypoglycaemia in type one diabetes.: Methods: Observational study of 4462 adults. Outcome measures were features associated with glucagon prescriptions and ... ...

Abstract	Aims: To assess features associated with glucagon prescribing and hospital admissions with hypoglycaemia in type one diabetes. Methods: Observational study of 4462 adults. Outcome measures were features associated with glucagon prescriptions and predictors of hospital admissions with hypoglycaemia and high levels of glucagon prescribing. Results: 74 % did not collect any glucagon prescriptions and 2.7 % collected >6 over 3.5 years. Hospital admission with hypoglycaemia (P = 0.032), impaired awareness (P = 0.049) and female sex (P < 0.001) were associated with glucagon collection. More frequent prescribing of glucagon was associated with diabetes duration (P < 0.001) and socioeconomic deprivation (P < 0.001). Higher average glucose (P = 0.047), higher time above 13.9 mM (P = 0.008) and higher SD (P = 0.002) were associated with glucagon prescribing. Diabetes duration (P < 0.001) and HbA1c (P < 0.001) were higher in people with hospitalised hypoglycaemia. Higher time above 13.9 mM (P = 0.004) and SD glucose (P < 0.001) were most clearly associated with hospitalised hypoglycaemia. Conclusions: A minority of people with type 1 diabetes have access to glucagon suggesting more could be done to better target this treatment. Individuals with risk factors and those with frequent glucagon prescriptions should be identified for interventions known to reduce hypoglycaemia.
MeSH term(s)	Adult ; Humans ; Female ; Glucagon ; Diabetes Mellitus, Type 1/complications ; Diabetes Mellitus, Type 1/drug therapy ; Diabetes Mellitus, Type 1/epidemiology ; Blood Glucose ; Blood Glucose Self-Monitoring/adverse effects ; Benchmarking ; Hypoglycemia/chemically induced ; Hypoglycemia/epidemiology ; Hypoglycemia/prevention & control ; Glucose ; Hospitals ; Hypoglycemic Agents/adverse effects
Chemical Substances	Glucagon (9007-92-5) ; Blood Glucose ; Glucose (IY9XDZ35W2) ; Hypoglycemic Agents
Language	English
Publishing date	2023-07-22
Publishing country	United States
Document type	Observational Study ; Journal Article
ZDB-ID	1105840-7
ISSN	1873-460X ; 1056-8727
ISSN (online)	1873-460X
ISSN	1056-8727
DOI	10.1016/j.jdiacomp.2023.108561
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Article ; Online: Changes in continuous glucose monitoring metrics and predictors of improvement 12 months after conversion from Freestyle Libre to Freestyle Libre 2.

Stimson, Roland H / Dover, Anna R / Strachan, Mark W J / Wright, Rohana J / Forbes, Shareen / Gibb, Fraser W

Diabetic medicine : a journal of the British Diabetic Association

2023 Volume 40, Issue 11, Page(s) e15130

Abstract: Aims: We sought to assess whether conversion from Freestyle Libre to Freestyle Libre 2 (with low and high glucose alert functions) was associated with improved glucose metrics.: Research design and methods: A prospective observational study to assess ...

Abstract	Aims: We sought to assess whether conversion from Freestyle Libre to Freestyle Libre 2 (with low and high glucose alert functions) was associated with improved glucose metrics. Research design and methods: A prospective observational study to assess changes in CGM metrics in 672 adults with type 1 diabetes when converting to Freestyle Libre 2. Secondary outcomes included predictors of reduction in time below range (TBR) and increase in time in range (TIR). Results: TBR fell by a median of 1.0% (IQR -2.7 to 0.3, p < 0.001) after 12 months and TIR decreased by 1.0% (-8.7 to 6.0, p = 0.004). TIR did not fall in people using high glucose alerts (p = 0.353). Average duration of low glucose events (<3.9 mmoL/L) fell by 10 min (-46 to 18, p < 0.001). Significant improvements in TIR (p = 0.029) and time above 13.9 mM (p = 0.002) were observed in those using high glucose alerts. Alert threshold settings were not associated with glycaemic response; however, low alert use was independently associated with a fall in TBR of ≥0.5% (HR 1.9 [95% CI 1.2-3.1], p = 0.009) and high alert use was independently associated with a rise in TIR of ≥5% (HR 1.6 [95% CI 1.0-2.5], p = 0.043) at 12 months. Conclusions: Conversion to Freestyle Libre 2 was associated with significant improvements in low glucose metrics. Alert function users were more likely to see improvements across all CGM metrics. Challenges remain in encouraging alert use, helping users set optimal alert thresholds and optimizing response to alerts.
MeSH term(s)	Adult ; Humans ; Blood Glucose ; Blood Glucose Self-Monitoring ; Diabetes Mellitus, Type 1 ; Prospective Studies
Chemical Substances	Blood Glucose
Language	English
Publishing date	2023-05-14
Publishing country	England
Document type	Observational Study ; Journal Article
ZDB-ID	605769-x
ISSN	1464-5491 ; 0742-3071 ; 1466-5468
ISSN (online)	1464-5491
ISSN	0742-3071 ; 1466-5468
DOI	10.1111/dme.15130
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Article: Nutritional Regulation of Human Brown Adipose Tissue

Suchacki, Karla J. / Stimson, Roland H.

