Brown Fat Activity Research Articles

Interplay between FGF21 and insulin action in the liver regulates metabolism

The hormone FGF21 regulates carbohydrate and lipid homeostasis as well as body weight, and increasing FGF21 improves metabolic abnormalities associated with obesity and diabetes. FGF21 is thought to act on its target tissues, including liver and adipose tissue, to improve insulin sensitivity and reduce adiposity. Here, we used mice with selective hepatic inactivation of the IR (LIRKO) to determine whether insulin sensitization in liver mediates FGF21 metabolic actions. Remarkably, hyperglycemia was completely normalized following FGF21 treatment in LIRKO mice, even though FGF21 did not reduce gluconeogenesis in these animals. Improvements in blood sugar were due in part to increased glucose uptake in brown fat, browning of white fat, and overall increased energy expenditure. These effects were preserved even after removal of the main interscapular brown fat pad. In contrast to its retained effects on reducing glucose levels, the effects of FGF21 on reducing circulating cholesterol and hepatic triglycerides and regulating the expression of key genes involved in cholesterol and lipid metabolism in liver were disrupted in LIRKO mice. Thus, FGF21 corrects hyperglycemia in diabetic mice independently of insulin action in the liver by increasing energy metabolism via activation of brown fat and browning of white fat, but intact liver insulin action is required for FGF21 to control hepatic lipid metabolism.

Energy Metabolism and Biochemical Features of Adipose Tissues in ICR Mice after Long-Term Calorie-Restricted Diet

Long-term calorie-restricted diet (8 weeks, 60% of control food intake) was followed by an increase in thermogenic activity of interscapular brown fat. The relative amount of DNA and protein and the rate of oxygen consumption increased and tissue-specific marker of brown fat (uncoupling protein UCP1) appeared in significantly reduced deep-pink abdominal adipose tissue.

Ketone esters increase brown fat in mice and overcome insulin resistance in other tissues in the rat

Brown adipose tissue (BAT) is classically activated by sympathetic nervous stimulation resulting from exposure to cold. Feeding a high-fat diet also induces development of brown fat, but is decreased by caloric restriction. Blood ketone bodies, which function as alternative energy substrates to glucose, are increased during caloric restriction. Here we discuss the unexpected observation that feeding an ester of ketone bodies to the mouse, which increases blood ketone body concentrations, results in an activation of brown fat. The mechanism of this activation of brown fat is similar to that occurring from cold exposure in that cyclic adenosine monophosphate (AMP) levels are increased as are levels of the transcription factor cyclic AMP-responsive element-binding protein, which is also increased by ketone ester feeding. Other effects of feeding ketone esters, in addition to their ability to induce brown fat, are discussed such as their ability to overcome certain aspects of insulin resistance and to ameliorate the accumulation of amyloid and phosphorylated tau protein in brain, and improve cognitive function, in a triple transgenic mouse model of Alzheimer's disease.

Brown adipose tissue: development, metabolism and beyond

Obesity represents a major risk factor for the development of several of our most common medical conditions, including Type2 diabetes, dyslipidaemia, non-alcoholic fatty liver, cardiovascular disease and even some cancers. Although increased fat mass is the main feature of obesity, not all fat depots are created equal. Adipocytes found in white adipose tissue contain a single large lipid droplet and play well-known roles in energy storage. By contrast, brown adipose tissue is specialized for thermogenic energy expenditure. Owing to its significant capacity to dissipate energy and regulate triacylglycerol (triglyceride) and glucose metabolism, and its demonstrated presence in adult humans, brown fat could be a potential target for the treatment of obesity and metabolic syndrome. Undoubtedly, fundamental knowledge about the formation of brown fat and regulation of its activity is imperatively needed to make such therapeutics possible. In the present review, we integrate the recent advancements on the regulation of brown fat formation and activity by developmental and hormonal signals in relation to its metabolic function.

