scholarly journals Cold-induction of afadin in brown fat supports its thermogenic capacity

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Morten Lundh ◽  
Ali Altıntaş ◽  
Marco Tozzi ◽  
Odile Fabre ◽  
Tao Ma ◽  
...  
Keyword(s):  
Cold Exposure ◽  
Functional Enrichment ◽  
Activation Process ◽  
Target Tissue ◽  
Cold Stimulation ◽  
Brown Adipocytes ◽  
Protein Levels ◽  
Mrna Induction ◽  
Metabolic Functions ◽  
Brown Adipose

AbstractThe profound energy-expending nature of brown adipose tissue (BAT) thermogenesis makes it an attractive target tissue to combat obesity-associated metabolic disorders. While cold exposure is the strongest inducer of BAT activity, the temporal mechanisms tuning BAT adaptation during this activation process are incompletely understood. Here we show that the scaffold protein Afadin is dynamically regulated by cold in BAT, and participates in cold acclimation. Cold exposure acutely increases Afadin protein levels and its phosphorylation in BAT. Knockdown of Afadin in brown pre-adipocytes does not alter adipogenesis but restricts β3-adrenegic induction of thermogenic genes expression and HSL phosphorylation in mature brown adipocytes. Consistent with a defect in thermogenesis, an impaired cold tolerance was observed in fat-specific Afadin knockout mice. However, while Afadin depletion led to reduced Ucp1 mRNA induction by cold, stimulation of Ucp1 protein was conserved. Transcriptomic analysis revealed that fat-specific ablation of Afadin led to decreased functional enrichment of gene sets controlling essential metabolic functions at thermoneutrality in BAT, whereas it led to an altered reprogramming in response to cold, with enhanced enrichment of different pathways related to metabolism and remodeling. Collectively, we demonstrate a role for Afadin in supporting the adrenergic response in brown adipocytes and BAT function.

Enhanced gene expression of endothelial nitric oxide synthase in brown adipose tissue during cold exposure

2002 ◽  
Vol 282 (2) ◽  
pp. R623-R626 ◽  
Author(s):  
Kazue Kikuchi-Utsumi ◽  
Bihu Gao ◽  
Hiroshi Ohinata ◽  
Masaaki Hashimoto ◽  
Noriyuki Yamamoto ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Cold Exposure ◽  
Inos Mrna ◽  
No Production ◽  
Mrna Levels ◽  
Cold Stimulation ◽  
Brown Adipose ◽  
Enos Mrna

It has been shown that norepinephrine (NE) can mediate vasodilatation by stimulating the production of nitric oxide (NO) in brown adipose tissue (BAT), resulting in an increase in BAT blood flow. We speculated that constitutive NO synthase (NOS) is involved in this NO production. However, it is not known whether constitutive NOS is expressed in BAT. To answer this question, we assessed the expression of two types of constitutive NOS, endothelial (eNOS) and neuronal NOS (nNOS), in BAT of rats. eNOS was abundantly expressed in both BAT and isolated brown adipocytes, whereas nNOS was not. Cold exposure, which is known to stimulate NE release from sympathetic nerve terminals in BAT, led to a significant increase in eNOS mRNA in this tissue. In contrast, very low levels of inducible NOS (iNOS) mRNA were expressed, and cold stimulation failed to increase iNOS mRNA levels in BAT. These results suggest that eNOS is the primary isoform that is responsible for NO production in BAT and that its expression may be under sympathetic control.

Differential regulation of fatty acid elongation enzymes in brown adipocytes implies a unique role for Elovl3 during increased fatty acid oxidation

2005 ◽  
Vol 289 (4) ◽  
pp. E517-E526 ◽  
Author(s):  
Andreas Jakobsson ◽  
Johanna A. Jörgensen ◽  
Anders Jacobsson
Keyword(s):  
Fatty Acid ◽  
Gene Family ◽  
Regulatory Element ◽  
Saturated Fatty Acids ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Cold Stimulation ◽  
Brown Adipocytes ◽  
Brown Adipose