Nutrients. 2021 May 21, v. 13, no. 6

2021

Abstract	The recent identification of brown adipose tissue in adult humans offers a new strategy to increase energy expenditure to treat obesity and associated metabolic disease. While white adipose tissue (WAT) is primarily for energy storage, brown adipose tissue (BAT) is a thermogenic organ that increases energy expenditure to generate heat. BAT is activated upon cold exposure and improves insulin sensitivity and lipid clearance, highlighting its beneficial role in metabolic health in humans. This review provides an overview of BAT physiology in conditions of overnutrition (obesity and associated metabolic disease), undernutrition and in conditions of altered fat distribution such as lipodystrophy. We review the impact of exercise, dietary macronutrients and bioactive compounds on BAT activity. Finally, we discuss the therapeutic potential of dietary manipulations or supplementation to increase energy expenditure and BAT thermogenesis. We conclude that chronic nutritional interventions may represent a useful nonpharmacological means to enhance BAT mass and activity to aid weight loss and/or improve metabolic health.
Keywords	adults ; brown adipose tissue ; cold stress ; energy expenditure ; exercise ; heat production ; humans ; insulin resistance ; lipids ; malnutrition ; metabolic diseases ; obesity ; overnutrition ; weight loss ; white adipose tissue
Language	English
Dates of publication	2021-0521
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
ZDB-ID	2518386-2
ISSN	2072-6643
ISSN	2072-6643
DOI	10.3390/nu13061748
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Interest in hybrid closed loop is high across the socioeconomic spectrum despite current inequalities in provision in a large UK diabetes centre.

Dover, Anna R / Ritchie, Stuart A / Wright, Rohana J / McMurray, Emily M / Strachan, Mark W J / Stimson, Roland H / Forbes, Shareen / Gibb, Fraser W

Diabetic medicine : a journal of the British Diabetic Association

2023 Volume 40, Issue 5, Page(s) e15058

MeSH term(s)	Humans ; Hypoglycemic Agents ; Hypoglycemia ; Socioeconomic Factors ; United Kingdom ; Diabetes Mellitus
Chemical Substances	Hypoglycemic Agents
Language	English
Publishing date	2023-02-07
Publishing country	England
Document type	Letter
ZDB-ID	605769-x
ISSN	1464-5491 ; 0742-3071 ; 1466-5468
ISSN (online)	1464-5491
ISSN	0742-3071 ; 1466-5468
DOI	10.1111/dme.15058
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Article: Substrate Utilization by Brown Adipose Tissue: What's Hot and What's Not?

McNeill, Ben T / Morton, Nicholas M / Stimson, Roland H

Frontiers in endocrinology

2020 Volume 11, Page(s) 571659

Abstract: Our understanding of brown adipose tissue (BAT) function in humans has increased rapidly over the past 10 years. This is predominantly due to the development of powerful non-invasive imaging techniques such as positron emission tomography that can ... ...

Abstract	Our understanding of brown adipose tissue (BAT) function in humans has increased rapidly over the past 10 years. This is predominantly due to the development of powerful non-invasive imaging techniques such as positron emission tomography that can quantify BAT mass and function using metabolic tracers. Activation of BAT during cold-induced thermogenesis is an effective way to dissipate energy to generate heat and requires utilization of multiple energy substrates for optimal function. This has led to interest in the activation of BAT as a potential therapeutic target for type 2 diabetes, dyslipidaemia, and obesity. Here, we provide an overview of the current understanding of BAT substrate utilization in humans and highlight additional mechanisms found in rodents, where BAT more prominently contributes to energy expenditure. During thermogenesis, BAT demonstrates substantially increased glucose uptake which appears to be critical for BAT function. However, glucose is not fully oxidized, with a large proportion converted to lactate. The primary energy substrate for thermogenesis is fatty acids, released from brown adipocyte triglyceride stores. Active BAT also sequesters circulating lipids to sustain optimal thermogenesis. Recent evidence reveals that metabolic intermediates from the tricarboxylic acid cycle and glycolytic pathways also play a critical role in BAT function. Understanding the role of these metabolites in regulating thermogenesis and whole body substrate utilization may elucidate novel strategies for therapeutic BAT activation.
MeSH term(s)	Adipose Tissue, Brown/metabolism ; Diabetes Mellitus, Type 2/metabolism ; Dyslipidemias/metabolism ; Energy Metabolism/physiology ; Fatty Acids/metabolism ; Glucose/metabolism ; Humans ; Obesity/metabolism ; Thermogenesis/physiology ; Triglycerides/metabolism
Chemical Substances	Fatty Acids ; Triglycerides ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2020-09-25
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2592084-4
ISSN	1664-2392
ISSN	1664-2392
DOI	10.3389/fendo.2020.571659
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: The ATP-binding cassette proteins ABCB1 and ABCC1 as modulators of glucocorticoid action.