Brown Fat Activation Mediates Cold-Induced Thermogenesis in Adult Humans in Response to a Mild Decrease in Ambient Temperature

The contribution of brown adipose tissue (BAT) to the energy balance in humans exposed to sustainable cold has not been completely established, partially because of measurement limitations of both BAT activity and energy expenditure (EE). The objective of the study was to characterize the role of BAT activation in cold-induced thermogenesis (CIT). This study was a single-blind, randomized crossover intervention. The study was conducted at the National Institutes of Health Clinical Center. Thirty-one healthy volunteers participated in the study. The intervention included mild cold exposure. CIT and BAT activation were the main outcomes in this study. Overnight EE measurement by whole-room indirect calorimeter at 24 °C or 19 °C was followed by 2-[18F]-fluoro-2-deoxy-D-glucose positron emission tomography (PET) scan. After 36 hours, volunteers crossed over to the alternate study temperature under identical conditions. BAT activity was measured in a 3-dimensional region of interest in the upper torso by comparing the uptake at the two temperatures. Twenty-four volunteers (14 males, 10 females) had a complete data set. When compared with 24 °C, exposure at 19 °C resulted in increased EE (5.3 ± 5.9%, P < .001), indicating CIT response and mean BAT activity (10.5 ± 11.1%, P < .001). Multiple regression analysis indicated that a difference in BAT activity (P < .001), age (P = .01), and gender (P = .037) were independent contributors to individual variability of CIT. A small reduction in ambient temperature, within the range of climate-controlled buildings, is sufficient to increase human BAT activity, which correlates with individual CIT response. This study uncovers for the first time a spectrum of BAT activation among healthy adults during mild cold exposure not previously recognized by conventional PET and PET-computed tomography methods. The enhancement of cold-induced BAT stimulation may represent a novel environmental strategy in obesity treatment.

Insulin resistance: a risk marker for disease and disability in the older person

Clinical metabolic studies have demonstrated that insulin action declines progressively with age in humans. In addition to its close association with Type 2 diabetes, which reduces life expectancy in older people, age-related insulin resistance is implicated in pathogenesis of several highly prevalent disorders for which ageing is a major risk factor. These include atherosclerotic cardiovascular disease, dementia, frailty and cancer. Accordingly, insulin resistance may be viewed as biomarker of age-related ill health and reduced lifespan. The rapidly rising number of older people, coupled with a high prevalence of insulin resistance resulting from obesity and sedentary lifestyles, presents unprecedented public health and societal challenges. Studies of centenarians have shown that preserved whole-body sensitivity to insulin is associated with longevity. The mechanisms through which insulin action is associated with age-related diseases remain unclear. Changes in body composition, i.e. sarcopenia and excess adiposity, may be more potent than age per se. Moreover, the impact of insulin resistance has been difficult to disentangle from the clustering of vascular risk factors that co-segregate with the insulin resistance-hyperinsulinaemia complex. Potentially modifiable mediators of age-related changes in insulin sensitivity include alterations in adipocytokines, impaired skeletal myocyte mitochondrial function and brown fat activity. The hypothesis that improving or maintaining insulin sensitivity preserves health and extends lifespan merits further evaluation. Practical non-pharmacological interventions directed against age-related insulin resistance remain underdeveloped. Novel metabolically active pharmacological agents with theoretical implications for some age-related disorders are entering clinical trials. However, recent adverse experiences with the thiazolidinediones suggest the need for a cautious approach to the use of insulin sensitizing drugs in older people. This could be particularly important in the absence of diabetes where the risk to benefit analysis may be less favourable.

