Amount Of Brown Adipose Tissue Research Articles

Very-low-density lipoprotein triglyceride and free fatty acid plasma kinetics in women with high or low brown adipose tissue volume and overweight/obesity

Although a high amount of brown adipose tissue (BAT) is associated with low plasma triglyceride concentration, the mechanism responsible for this relationship in people is not clear. Here, we evaluate the interrelationships among BAT, very-low-density lipoprotein triglyceride (VLDL-TG), and free fatty acid (FFA) plasma kinetics during thermoneutrality in women with overweight/obesity who had a low (<20mL) or high (≥20mL) volume of cold-activated BAT (assessed by using positron emission tomography in conjunction with 2-deoxy-2-[18F]-fluoro-glucose). We find that plasma TG and FFA concentrations are lower and VLDL-TG and FFA plasma clearance rates are faster in women with high BAT than low BAT volume, whereas VLDL-TG and FFA appearance rates in plasma are not different between the two groups. These findings demonstrate that women with high BAT volume have lower plasma TG and FFA concentrations than women with low BAT volumes because of increased VLDL-TG and FFA clearance rates. This study was registered at ClinicalTrials.gov (NCT02786251).

Browning of white adipose tissue may be an appropriate adaptive response to critical illness.

Both the baseline amount of brown adipose tissue (BAT) and the capacity to stimulate browning of white adipose tissue (WAT) may provide a protective effect to the patient in a critical care setting. Critical illness is associated with reduced mitochondrial volume and function resulting in the increased production of reactive oxygen species, greater demand for adenosine triphosphate, a switch to uncoupled fat metabolism, and hibernation of the organelle, which all contribute to multiple organ failure. Increasing insulin resistance, decreasing fatty acid oxidation, and dependence on carbohydrate metabolism result. Browning of WAT may oppose many of these adverse effects. The presence of BAT and the changes associated with browning may help dissipate oxidative stress, increase consumption and utilization of metabolites, and reduce pro-inflammatory actions. The number of mitochondria increases, and there is greater infiltration of macrophages into adipose tissue. A shift occurs in macrophage expression from the M1 to M2 phenotype, an effect which further dampens inflammation, increases insulin sensitivity, and improves tissue healing and remodeling. Any benefit from these responses may be lost in the disease states of chronic hypermetabolism (such as burns or cancer cachexia) in which the persistence of these physiologic effects may become detrimental, contributing to excessive weight loss, adipose wasting, and loss of lean body mass. This paper discusses the plasticity of adipose tissue and whether shifts in its physiology provide clinical advantages in the intensive care unit.

Linsitinib, an IGF-1R inhibitor, attenuates disease development and progression in a model of thyroid eye disease.

Graves' disease (GD) is an autoimmune disorder caused by autoantibodies against the thyroid stimulating hormone receptor (TSHR) leading to overstimulation of the thyroid gland. Thyroid eye disease (TED) is the most common extra thyroidal manifestation of GD. Therapeutic options to treat TED are very limited and novel treatments need to be developed. In the present study we investigated the effect of linsitinib, a dual small-molecule kinase inhibitor of the insulin-like growth factor 1 receptor (IGF-1R) and the Insulin receptor (IR) on the disease outcome of GD and TED. Linsitinib was administered orally for four weeks with therapy initiating in either the early ("active") or the late ("chronic") phases of the disease. In the thyroid and the orbit, autoimmune hyperthyroidism and orbitopathy were analyzed serologically (total anti-TSHR binding antibodies, stimulating anti TSHR antibodies, total T4 levels), immunohistochemically (H&E-, CD3-, TNFa- and Sirius red staining) and with immunofluorescence (F4/80 staining). An MRI was performed to quantify in vivo tissue remodeling inside the orbit. Linsitinib prevented autoimmune hyperthyroidism in the early state of the disease, by reducing morphological changes indicative for hyperthyroidism and blocking T-cell infiltration, visualized by CD3 staining. In the late state of the disease linsitinib had its main effect in the orbit. Linsitinib reduced immune infiltration of T-cells (CD3 staining) and macrophages (F4/80 and TNFa staining) in the orbita in experimental GD suggesting an additional, direct effect of linsitinib on the autoimmune response. In addition, treatment with linsitinib normalized the amount of brown adipose tissue in both the early and late group. An in vivo MRI of the late group was performed and revealed a marked decrease of inflammation, visualized by 19F MR imaging, significant reduction of existing muscle edema and formation of brown adipose tissue. Here, we demonstrate that linsitinib effectively prevents development and progression of thyroid eye disease in an experimental murine model for Graves' disease. Linsitinib improved the total disease outcome, indicating the clinical significance of the findings and providing a path to therapeutic intervention of Graves' Disease. Our data support the use of linsitinib as a novel treatment for thyroid eye disease.