Devine, Kerri / Villalobos, Elisa / Kyle, Catriona J / Andrew, Ruth / Reynolds, Rebecca M / Stimson, Roland H / Nixon, Mark / Walker, Brian R

Nature reviews. Endocrinology

2022 Volume 19, Issue 2, Page(s) 112–124

Abstract: Responses to hormones that act through nuclear receptors are controlled by modulating hormone concentrations not only in the circulation but also within target tissues. The role of enzymes that amplify or reduce local hormone concentrations is well ... ...

Abstract	Responses to hormones that act through nuclear receptors are controlled by modulating hormone concentrations not only in the circulation but also within target tissues. The role of enzymes that amplify or reduce local hormone concentrations is well established for glucocorticoid and other lipophilic hormones; moreover, transmembrane transporters have proven critical in determining tissue responses to thyroid hormones. However, there has been less consideration of the role of transmembrane transport for steroid hormones. ATP-binding cassette (ABC) proteins were first shown to influence the accumulation of glucocorticoids in cells almost three decades ago, but observations over the past 10 years suggest that differential transport propensities of both exogenous and endogenous glucocorticoids by ABCB1 and ABCC1 transporters provide a mechanism whereby different tissues are preferentially sensitive to different steroids. This Review summarizes this evidence and the new insights provided for the physiology and pharmacology of glucocorticoid action, including new approaches to glucocorticoid replacement.
MeSH term(s)	Humans ; Adenosine Triphosphate ; ATP Binding Cassette Transporter, Subfamily B/genetics ; ATP-Binding Cassette Transporters/metabolism ; Glucocorticoids/metabolism ; Multidrug Resistance-Associated Proteins/metabolism
Chemical Substances	ABCB1 protein, human ; Adenosine Triphosphate (8L70Q75FXE) ; ATP Binding Cassette Transporter, Subfamily B ; ATP-Binding Cassette Transporters ; Glucocorticoids ; multidrug resistance-associated protein 1 (Y49M64GZ4Q) ; Multidrug Resistance-Associated Proteins
Language	English
Publishing date	2022-10-11
Publishing country	England
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	2489381-X
ISSN	1759-5037 ; 1759-5029
ISSN (online)	1759-5037
ISSN	1759-5029
DOI	10.1038/s41574-022-00745-9
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Article ; Online: C-type natriuretic peptide is a pivotal regulator of metabolic homeostasis.

Perez-Ternero, Cristina / Aubdool, Aisah A / Makwana, Raj / Sanger, Gareth J / Stimson, Roland H / Chan, Li F / Moyes, Amie J / Hobbs, Adrian J

Proceedings of the National Academy of Sciences of the United States of America

2022 Volume 119, Issue 13, Page(s) e2116470119

Abstract: Thermogenesis and adipogenesis are tightly regulated mechanisms that maintain lipid homeostasis and energy balance; dysfunction of these critical processes underpins obesity and contributes to cardiometabolic disease. C-type natriuretic peptide (CNP) ... ...

Abstract	Thermogenesis and adipogenesis are tightly regulated mechanisms that maintain lipid homeostasis and energy balance; dysfunction of these critical processes underpins obesity and contributes to cardiometabolic disease. C-type natriuretic peptide (CNP) fulfills a multimodal protective role in the cardiovascular system governing local blood flow, angiogenesis, cardiac function, and immune cell reactivity. Herein, we investigated a parallel, preservative function for CNP in coordinating metabolic homeostasis. Global inducible CNP knockout mice exhibited reduced body weight, higher temperature, lower adiposity, and greater energy expenditure in vivo. This thermogenic phenotype was associated with increased expression of uncoupling protein-1 and preferential lipid utilization by mitochondria, a switch corroborated by a corresponding diminution of insulin secretion and glucose clearance. Complementary studies in isolated murine and human adipocytes revealed that CNP exerts these metabolic regulatory actions by inhibiting sympathetic thermogenic programming via Gi-coupled natriuretic peptide receptor (NPR)-C and reducing peroxisome proliferator-activated receptor-γ coactivator-1α expression, while concomitantly driving adipogenesis via NPR-B/protein kinase-G. Finally, we identified an association between CNP/NPR-C expression and obesity in patient samples. These findings establish a pivotal physiological role for CNP as a metabolic switch to balance energy homeostasis. Pharmacological targeting of these receptors may offer therapeutic utility in the metabolic syndrome and related cardiovascular disorders.
MeSH term(s)	Animals ; Atrial Natriuretic Factor ; Cardiovascular Diseases/metabolism ; Homeostasis ; Metabolic Diseases/metabolism ; Mice ; Mice, Knockout ; Natriuretic Peptide, C-Type/genetics ; Natriuretic Peptide, C-Type/physiology ; Receptors, Atrial Natriuretic Factor/metabolism ; Thermogenesis
Chemical Substances	Natriuretic Peptide, C-Type (127869-51-6) ; Atrial Natriuretic Factor (85637-73-6) ; Receptors, Atrial Natriuretic Factor (EC 4.6.1.2)
Language	English
Publishing date	2022-03-25
Publishing country	United States
Document type	Journal Article
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2116470119
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