The expression of the Elovl3 gene, which belongs to the Elovl gene family coding for microsomal enzymes involved in very long-chain fatty acid (VLCFA) elongation, is dramatically increased in mouse brown adipose tissue upon cold stimulation. In the present study, we show that the cold-induced Elovl3 expression is under the control of peroxisome proliferator-activated receptor-α (PPARα) and that this regulation is part of a fundamental divergence in the regulation of expression for the different members of the Elovl gene family. In cultured brown adipocytes, a mixture of norepinephrine, dexamethasone, and the PPARα ligand Wy-14643, which rendered the adipocytes a high oxidative state, was required for substantial induction of Elovl3 expression, whereas the same treatment suppressed Elovl1 mRNA levels. The nuclear liver X receptor (LXR) has been implicated in the control of fatty acid synthesis and subsequent lipogenic processes in several tissues. This regulation is also exerted in part by sterol regulatory element-binding protein (SREBP-1), which is a target gene of LXR. We found that stimulation of Elovl3 expression was independent of LXR and SREBP-1 activation. In addition, exposure to the LXR agonist TO-901317 increased nuclear abundance of LXR and mature SREBP-1 as well as expression of the elongases Lce and Elovl1 in a lipogenic fashion but repressed Elovl3 expression. A functional consequence of this was seen on the level of esterified saturated fatty acids, such as C22:0, which was coupled to Elovl3 expression. These data demonstrate differential transcriptional regulation and concomitantly different functional roles for fatty acid elongases in lipid metabolism of brown adipocytes, which reflects the metabolic status of the cells.

scholarly journals Role of Ubiquilins for Brown Adipocyte Proteostasis and Thermogenesis

2021 ◽  
Vol 12 ◽  
Author(s):  
Carolin Muley ◽  
Stefan Kotschi ◽  
Alexander Bartelt
Keyword(s):  
Gene Expression ◽  
Quality Control ◽  
Adipose Tissue ◽  
Cold Exposure ◽  
Protein Quality ◽  
Brown Adipocyte ◽  
Brown Adipocytes ◽  
Brown Adipose ◽  
Shivering Thermogenesis

The acclimatization of brown adipose tissue (BAT) to sustained cold exposure requires an adaptive increase in proteasomal protein quality control. Ubiquilins represent a recently identified family of shuttle proteins with versatile functions in protein degradation, such as facilitating substrate targeting and proteasomal degradation. However, whether ubiquilins participate in brown adipocyte function has not been investigated so far. Here, we determine the role of ubiquilins for proteostasis and non-shivering thermogenesis in brown adipocytes. We found that Ubqln1, 2 and 4 are highly expressed in BAT and their expression was induced by cold and proteasomal inhibition. Surprisingly, silencing of ubiquilin gene expression (one or multiple in combinations) did not lead to aggravated ER stress or inflammation. Moreover, ubiquitin level and proteasomal activity under basal conditions were not impacted by loss of ubiquilins. Also, non-shivering thermogenesis measured by norepinephrine-induced respiration remained intact after loss of ubiquilins. In conclusion, ubiquilin proteins are highly abundant in BAT and regulated by cold, but they are dispensable for brown adipocyte proteostasis and thermogenesis.

scholarly journals The Nuanced Metabolic Functions of Endogenous FGF21 Depend on the Nature of the Stimulus, Tissue Source, and Experimental Model

2022 ◽  
Vol 12 ◽  
Author(s):  
Redin A. Spann ◽  
Christopher D. Morrison ◽  
Laura J. den Hartigh
Keyword(s):  
Expression Patterns ◽  
Nutritional Stress ◽  
Receptor Expression ◽  
Metabolic Effects ◽  
Fibroblast Growth Factor 21 ◽  
Target Tissue ◽  
Alcoholic Fatty Liver ◽  
Metabolic Functions ◽  
Brown Adipose ◽  
Fgf21 Expression

Fibroblast growth factor 21 (FGF21) is a hormone that is involved in the regulation of lipid, glucose, and energy metabolism. Pharmacological FGF21 administration promotes weight loss and improves insulin sensitivity in rodents, non-human primates, and humans. However, pharmacologic effects of FGF21 likely differ from its physiological effects. Endogenous FGF21 is produced by many cell types, including hepatocytes, white and brown adipocytes, skeletal and cardiac myocytes, and pancreatic beta cells, and acts on a diverse array of effector tissues such as the brain, white and brown adipose tissue, heart, and skeletal muscle. Different receptor expression patterns dictate FGF21 function in these target tissues, with the primary effect to coordinate responses to nutritional stress. Moreover, different nutritional stimuli tend to promote FGF21 expression from different tissues; i.e., fasting induces hepatic-derived FGF21, while feeding promotes white adipocyte-derived FGF21. Target tissue effects of FGF21 also depend on its capacity to enter the systemic circulation, which varies widely from known FGF21 tissue sources in response to various stimuli. Due to its association with obesity and non-alcoholic fatty liver disease, the metabolic effects of endogenously produced FGF21 during the pathogenesis of these conditions are not well known. In this review, we will highlight what is known about endogenous tissue-specific FGF21 expression and organ cross-talk that dictate its diverse physiological functions, with particular attention given to FGF21 responses to nutritional stress. The importance of the particular experimental design, cellular and animal models, and nutritional status in deciphering the diverse metabolic functions of endogenous FGF21 cannot be overstated.