Evidence of Brown Fat Activity in Constitutional Leanness

Brown adipose tissue (BAT) was considered essentially nonexistent in adults until recent evidence obtained using 18-fluorodeoxyglucose (18-FDG) positron emission tomography/computed tomography. It seems to play a role in whole body metabolism, but it has not been evaluated in underweight conditions, such as in young females with constitutional leanness (CL) or anorexia nervosa (AN). Thirty-eight subjects were evaluated from October 2011 to March 2012 : 7 CL (21.7 ± 3.6 y, body mass index [BMI] 16.2 ± 1.0 kg/m(2)), 7 AN (23.4 ± 4.5 y, BMI 15.5 ± 0.8), 3 of the 7 AN after stable refeeding (R-AN, 21.3 ± 1.5 y, BMI 18.8 ± 1.1), and 24 normal weight (NW) women (25.6 ± 3.9 y, BMI 22.2 ± 1.5). Fasting resting metabolic rate and respiratory quotient were measured by indirect calorimetry, body composition by bioimpedentiometry (only in CL, AN, and refed AN), and BAT activity by 18-FDG positron emission tomography/computed tomography scan, all in standardized conditions. All CL (100%), none of the AN and refed AN (0%), and 3 of the 24 NW (12%) subjects showed FDG uptake. Average FDG maximum standardized uptake value was 11.4 + 6.7 g/mL in CL and 5.5 ± 1.2 g/mL (min 3.7, max 8.3) in the 3 NW subjects. In CL, the maximum standardized uptake value was directly correlated to resting metabolic rate, corrected for fat-free mass, and inversely correlated with respiratory quotient. BAT activity has been shown in CL in resting thermoneutral conditions and may exert a role against adipose tissue deposition.

Brown adipose tissue biology and therapeutic potential

BROWN ADIPOSE TISSUE Brown adipose tissue (BAT) (Figure 1) has been recognized as a key thermogenic tissue in rodents for several decades. However, in the last few years, there has been a resurgent interest in the biology and therapeutic potential of BAT. This has been largely driven by a new understanding that most, if not all, healthy adult humans have significant deposits of BAT which can be activated by cold. Moreover, recent insights into the developmental origins of brown adipose cells and the identification of molecules that regulate brown adipocyte activity have provided a conceptual framework for the design of brown fat-based therapies. Brown fat cells, when activated, are able to take up and oxidize large amounts of fat and carbohydrate for the purpose of producing heat—a process called adaptive thermogenesis. This transformation of chemical energy into heat at the expense of ATP production is mediated by the presence of Uncoupling Protein1 (Ucp1) in the inner mitochondrial membrane. Ucp1 catalyzes the leak of protons from the intermembrane space back into the matrix, thus reducing the gradient (and its potential energy) used for ATP production. BAT presumably evolved to protect animals against hypothermia in response to cold exposure. However, BAT is also known to powerfully counteract obesity and metabolic disease, at least in rodents. Numerous studies over recent years revealed that mice with increased amounts of active brown fat are lean, healthy, and able to resist the harmful metabolic effects of high fat diets. Intriguingly, imaging studies in humans show that brown fat activity is reduced in obesity and aging. The field must now address whether the variation in brown fat activity is a cause or consequence of weight gain. Brown fat cells are localized in discrete depots of BAT and are also found clustered amongst white fat cells in white depots. The prevalence and function of these so-called “beige” or “brite” (brown-in-white) cells in humans remains unknown. There is a growing consensus in the field that brown fattargeted therapies hold tremendous promise for the treatment of obesity and associated health consequences. It is also increasingly clear that brown fat can function as an effective sink for disposing of excess glucose and fatty acids. This suggests that brown fat-based therapies could be very effective for treating insulin FIGURE 1 | Brown adipose tissue. Immunohistochemical staining of Ucp1 expression in brown adipose tissue showing a mixture of large and small adipocytes.

Inactivation of MARK4, an AMP-activated Protein Kinase (AMPK)-related Kinase, Leads to Insulin Hypersensitivity and Resistance to Diet-induced Obesity

MARK4, also known as Par-1d/MarkL1, is a member of the AMP-activated protein kinase (AMPK)-related family of kinases, which are implicated in the regulation of dynamic biological functions, including glucose and energy homeostasis. However, the physiological function of MARK4 in mammals remains elusive. Here, we investigated a role for MARK4 in regulating energy homeostasis by generating mice with targeted inactivation of the mark4 gene. We show that MARK4 deficiency in mice caused hyperphagia, hyperactivity, and hypermetabolism, leading to protection from diet-induced obesity and its related metabolic complications through up-regulation of brown fat activity. Consequently, MARK4 deficiency mitigated insulin resistance associated with diet-induced obesity by dramatically enhancing insulin-stimulated AKT phosphorylation in major metabolic tissues. Ablation of MARK4 also significantly improved glucose homeostasis by up-regulating the activity and expression of AMPK kinase in key metabolic tissues. Taken together, these data identify a key role of MARK4 in energy metabolism, implicating the kinase as a novel drug target for the treatment of obesity and type 2 diabetes.