Extinction of Lipomatous Hypertrophy of the Interatrial Septum FDG Uptake With Propranolol Premedication.

Lipomatous hypertrophy of the interatrial septum is a rare lesion of the heart. CT and cardiac MR are often sufficient to determine the benign lipomatous nature of the tumor and can avoid the need for histological confirmation. Lipomatous hypertrophy of the interatrial septum contains variable amounts of brown adipose tissue, resulting in different degrees of 18F-FDG uptake in PET. We report the case of a patient with an interatrial lesion suspected of malignancy, discovered on CT and failing cardiac MR, with initial 18F-FDG uptake. Final characterization was made thanks to 18F-FDG PET with β-blocker premedication, avoiding an invasive procedure.

Irizin: a new myokine and its effect on metabolism

Muscles release hormones (myokines) into the bloodstream, which affect the production of cytokines and their metabolism in various organs and tissues. One of them is irisin, a new adipokine with important autocrine and endocrine functions. It is produced not only by muscle tissue, but also by lymphoid organs, adipose and nervous tissue. It has been proven that this myokine can play a role in the pathogenesis of metabolic and oncological diseases, inflammation, aging and neurogenesis. The content of irisin in the blood is regulated not only by physical activity, but also by diet, changes in body weight, and drugs. The increased interest in studying the relationship of irisin with metabolic diseases is due to the search for a potentially new point of application for overcoming type 2 diabetes mellitus and insulin resistance. Irisin plays a major role in the interaction of the muscle­adiposetissue­bone­brain axis. It has been found that exercise has a positive effect on the functioning of the nervous system. Irisin has an anabolic effect on the skeleton and plays a significant role in bone metabolism. It has been established that exercise is a protective factor in people with cancer, reduces the toxicity of chemotherapy and improves the quality of life of patients, although the mechanisms of this phenomenon require further study. The relationship between circulating irisin levels and impaired glucose metabolism in children is discussed. It is proposed to use irisin as one of the predictors of childhood obesity. Its protective role in pregnancy and in newborns is being studied. A decrease in serum irisin levels is considered a marker of gestational diabetes. It has been suggested that cord blood irisin levels may be a reliable predictor of obesity in the future. Further research is needed to better understand the mechanism of action of this myokine in various diseases in children and to identify the relationship between circulating irisin levels and the amount of brownadipose tissue in newborns of different gestational age and with different birth weights.

Melatonin Enhances the Mitochondrial Functionality of Brown Adipose Tissue in Obese—Diabetic Rats

Developing novel drugs/targets remains a major effort toward controlling obesity-related type 2 diabetes (diabesity). Melatonin controls obesity and improves glucose homeostasis in rodents, mainly via the thermogenic effects of increasing the amount of brown adipose tissue (BAT) and increases in mitochondrial mass, amount of UCP1 protein, and thermogenic capacity. Importantly, mitochondria are widely known as a therapeutic target of melatonin; however, direct evidence of melatonin on the function of mitochondria from BAT and the mechanistic pathways underlying these effects remains lacking. This study investigated the effects of melatonin on mitochondrial functions in BAT of Zücker diabetic fatty (ZDF) rats, which are considered a model of obesity-related type 2 diabetes mellitus (T2DM). At five weeks of age, Zücker lean (ZL) and ZDF rats were subdivided into two groups, consisting of control and treated with oral melatonin for six weeks. Mitochondria were isolated from BAT of animals from both groups, using subcellular fractionation techniques, followed by measurement of several mitochondrial parameters, including respiratory control ratio (RCR), phosphorylation coefficient (ADP/O ratio), ATP production, level of mitochondrial nitrites, superoxide dismutase activity, and alteration in the mitochondrial permeability transition pore (mPTP). Interestingly, melatonin increased RCR in mitochondria from brown fat of both ZL and ZDF rats through the reduction of the proton leak component of respiration (state 4). In addition, melatonin improved the ADP/O ratio in obese rats and augmented ATP production in lean rats. Further, melatonin reduced mitochondrial nitrosative and oxidative status by decreasing nitrite levels and increasing superoxide dismutase activity in both groups, as well as inhibited mPTP in mitochondria isolated from brown fat. Taken together, the present data revealed that chronic oral administration of melatonin improved mitochondrial respiration in brown adipocytes, while decreasing oxidative and nitrosative stress and susceptibility of adipocytes to apoptosis in ZDF rats, suggesting a beneficial use in the treatment of diabesity. Further research regarding the molecular mechanisms underlying the effects of melatonin on diabesity is warranted.