The emergence of cold-induced brown adipocytes in mouse white fat depots is determined predominantly by white to brown adipocyte transdifferentiation

2010 ◽  
Vol 298 (6) ◽  
pp. E1244-E1253 ◽  
Author(s):  
G. Barbatelli ◽  
I. Murano ◽  
L. Madsen ◽  
Q. Hao ◽  
M. Jimenez ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Cold Exposure ◽  
Brown Adipocyte ◽  
Brown Adipocytes ◽  
Cold Acclimatization ◽  
Fat Depots ◽  
Gene Coding ◽  
Adrenoceptor Agonist ◽  
Brown Adipose ◽  
Enhanced Expression

The origin of brown adipocytes arising in white adipose tissue (WAT) after cold acclimatization is unclear. Here, we demonstrate that several UCP1-immunoreactive brown adipocytes occurring in WAT after cold acclimatization have a mixed morphology (paucilocular adipocytes). These cells also had a mixed mitochondrioma with classic “brown” and “white” mitochondria, suggesting intermediate steps in the process of direct transformation of white into brown adipocytes (transdifferentiation). Quantitative electron microscopy disclosed that cold exposure (6°C for 10 days) did not induce an increase in WAT preadipocytes. β3-adrenoceptor-knockout mice had a blunted brown adipocyte occurrence upon cold acclimatization. Administration of the β3-adrenoceptor agonist CL316,243 induced the occurrence of brown adipocytes, with the typical morphological features found after cold acclimatization. In contrast, administration of the β1-adrenoceptor agonist xamoterol increased only the number of preadipocytes. These findings indicate that transdifferentiation depends on β3-adrenoceptor activation, whereas preadipocyte recruitment is mediated by β1-adrenoceptor. RT-qPCR experiments disclosed that cold exposure induced enhanced expression of the thermogenic genes and of genes expressed selectively in brown adipose tissue (iBAT) and in both interscapular BAT and WAT. β3-adrenoceptor suppression blunted their expression only in WAT. Furthermore, cold acclimatization induced an increased WAT expression of the gene coding for C/EBPα (an antimitotic protein), whereas Ccna1 expression (related to cell proliferation) was unchanged. Overall, our data strongly suggest that the cold-induced emergence of brown adipocytes in WAT predominantly reflects β3-adrenoceptor-mediated transdifferentiation.

scholarly journals Nipsnap1 – A Novel Thermogenic Regulator

2021 ◽  
Vol 5 (Supplement_2) ◽  
pp. 1228-1228
Author(s):  
Yang Liu ◽  
Yue Qu ◽  
Chloe Cheng ◽  
Pei-Yin Tsai ◽  
Joeva Barrow
Keyword(s):  
Energy Expenditure ◽  
Cold Exposure ◽  
Proteomic Analysis ◽  
Uncoupling Protein ◽  
Treatment Options ◽  
Oxidative Capacity ◽  
Loss Of Function ◽  
Brown Adipocytes ◽  
Brown Adipose