290P - Brown Fat Seen on FDG PET/CT is Increased in Breast Cancer Patients Compared to their Age- and Weight-Matched Controls With Other Cancers

ABSTRACT Purpose We previously found increased brown fat deposits in mammary tissue of Rrca1 mutant breast cancer mouse models suggesting a potential role of brown fat environment in the early breast tumorigenesis. The goal of the current human study is to test the hypothesis that the prevalence of brown fat activity seen on FDG PET/CT is increased in breast cancer (BC) patients. Methods We conducted a retrospective study to assess the distribution and intensity of brown fat activity on FDG PET/CT in female BC patients compared to age- and weight-matched control subjects with other cancers mostly colon cancer. We analyzed 124 FDG PET/CT scans of BC patients done at the University of Maryland and 124 age- and weight-matched control subjects who had FDG PET/CT scan on the same day for staging of other cancers (the majority were colon cancer). Results The prevalence of brown fat was higher in BC (12.9% or 16/124) than in their age- and weight-matched control subjects (5.6% or 7/124) (p 50 years of age, there was no difference in brown fat prevalence between BC patients and controls (5.4% or 5/93 vs 4.4% or 4/91; p = NS), respectively. Brown fat was more commonly identified in the bilateral supraclavicular regions in BC patients than controls (22 vs 6, p = 0.049). There was no difference in the intensity of brown fat between the 2 groups (mean SUV max = 3.5 ± 1.5 in BC vs 3.4 ± 0.7 in controls, p = NS). Conclusion The prevalence of brown fat seen on FDG PET/CT is increased in BC patients compared to their age- and weight-matched controls with other cancers, particularly in patients aged Disclosure All authors have declared no conflicts of interest.

Molecular and histological evidence of brown adipose tissue in adult cats

Brown adipose tissue (BAT) can influence glucose, lipid, and energy metabolism in rodents. Active BAT is now known to be present in adult humans, and interventions targeting BAT are being investigated for the treatment of human obesity and disorders of glucose and lipid metabolism. Domestic cats, like humans, are at increasing risk for obesity and diabetes but little is known about the presence and role of BAT in adult cats. The purpose of this study was to determine if brown adipocytes, identifiable by histological features and molecular markers, were present in the fat depots of adult cats. Adipose tissue samples from intrascapular, perirenal, and subcutaneous depots of eleven 8-12 year old cats (6 lean, 5 obese), were analyzed by real-time PCR for brown adipocyte markers uncoupling protein 1 (UCP1) and Type II iodothyronine 5'deiodinase (D2), by histological examination and by immunohistochemistry for UCP1. UCP1 mRNA was detectable in interscapular and subcutaneous depots in all cats, and in the perirenal depot in 10/11 cats. D2 mRNA was detectable in all depots from all cats. Multilocular adipocytes were identified in the interscapular depots of 4/11 cats and these were positive for UCP1 immunoreactivity. The results demonstrate that UCP1-expressing brown adipocytes are present in multiple depots of adult lean and long-term obese cats, even at 8-12 years of age. It is possible that dietary components or pharmacological agents that influence brown fat activity could exert a relevant biological effect in cats.

Blockade of the Activin Receptor IIB Activates Functional Brown Adipogenesis and Thermogenesis by Inducing Mitochondrial Oxidative Metabolism

Brown adipose tissue (BAT) is a key tissue for energy expenditure via fat and glucose oxidation for thermogenesis. In this study, we demonstrate that the myostatin/activin receptor IIB (ActRIIB) pathway, which serves as an important negative regulator of muscle growth, is also a negative regulator of brown adipocyte differentiation. In parallel to the anticipated hypertrophy of skeletal muscle, the pharmacological inhibition of ActRIIB in mice, using a neutralizing antibody, increases the amount of BAT without directly affecting white adipose tissue. Mechanistically, inhibition of ActRIIB inhibits Smad3 signaling and activates the expression of myoglobin and PGC-1 coregulators in brown adipocytes. Consequently, ActRIIB blockade in brown adipose tissue enhances mitochondrial function and uncoupled respiration, translating into beneficial functional consequences, including enhanced cold tolerance and increased energy expenditure. Importantly, ActRIIB inhibition enhanced energy expenditure only at ambient temperature or in the cold and not at thermoneutrality, where nonshivering thermogenesis is minimal, strongly suggesting that brown fat activation plays a prominent role in the metabolic actions of ActRIIB inhibition.