Olive Leaf Extract Supplementation to Old Wistar Rats Attenuates Aging-Induced Sarcopenia and Increases Insulin Sensitivity in Adipose Tissue and Skeletal Muscle.

Aging is associated with increased visceral adiposity and a decrease in the amount of brown adipose tissue and muscle mass, known as sarcopenia, which results in the development of metabolic alterations such as insulin resistance. In this study, we aimed to analyze whether 3-week supplementation with a phenolic-rich olive leaf extract (OLE) to 24 months-old male Wistar rats orally (100 mg/kg) attenuated the aging-induced alterations in body composition and insulin resistance. OLE treatment increased brown adipose tissue and attenuated the aging-induced decrease in protein content and gastrocnemius weight. Treatment with OLE prevented the aging-induced increase in the expression of PPAR-γ in visceral and brown adipose tissues, while it significantly increased the expression of PPAR-α in the gastrocnemius of old rats and reduced various markers related to sarcopenia such as myostatin, HDAC-4, myogenin and MyoD. OLE supplementation increased insulin sensitivity in explants of gastrocnemius and epididymal visceral adipose tissue from aged rats through a greater activation of the PI3K/Akt pathway, probably through the attenuation of inflammation in both tissues. In conclusion, supplementation with OLE prevents the loss of muscle mass associated with aging and exerts anti-inflammatory and insulin-sensitizing effects on adipose tissue and skeletal muscle.

Filling the Gap: Entirely Beige/Brite Adipose Tissues in One of the Smallest Mammals, Suncus etruscus

Mammalian brown adipose tissue provides a means of non-shivering thermogenesis to defend normothermia in the cold by uncoupling protein 1 (UCP1) mediated uncoupling of mitochondrial respiration from ATP production. Apart from brown adipose tissue, thermogenic beige/brite adipocytes reside interspersed within white adipose tissue depots. In rodents, the number of beige/brite adipocytes is highly variable and adapts to thermogenic requirements. We here studied adipose tissue composition of the Etruscan shrew S. etruscus, an insectivore and one of the smallest known mammals with a consequently extreme thermogenic demand in its temperate habitat with cold winters. By dissection, phase contrast computer tomography, histology and mitochondrial enzyme activity assays, we mapped the distribution of adipose tissue depots in shrews from a research colony kept at room temperature. In similar anatomical locations as typically found in rodents, an especially large amount of brown adipose tissue concentrated to the interscapular and subscapular region, while white adipose tissue with a very high content of multilocular cells formed the inguinal and gluteal depots. Uniquely, shrews featured a large, interrenal adipose tissue that by visual inspection, mitochondrial density, fat content, UCP1 transcript abundance, histological analysis and mitochondrial enzyme activity appeared to be an intermediate between classical brown and very beige/brite adipose tissue. This unusual, centrally located depot expansively sheathed both the Vena cava inferior and the Aorta abdominalis, the two largest blood vessels, and must be assumed to provide considerable thermogenic capacity. In conclusion, we identified a novel adipose tissue depot with unique properties placing it in between very beige/brite and brown adipose tissue. Importantly, this finding fills in a conceptual gap within our understanding of adipose tissue plasticity previously thought to include a range from white to beige/brite on the one end, and brown on the other. Etruscan shrew fat depots, however, demonstrate the existence of a gapless continuum of white-to-brown characteristics. Functionally, the transitional, interrenal depot appears strategically placed to deliver heat into circulation via the penetrating, large blood vessels in an animal with extreme thermogenic demand.