Abstract Objectives We aim to discover molecular treatment options to combat obesity by studying a process known as non-shivering thermogenesis (NST). The major objective is to determine if Nipsnap1 can regulate NST in brown adipose tissue (BAT) and evaluate its potential for obesity treatment. Methods 1. Identification of Nipsnap1 and loss-of-function study•Unbiased proteomic analysis is performed on BAT isolated mitochondria samples from 6-week-old mice exposed to cold to activate NST (n = 3). •siRNA-mediated knockdown of Nipsnap1 is performed on primary brown adipocytes isolated from mice. Seahorse Bioanalyzer is used for Mitochondria Respiration Test. •Thermogenic tissue-specific Nipsnap1 knockout mice (N1-KO) are generated by crossing floxed Nipsnap1 (N1-Flox) transgenic mice with UCP1-Cre mice. 2. Role of Nipsnap1 in thermogenesis•Phenotypical studies in vivo are performed on 6-week-old N1-KO and N1-Flox mice (n = 8). Mice are acclimated in 30°C followed by cold exposure in 4°C for ten days. Rectal temperature is measured. •N1-KO mice metabolism level and locomotive movement are monitored by the Sable Promethion Metabolic Cage system (n = 8). Results Nipsnap1 displays potent thermogenic properties. By unbiased proteomic analysis, we identify Nipsnap1, which is highly induced when NST is activated and strongly correlates with the NST key protein Uncoupling Protein 1 (UCP1). Nipsnap1 ablation in primary brown adipocytes reveals significant reductions in thermogenic adipose function. siNipsnap1 causes complete ablation of UCP1 protein levels. Moreover, it causes a 50% reduction (P < 0.001) of mitochondrial oxidative capacity and a 40% reduction (P < 0.05) of glycolytic capacity in cells. Nipsnap1 KO mice have impaired NST and reduced energy expenditure in vivo. Under prolonged cold exposure (day 7–10), N1-KO mice exhibit significant defects (day 10, P < 0.05) to maintain body temperature by NST. We demonstrated that the N1-KO mice had a 10% (P < 0.01) reduction in energy expenditure during the active night period after prolonged cold (day 5–8) treatment compared to controls. Conclusions Nipsnap1 plays an essential role in regulating NST. Targeting Nipsnap1 to increase energy expenditure at the molecular level will provide new insights into developing a safe and effective method to combat obesity and metabolic disease. Funding Sources Agency: NIH; Institute: NIDDK.

scholarly journals The Effect of Hyperbaric Therapy on Brown Adipose Tissue in Rats

2021 ◽  
Vol 18 (17) ◽  
pp. 9165
Author(s):  
Chang-Hyung Lee ◽  
Young-A Choi ◽  
Sung-Jin Heo ◽  
Parkyong Song
Keyword(s):  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Cold Exposure ◽  
Therapeutic Potential ◽  
Uncoupling Protein ◽  
Peroxisome Proliferator ◽  
Sprague Dawley ◽  
Protein Levels ◽  
Brown Adipose ◽  
Ucp1 Expression

Brown adipose tissue (BAT) plays an important role in thermogenic regulation, which contributes to alleviating diet-induced obesity through uncoupling protein 1 (UCP1) expression. While cold exposure and physical exercise are known to increase BAT development and UCP1 expression, the contribution of hyperbaric oxygen (HBO) therapy to BAT maturation remains largely unknown. Here, we show that HBO treatment sufficiently increases BAT volumes and thermogenic protein levels in Sprague-Dawley rats. Through 18F-FDG PET/CT analysis, we found that exposure to high-pressure oxygen (1.5–2.5 ATA) for 7 consecutive days increased radiolabeled glucose uptake and BAT development to an extent comparable to cold exposure. Consistent with BAT maturation, thermogenic protein levels, such as those of UCP1 and peroxisome proliferator-activated receptor γ coactivator 1α (PGC−1α), were largely increased by HBO treatment. Taken together, we suggest HBO therapy as a novel method of inducing BAT development, considering its therapeutic potential for the treatment of metabolic disorders.

scholarly journals Selenoprotein P-mediated reductive stress impairs cold-induced thermogenesis in brown fat

2021 ◽  
Author(s):  
Swe Mar Oo ◽  
Hein Ko Oo ◽  
Hiroaki Takayama ◽  
Takehiro Kanamori ◽  
Yumie Takeshita ◽  
...  
Keyword(s):  
Glucose Uptake ◽  
Cold Exposure ◽  
Intrinsic Factor ◽  
Serum Levels ◽  
Selenoprotein P ◽  
Brown Adipocytes ◽  
Reductive Stress ◽  
Obesity And Diabetes ◽  
Mitochondrial Ros ◽  
Brown Adipose