Brown fat activation pathways ‘highly specific’

Brown fat activation pathways ‘highly specific’

GRK2 contribution to the regulation of energy expenditure and brown fat function

Obesity is a major health problem and an important risk factor for the development of multiple disorders. Previous studies in our laboratory have revealed that down-regulation of GRK2 decreases age-related adiposity, but the physiological and molecular mechanisms underlying this outcome remain unclear. We evaluate whether the lean phenotype results from a direct effect of GRK2 on energy homeostasis. The study of white adipose tissue (WAT) in wild-type (WT) and GRK2(+/-) littermates showed a reduced expression of lipogenic enzymes and enhanced lipolytic rate in adult GRK2(+/-) mice. Moreover, hemizygous mice display higher energy expenditure and lower respiratory exchange ratio. Analysis of brown adipose tissue (BAT) from adult GRK2(+/-) mice showed a less deteriorated morphology associated with age compared to WT, which is correlated with a higher basal core temperature. BAT from young GRK2(+/-) mice showed an increase in gene expression of thermogenesis-related genes. Accordingly, hemizygous mice displayed better thermogenic capacity and exhibited a more oxidative phenotype in both BAT and WAT than WT littermates. Overexpression of GRK2 in brown adipocytes corroborated the negative effect of this kinase in BAT function and differentiation. Collectively, our data point to GRK2 inhibition as a potential tool for the enhancement of brown fat activity, which may have important therapeutic implications for the treatment of obesity and associated metabolic disorders.

The Secret Life of Fat Suggests New Therapeutic Targets

Not so many years ago, most considered fat a passive recipient of our indulgence. But since the discovery of leptin in 1994,1 it has become ever clearer that fat is more than a storage site for excess calories. Rather, fat plays an active, communicative role in metabolism that research is beginning to uncover. Two recent studies not only represent our rapidly changing grasp of the biology of fat but also suggest potential treatments for one of the world's most intractable chronic health conditions: obesity. A paper in Nature 2 in January 2012 from the laboratory of Bruce Spiegelman, PhD, of the Dana-Farber Cancer Institute in Boston, MA, reported the discovery of a new hormone released by muscle that converts white fat deposits into thermogenic brown fat. Whereas white fat acts as a repository for excess, mitochondria-rich brown fat cells burn ordinary fat as energy to produce heat. Once thought to only exist in rodents and infants, several groups have confirmed brown fat in humans. It is found in small patches along the spine, in the upper back, on the sides of the neck, and between the collarbone and shoulder. A few weeks after Spiegelman's Nature paper was published, a publication3 in the Journal of Clinical Investigation from the laboratory of Shelia Collins, PhD, of the Sanford-Burnham Medical Research Institute in Orlando, FL, revealed the heart plays a role in the regulation of fat burning. Collins, first author Marica Bordicchia, and colleagues reported that cardiac natriuretic peptides increased browning of white fat, elevating uncoupling protein 1 (UCP1)–dependent energy expenditure. C. Ronald Kahn, MD, chief academic officer at the Joslin Diabetes Center in Boston, MA, says the recent discoveries are likely just the opening act in our growing knowledge about fat metabolism. “Right now we're looking at the first things …

Impaired thermogenesis and adipose tissue development in mice with fat-specific disruption of insulin and IGF-1 signalling

Insulin and insulin-like growth factor 1 (IGF-1) play important roles in adipocyte differentiation, glucose tolerance and insulin sensitivity. Here, to assess how these pathways can compensate for each other, we created mice with a double tissue-specific knockout of insulin and IGF-1 receptors to eliminate all insulin/IGF-1 signaling in fat. These FIGIRKO mice had markedly decreased white and brown fat mass and were completely resistant to high fat diet (HFD) induced obesity and age- and HFD-induced glucose intolerance. Energy expenditure was increased in FIGIRKO mice despite a >85% reduction in brown fat mass. However, FIGIRKO mice were unable to maintain body temperature when placed at 4°C. Brown fat activity was markedly decreased in FIGIRKO mice but was responsive to β3-receptor stimulation. Thus, insulin/IGF-1 signaling has a crucial role in the control of brown and white fat development, and, when disrupted, leads to defective thermogenesis and a paradoxical increase in basal metabolic rate.