Biliary diversion increases resting energy expenditure leading to decreased blood glucose level in mice with type2 diabetes.

Aims/IntroductionType 2 diabetes mellitus is a group of metabolism abnormalities in carbohydrates and energy. Our aim was to investigate resting energy expenditure (REE) and blood glucose changes after biliary diversion in mice with diabetes.Materials and MethodsMale mice with diabetes were randomly divided into biliary diversion and sham groups. REE was detected by indirect calorimetry, the levels of fasting blood glucose, total bile acids and triiodothyronine were analyzed. After mice were killed, the weight amount of brown adipose tissue (BAT) and gastrocnemius was measured, and the expression level of G protein‐coupled bile acid receptor and type 2 iodothyronine deiodinase in BAT and gastrocnemius were examined.ResultsThe two groups of mice were pair‐fed, the bodyweights (P < 0.001) and the fasting blood glucose level (P < 0.001) in the biliary diversion group significantly decreased 24 weeks after surgery. The intraperitoneal glucose tolerance test (P = 0.035) and oral glucose tolerance test (P = 0.027) showed improvement in glucose tolerance after surgery. The REE level significantly increased 24 weeks after surgery (P = 0.005), the levels of total bile acids (P = 0.014) and triiodothyronine (P < 0.001) increased at the 24th postoperative week. The weight ratio of BAT (P = 0.038) and gastrocnemius (P = 0.026) in the biliary diversion group were higher than that in the sham group. The expression of G protein‐coupled bile acid receptor in BAT (P < 0.001) and gastrocnemius (P = 0.003) were upregulated after surgery, and the type 2 iodothyronine deiodinase expression also increased in BAT (P = 0.015) and gastrocnemius (P = 0.015).ConclusionsThe REE level increased and the glucose metabolism improved in mice with diabetes after biliary diversion.

Paraspinal structures of thermoregulation

A detailed analysis of the literature on the structure and functions of the paraspinal structures of human thermoregulation involved in maintaining temperature homeostasis is presented. It is shown that in the process of evolution, a peculiar paraspinal morphofunctional complex is formed around the spinal center of thermoregulation, including thermal- generating structures (adipose and muscle tissue); venous thermal distribution rings formed by paraspinal venous plexuses and thermoregulatory nervous apparatus (meningeal and posterior branches of the spinal nerves and their nerve endings). It was found that the heat-generating structures are represented by adipose tissue of the epidural space, adipose tissue of the bone marrow, paravertebral and interscapular adipose tissue, back muscles and intercostal muscles). Bone marrow fatty tissue plays an important role not only in thermoregulation, but also in bone remodeling. Fatty tissue mainly includes components of white and a small amount of brown adipose tissue. Heat from muscles through the venous system of the spinal column affects the functioning of the spinal center of thermoregulation by contractile thermogenesis. It has been shown that around the center of thermoregulation of the spinal cord, venous vessels form four thermal distribution rings. The first of them is the venous bed of the soft membrane of the spinal cord and cerebrospinal fluid of the subarachnoid space; the second is the internal vertebral venous plexus; the third - intraosseous (intraorgan) venous plexuses of the vertebrae; the fourth is the anterior and posterior external vertebral venous plexuses. All four thermal distribution venous rings anastomose among themselves, forming a single thermal distribution system around the spinal center of thermoregulation. The innervation of thermal generating structures and thermal distribution of venous rings is carried out by somatic and autonomic nerve fibers.

Leucine Potentiates Glucose-mediated 18F-FDG Uptake in Brown Adipose Tissue via β-Adrenergic Activation.

Significant depots of brown adipose tissue (BAT) have been identified in many adult humans through positron emission tomography (PET), with the amount of BAT being inversely correlated with obesity. As dietary activation of BAT has implications for whole body glucose metabolism, leucine was used in the present study to determine its ability to promote BAT activation resulting in increased glucose uptake. In order to assess this, 2-deoxy-2-(fluorine-18)fluoro-d-glucose (18F-FDG) uptake was measured in C57BL/6 mice using microPET after treatment with leucine, glucose, or both in interscapular BAT (IBAT). Pretreatment with propranolol (PRP) was used to determine the role of β-adrenergic activation in glucose and leucine-mediated 18F-FDG uptake. Analysis of maximum standardized uptake values (SUVMAX) determined that glucose administration increased 18F-FDG uptake in IBAT by 25.3%. While leucine did not promote 18F-FDG uptake alone, it did potentiate glucose-mediated 18F-FDG uptake, increasing 18F-FDG uptake in IBAT by 22.5%, compared to glucose alone. Pretreatment with PRP prevented the increase in IBAT 18F-FDG uptake following the combination of glucose and leucine administration. These data suggest that leucine is effective in promoting BAT 18F-FDG uptake through β-adrenergic activation in combination with glucose.