Abstract Reactive oxygen species (ROS) oxidize and activate the uncoupler protein 1 (UCP1) in brown adipose tissue (BAT) under physiological cold exposure and noradrenaline (NA) stimulation to increase thermogenesis. However, pathological significance and the endogenous regulator of the ROS-mediated BAT activation remain unclear. Here, we show that serum levels of selenoprotein P (SeP, encoded by Selenop) are negatively correlated with BAT activity in humans. SeP impairs UCP1 activity and thermogenesis. Physiological cold exposure downregulates Selenop in BAT. BAT-specific Selenop-deficient (BAT-Selenop KO) mice presented elevated NA-induced mitochondrial ROS production, sulfenylated UCP1, and enhanced thermogenesis and glucose uptake in BAT during cold exposure. SeP inhibits mitochondrial ROS by upregulating the expression of the antioxidant enzyme, glutathione peroxidase 4, and impairs glucose uptake in brown adipocytes. High fat/high sucrose diet upregulates Selenop in the liver and inhibits the NA-induced BAT thermogenesis in BAT-Selenop KO mice. Our data indicate that SeP, as the hepatokine and BATkine, is the first identified intrinsic factor inducing reductive stress that impairs UCP1 activation and thermogenesis in BAT, and therefore may be a potential therapeutic target for obesity and diabetes.

scholarly journals Evaluation of Active Brown Adipose Tissue by the Use of Hyperpolarized [1-13C]Pyruvate MRI in Mice

2018 ◽  
Vol 19 (9) ◽  
pp. 2597 ◽  
Author(s):  
Mette Riis-Vestergaard ◽  
Peter Breining ◽  
Steen Pedersen ◽  
Christoffer Laustsen ◽  
Hans Stødkilde-Jørgensen ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Cold Exposure ◽  
Fdg Pet ◽  
Metabolic Diseases ◽  
Uncoupling Protein ◽  
Protein Levels ◽  
Positron Emission ◽  
Brown Adipose

The capacity to increase energy expenditure makes brown adipose tissue (BAT) a putative target for treatment of metabolic diseases such as obesity. Presently, investigation of BAT in vivo is mainly performed by fluoro-d-glucose positron emission tomography (FDG PET)/CT. However, non-radioactive methods that add information on, for example, substrate metabolism are warranted. Thus, the aim of this study was to evaluate the potential of hyperpolarized [1-13C]pyruvate Magnetic Resonance Imaging (HP-MRI) to determine BAT activity in mice following chronic cold exposure. Cold (6 °C) and thermo-neutral (30 °C) acclimated mice were scanned with HP-MRI for assessment of the interscapular BAT (iBAT) activity. Comparable mice were scanned with the conventional method FDG PET/MRI. Finally, iBAT was evaluated for gene expression and protein levels of the specific thermogenic marker, uncoupling protein 1 (UCP1). Cold exposure increased the thermogenic capacity 3–4 fold (p < 0.05) as measured by UCP1 gene and protein analysis. Furthermore, cold exposure as compared with thermo-neutrality increased iBAT pyruvate metabolism by 5.5-fold determined by HP-MRI which is in good agreement with the 5-fold increment in FDG uptake (p < 0.05) measured by FDG PET/MRI. iBAT activity is detectable in mice using HP-MRI in which potential changes in intracellular metabolism may add useful information to the conventional FDG PET studies. HP-MRI may also be a promising radiation-free tool for repetitive BAT studies in humans.

scholarly journals MECHANISMS IN ENDOCRINOLOGY: Brown adipose tissue in humans: regulation and metabolic significance

2016 ◽  
Vol 175 (1) ◽  
pp. R11-R25 ◽  
Author(s):  
Moe Thuzar ◽  
Ken K Y Ho
Keyword(s):  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Cold Exposure ◽  
Brown Adipocytes ◽  
Metabolic Hormones ◽  
Bat Activity ◽  
Adipose Tissue Depots ◽  
Brown Adipose ◽  
Adult Humans ◽  
Metabolic Significance

The recent discovery that functional brown adipose tissue (BAT) persists in adult humans has enkindled a renaissance in metabolic research, with a view of harnessing its thermogenic capacity to combat obesity. This review focuses on the advances in the regulation and the metabolic significance of BAT in humans. BAT activity in humans is stimulated by cold exposure and by several factors such as diet and metabolic hormones. BAT function is regulated at two levels: an acute process involving the stimulation of the intrinsic thermogenic activity of brown adipocytes and a chronic process of growth involving the proliferation of pre-existing brown adipocytes or differentiation to brown adipocytes of adipocytes from specific white adipose tissue depots. BAT activity is reduced in the obese, and its stimulation by cold exposure increases insulin sensitivity and reduces body fat. These observations provide strong evidence that BAT plays a significant role in energy balance in humans and has the potential to be harnessed as a therapeutic target for the management of obesity.

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