Activity of the mitochondrial calcium uniporter varies greatly between tissues

The mitochondrial calcium uniporter (MCU) is a highly selective channel responsible for mitochondrial Ca2+ uptake. The MCU shapes cytosolic Ca2+ signals, controls mitochondrial ATP production, and is involved in cell death. Here, using direct patch-clamp recording from the inner mitochondrial membrane, we compare MCU activity in mouse heart, skeletal muscle, liver, kidney, and brown fat. Surprisingly, heart mitochondria shows a dramatically lower MCU current density than the other tissues studied. Similarly, in Drosophila flight muscle, MCU activity is barely detectable compared to that in other fly tissues. Because mitochondria occupy up to 40% of the cell volume in highly metabolically active heart and flight muscle, low MCU activity is likely essential to avoid cytosolic Ca2+ sink due to excessive mitochondrial Ca2+ uptake. Simultaneously, low MCU activity may also prevent mitochondrial Ca2+ overload in such active tissues exposed to frequent cytosolic Ca2+ activity.

Can having fun protect you from obesity and its cancer risk?

Can having fun protect you from obesity and its cancer risk?

Brown Fat Activity Is not Apparent in Subjects With HIV Lipodystrophy and Increased Resting Energy Expenditure

The HIV lipodystrophy (LD) syndrome is associated with increased resting energy expenditure (REE), but the basis of this hypermetabolism has not been determined. The objective of this pilot study was to determine if brown fat is activated in subjects with HIV LD and increased REE. In this descriptive study of four subjects with HIV LD and marked hypermetabolism, REE was measured by indirect calorimetry and brown fat activity was determined by (18)F-fluorodeoxyglucose (FDG) positron-emission tomography (PET) combined with anatomic computed tomography (CT). Brown fat activity was not apparent in any subject with HIV LD and resting hypermetabolism. Therefore, brown fat activation is unlikely to be the principal cause of the increased REE associated with the HIV LD syndrome. Evidence of adaptive thermogenesis has been demonstrated in this syndrome, but this study suggests that tissues other than brown adipose tissue (BAT) are responsible. Further understanding of the chronic hypermetabolism associated with HIV LD could provide new insights into the regulation of energy balance.

Determinants of brown adipocyte development and thermogenesis

The brown adipocyte is a thermogenic cell. Its thermogenic potential is conferred by uncoupling protein-1, which 'uncouples' adenosine triphosphate synthesis from energy substrate oxidation. Brown fat cells in so-called classical brown adipose tissue (BAT) share their origin with myogenic factor-5-expressing myoblasts. The development of myocyte/brown adipocyte progenitor cells into a brown adipocyte lineage is apparently triggered by bone morphogenetic protein-7, which stimulates inducers of brown fat cell differentiation, such as PRD1-BF1-RIZ1 homologous domain-containing-16 and peroxisome proliferator-activated receptor-γ co-activator-1-α. The control of brown fat cell development and activity is physiologically ensured by the sympathetic nervous system (SNS), which densely innervates BAT. SNS-mediated thermogenesis is largely governed by hypothalamic and brainstem neurons. With regard to energy balance, the leptin-melanocortin pathway appears to be a major factor in controlling brown adipocyte thermogenesis. The involvement of this homeostatic pathway further supports the role of the brown adipocyte in energy balance regulation. The interest for the brown fat cell and its potential role in energy balance has been further rejuvenated recently by the demonstration that BAT can be present in substantial amounts in humans, in contrast to what has always been thought. Positron emission tomography/computed tomography scanning investigations have indeed revealed the presence in humans of important neck and shoulder cold-activable BAT depots, in particular, in young, lean and female subjects. This short review summarizes recent progress made in the biology of the brown fat cell and focuses on the determinants of the brown adipocyte development and activity.