Constitutionally High Serotonin Tone Favors Obesity: Study on Rat Sublines With Altered Serotonin Homeostasis.

Central and peripheral pools of biogenic monoamine serotonin (5-hydroxytryptamine [5HT]) exert opposite effects on the body weight regulation: increase in brain 5HT activity is expected to decrease body weight, whereas increase in peripheral 5HT activity will increase body weight and adiposity. In a genetic model of rats with constitutionally high- or low-5HT homeostasis (hyperserotonergic/hyposerotonergic rats), we have studied how individual differences in endogenous 5HT tone modulate net energy balance of the organism. The high-5HT and low-5HT sublines of the model were developed by selective breeding toward extreme platelet activities of 5HT transporter, a key molecule determining 5HT bioavailability/activity. In animals from high-5HT and low-5HT sublines, we assessed physiological characteristics associated with body weight homeostasis and expression profile of a large scale of body weight–regulating genes in hypothalamus, a major brain region controlling energy balance. Results showed that under standard chow diet animals from the high-5HT subline, as compared to low-5HT animals, have lifelong increased body weight (by 12%), higher absolute daily food intake (by 9%), and different pattern of fat distribution (larger amount of white adipose tissue and lower amount of brown adipose tissue). A large number of body weight–regulating hypothalamic genes were analyzed for their mRNA expression: 24 genes by reverse transcription–quantitative polymerase chain reaction (n = 9–10 rats/subline) including neuropeptides and their receptors, growth factors, transcriptional factors, and receptors for peripheral signals, and a total of 84 genes of various classes by polymerase chain reaction array (pools of six rats/subline). Only few genes showed significant differences in mRNA expression levels between 5HT sublines (e.g. neuropeptide Y receptor, fibroblast growth factor 10), but high-5HT animals displayed a clear trend to upregulation of mRNAs for a number of orexigenic signaling peptides, their receptors, and other molecules with orexigenic activity. Receptors for peripheral signals (leptin, insulin) and molecules in their downstream signaling were not altered, indicating no changes in central insulin/leptin resistance. At the protein level, there were no differences in the content of hypothalamic leptin receptor between 5HT sublines, but significant sex and age effects were observed. Results show that higher constitutive/individual 5HT tone favors higher body weight and adiposity probably due to concurrent upregulation of several hypothalamic orexigenic pathways.

Natural Histogel-Based Bio-Scaffolds for Sustaining Angiogenesis in Beige Adipose Tissue.

In the treatment of obesity and its related disorders, one of the measures adopted is weight reduction by controlling nutrition and increasing physical activity. A valid alternative to restore the physiological function of the human body could be the increase of energy consumption by inducing the browning of adipose tissue. To this purpose, we tested the ability of Histogel, a natural mixture of glycosaminoglycans isolated from animal Wharton jelly, to sustain the differentiation of adipose derived mesenchymal cells (ADSCs) into brown-like cells expressing UCP-1. Differentiated cells show a higher energy metabolism compared to undifferentiated mesenchymal cells. Furthermore, Histogel acts as a pro-angiogenic matrix, induces endothelial cell proliferation and sprouting in a three-dimensional gel in vitro, and stimulates neovascularization when applied in vivo on top of the chicken embryo chorioallantoic membrane or injected subcutaneously in mice. In addition to the pro-angiogenic activity of Histogel, also the ADSC derived beige cells contribute to activating endothelial cells. These data led us to propose Histogel as a promising scaffold for the modulation of the thermogenic behavior of adipose tissue. Indeed, Histogel simultaneously supports the acquisition of brown tissue markers and activates the vasculature process necessary for the correct function of the thermogenic tissue. Thus, Histogel represents a valid candidate for the development of bioscaffolds to increase the amount of brown adipose tissue in patients with metabolic disorders.

The apolipoprotein M/S1P axis controls triglyceride metabolism and brown fat activity

Apolipoprotein M (apoM) is the carrier of sphingosine-1-phosphate (S1P) in plasma high-density lipoproteins. S1P is a bioactive lipid interacting with five receptors (S1P1-5). We show that lack of apoM in mice increases the amount of brown adipose tissue (BAT), accelerates the clearance of postprandial triglycerides, and protects against diet-induced obesity (i.e., a phenotype similar to that induced by cold exposure or β3-adrenergic stimulation). Moreover, the data suggest that the phenotype of apoM-deficient mice is S1P dependent and reflects diminished S1P1 stimulation. The results reveal a link between the apoM/S1P axis and energy metabolism.

Looking on the "brite" side exercise-induced browning of white adipose tissue.

The need for effective and convenient ways of combatting obesity has created great interest in brown adipose tissue (BAT). However, because adult humans have relatively little amounts of BAT, the possibility of browning white adipose tissue (WAT), i.e., switching the metabolism of WAT from an energy storing to energy burning organ, has gained considerable attention. Exercise has countless health benefits, and has consistently been shown to cause browning in rodent white adipose tissue. The purpose of this review is to provide an overview of recent studies examining the effects of exercise and other interventions on the browning of white adipose tissue. The role of various endocrine factors, including catecholamines, interleukin-6, irisin, and meteorin-like in addition to local re-esterification-mediated mechanisms in inducing the browning of WAT will be discussed. The physiological importance of browning will be discussed, as will discrepancies in the literature between human and rodent studies.

Water-fat magnetic resonance imaging quantifies relative proportions of brown and white adipose tissues: ex-vivo experiments.

.Quantifying the amount of brown adipose tissue (BAT) within white adipose tissue (WAT) in human depots may serve as a target to combat obesity. We aimed to quantify proton density fat fraction (PDFF) of BAT and WAT in relatively pure and in mixed preparation using water–fat imaging. Three ex-vivo experiments were performed at 3 T using excised interscapular BAT and inguinal/subcutaneous WAT from mice. The first two experiments consisted of BAT and WAT in separate tubes, and the third used mixed preparation with graded quantities of BAT and WAT. To investigate the influence of partial volume on PDFF metrics, low () and high spatial resolution ( acquired voxels) in two orthogonal three-dimensional sections were compared. The low-resolution acquisitions are corrected for T2* and multipeak lipid spectrum, thus considered “quantitative,” whereas the high-resolution acquisitions are not corrected but were performed to better spatially segment BAT from WAT zones. As potential BAT metrics, we quantified the average PDFF and the volume of tissue having PDFF () based on the PDFF histogram. In the first experiment, the average PDFF of BAT was and and the average PDFF of WAT was and using high- and low-resolution techniques, respectively. A similar trend with excellent reproducibility in average PDFF of BAT and WAT was observed in the second experiment. In the third experiment over the four acquisitions, the BAT-dominant tube demonstrated lower PDFF (mean ± SD) of than WAT-dominant and WAT-only tubes . Estimating , the BAT-dominant tube demonstrated higher volume of than WAT-dominant () and WAT-only tubes (). The presence of BAT exhibits a lower PDFF relative to WAT, thus allowing segmentation of low PDFF tissue for quantification of volume representative of BAT. Future studies will determine the clinical relevance of BAT volume within human depots.

The Apolipoprotein M/S1P Axis Controls Triglyceride Metabolism and Brown Fat Activity

Apolipoprotein M (apoM) is the carrier of sphingosine-1-phosphate (S1P) in plasma high-density lipoproteins. S1P is a bioactive lipid interacting with five receptors (S1P1-5). We show that lack of apoM in mice increases the amount of brown adipose tissue (BAT), accelerates the clearance of postprandial triglycerides, and protects against diet-induced obesity (i.e., a phenotype similar to that induced by cold exposure or β3-adrenergic stimulation). Moreover, the data suggest that the phenotype of apoM-deficient mice is S1P dependent and reflects diminished S1P1 stimulation. The results reveal a link between the apoM/S1P axis and energy metabolism.

Effects of intermittent fasting and chronic swimming exercise on body composition and lipid metabolism.

Intermittent fasting protocol (IFP) has been suggested as a strategy to change body metabolism and improve health. The effects of IFP seem to be similar to aerobic exercise, having a hormetic adaptation according to intensity and frequency. However, the effects of combining both interventions are still unknown. Therefore, the aim of the present study was to evaluate the effects of IFP with and without endurance-exercise training on body composition, food behavior, and lipid metabolism. Twenty-week-old Wistar rats were kept under an inverted circadian cycle of 12 h with water ad libitum and assigned to 4 different groups: control group (ad libitum feeding and sedentary), exercise group (ad libitum feeding and endurance training), intermittent fasting group (IF; intermittent fasting and sedentary), and intermittent fasting and exercise group (IFEX; intermittent fasting and endurance training). After 6 weeks, the body weight of IF and IFEX animals decreased without changes in food consumption. Yet, the body composition between the 2 groups was different, with the IFEX animals containing higher total protein and lower total fat content than the IF animals. The IFEX group also showed increases in total high-density lipoprotein cholesterol and increased intramuscular lipid content. The amount of brown adipose tissue was higher in IF and IFEX groups; however, the IFEX group showed higher expression levels of uncoupling protein 1 in this tissue, indicating a greater thermogenesis. The IFP combined with endurance training is an efficient method for decreasing body mass and altering fat metabolism, without inflicting losses in protein content.

Cell-cycle arrest in mature adipocytes impairs BAT development but not WAT browning, and reduces adaptive thermogenesis in mice

We previously reported brown adipocytes can proliferate even after differentiation. To test the involvement of mature adipocyte proliferation in cell number control in fat tissue, we generated transgenic (Tg) mice over-expressing cell-cycle inhibitory protein p27 specifically in adipocytes, using the aP2 promoter. While there was no apparent difference in white adipose tissue (WAT) between wild-type (WT) and Tg mice, the amount of brown adipose tissue (BAT) was much smaller in Tg mice. Although BAT showed a normal cellular morphology, Tg mice had lower content of uncoupling protein 1 (UCP1) as a whole, and attenuated cold exposure- or β3-adrenergic receptor (AR) agonist-induced thermogenesis, with a decrease in the number of mature brown adipocytes expressing proliferation markers. An agonist for the β3-AR failed to increase the number of proliferating brown adipocytes, UCP1 content in BAT, and oxygen consumption in Tg mice, although the induction and the function of beige adipocytes in inguinal WAT from Tg mice were similar to WT mice. These results show that brown adipocyte proliferation significantly contributes to BAT development and adaptive thermogenesis in mice, but not to induction of beige adipocytes.

FKBP51 Null Mice Are Resistant to Diet-Induced Obesity and the PPARγ Agonist Rosiglitazone.

FK506-binding protein-51 (FKBP51) is a molecular cochaperone recently shown to be a positive regulator of peroxisome proliferator-activated receptor (PPAR)γ, the master regulator of adipocyte differentiation and function. In cellular models of adipogenesis, loss of FKBP51 not only reduced PPARγ activity but also reduced lipid accumulation, suggesting that FKBP51 knock-out (KO) mice might have insufficient development of adipose tissue and lipid storage ability. This model was tested by examining wild-type (WT) and FKBP51-KO mice under regular and high-fat diet conditions. Under both diets, FKBP51-KO mice were resistant to weight gain, hepatic steatosis, and had greatly reduced white adipose tissue (WAT) but higher amounts of brown adipose tissue. Under high-fat diet, KO mice were highly resistant to adiposity and exhibited reduced plasma lipids and elevated glucose and insulin tolerance. Profiling of perigonadal and sc WAT revealed elevated expression of brown adipose tissue lineage genes in KO mice that correlated increased energy expenditure and a shift of substrate oxidation to carbohydrates, as measured by indirect calorimetry. To directly test PPARγ involvement, WT and KO mice were fed rosiglitazone agonist. In WT mice, rosiglitazone induced whole-body weight gain, increased WAT mass, a shift of substrate oxidation to lipids, and elevated expression of PPARγ-regulated lipogenic genes in WAT. In contrast, KO mice had reduced rosiglitazone responses for these parameters. Our results identify FKBP51 as an important regulator of PPARγ in WAT and as a potential new target in the treatment of obesity and diabetes.