scholarly journals PAT2 regulates autophagy through vATPase assembly and lysosomal acidification in brown adipocytes

2020 ◽  
Author(s):  
Jiefu Wang ◽  
Martin Krueger ◽  
Stefanie M. Hauck ◽  
Siegfried Ussar
Keyword(s):  
Amino Acid ◽  
Brown Adipocyte ◽  
Amino Acid Transporters ◽  
Mitochondrial Uncoupling ◽  
Brown Adipocytes ◽  
Brown Adipose ◽  
Glucose And Lipid Homeostasis ◽  
Mtorc1 Activation ◽  
Lysosomal Acidification

Brown adipose tissue (BAT) plays a key role in maintaining body temperature as well as glucose and lipid homeostasis by its ability to dissipate energy through mitochondrial uncoupling. To facilitate these tasks BAT needs to adopt its thermogenic activity and substrate utilization to changes in nutrient availability, regulated by a complex network of neuronal, endocrine and nutritional inputs. Amongst this multitude of factors influencing BAT activity changes in the autophagic response of brown adipocytes are an important regulator of its thermogenic capacity and activity. Increasing evidence supports an important role of amino acid transporters in mTORC1 activation and the regulation of autophagy. However, a specific role of amino acid transporters in BAT regulating its function has not been described. Here we show that the brown adipocyte specific proton coupled amino acid transporter PAT2 rapidly translocates from the plasma membrane to the lysosome in response to amino acid withdrawal, where it facilitates the assembly of the lysosomal vATPase. Loss or overexpression of PAT2 therefore impair lysosomal acidification, autophagolysosome formation and starvation induced mTORC1 activation.

Hypoxic Stress Upregulates the Expression of Slc38a1 in Brown Adipocytes via Hypoxia-Inducible Factor-1α

Pharmacology ◽  
2017 ◽  
Vol 101 (1-2) ◽  
pp. 64-71 ◽  
Author(s):  
Tetsuhiro Horie ◽  
Kazuya Fukasawa ◽  
Takashi Iezaki ◽  
Gyujin Park ◽  
Yuki Onishi ◽  
...  
Keyword(s):  
Amino Acid ◽  
Hypoxia Inducible Factor ◽  
Amino Acid Transporters ◽  
Hypoxic Stress ◽  
Gene Encoding ◽  
Brown Adipocytes ◽  
Hypoxia Inducible Factor 1Α ◽  
Brown Adipose

The availability of amino acid in the brown adipose tissue (BAT) has been shown to be altered under various conditions; however, little is known about the possible expression and pivotal role of amino acid transporters in BAT under physiological and pathological conditions. The present study comprehensively investigated whether amino acid transporters are regulated by obesogenic conditions in BAT in vivo. Moreover, we investigated the mechanism underlying the regulation of the expression of amino acid transporters by various stressors in brown adipocytes in vitro. The expression of solute carrier family 38 member 1 (Slc38a1; gene encoding sodium-coupled neutral amino acid transporter 1) was preferentially upregulated in the BAT of both genetic and acquired obesity mice in vivo. Moreover, the expression of Slc38a1 was induced by hypoxic stress through hypoxia-inducible factor-1α, which is a master transcription factor of the adaptive response to hypoxic stress, in brown adipocytes in vitro. These results indicate that Slc38a1 is an obesity-associated gene in BAT and a hypoxia-responsive gene in brown adipocytes.

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 Effects of hypothyroidism and hyperthyroidism on GDP binding to brown-adipocyte mitochondria from rats

1989 ◽  
Vol 263 (2) ◽  
pp. 341-345 ◽  
Author(s):  
J A Woodward ◽  
E D Saggerson
Keyword(s):  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Dna Content ◽  
Brown Adipocyte ◽  
Thyroid Status ◽  
Mitochondrial Uncoupling ◽  
Brown Adipocytes ◽  
Period 2 ◽  
Brown Adipose

1. Rats were made hypothyroid by giving them a low-iodine diet with propylthiouracil for 4 weeks, or were made hyperthyroid by injection with tri-iodothyronine (T3) over a 3-day period. 2. Brown adipocytes were isolated from the interscapular depots of these animals or from their euthyroid controls, followed by isolation of mitochondria from the cells. 3. Relative to cell DNA content, hypothyroidism decreased the maximum binding (Bmax.) of [3H]GDP to mitochondria by 50%. T3 treatment increased binding by 37%. 4. These findings, which are discussed in relation to previously observed changes in brown adipose tissue after alteration of thyroid status, suggest that mitochondrial uncoupling for thermogenesis is less or more effective in hypothyroidism or hyperthyroidism respectively.

Activation of pattern recognition receptors in brown adipocytes induces inflammation and suppresses uncoupling protein 1 expression and mitochondrial respiration

2014 ◽  
Vol 306 (10) ◽  
pp. C918-C930 ◽  
Author(s):  
Jiyoung Bae ◽  
Carolyn J. Ricciardi ◽  
Debora Esposito ◽  
Slavko Komarnytsky ◽  
Pan Hu ◽  
...  
Keyword(s):  
Pattern Recognition ◽  
Mitochondrial Respiration ◽  
Uncoupling Protein ◽  
Mapk Signaling ◽  
Pattern Recognition Receptors ◽  
Brown Adipocyte ◽  
Uncoupling Protein 1 ◽  
Brown Adipocytes ◽  
Brown Adipose

Pattern recognition receptors (PRR), Toll-like receptors (TLR), and nucleotide-oligomerization domain-containing proteins (NOD) play critical roles in mediating inflammation and modulating functions in white adipocytes in obesity. However, the role of PRR activation in brown adipocytes, which are recently found to be present in adult humans, has not been studied. Here we report that mRNA of TLR4, TLR2, NOD1, and NOD2 is upregulated, paralleled with upregulated mRNA of inflammatory cytokines and chemokines in the brown adipose tissue (BAT) of the obese mice. During brown adipocyte differentiation, mRNA and protein expression of NOD1 and TLR4, but not TLR2 and NOD2, is also increased. Activation of TLR4, TLR2, or NOD1 in brown adipocytes induces activation of NF-κB and MAPK signaling pathways, leading to inflammatory cytokine/chemokine mRNA expression and/or protein secretion. Moreover, activation of TLR4, TLR2, or NOD1 attenuates both basal and isoproterenol-induced uncoupling protein 1 (UCP-1) expression without affecting mitochondrial biogenesis and lipid accumulation in brown adipocytes. Cellular bioenergetics measurements confirm that attenuation of UCP-1 expression by PRR activation is accompanied by suppression of both basal and isoproterenol-stimulated oxygen consumption rates and isoproterenol-induced uncoupled respiration from proton leak; however, maximal respiration and ATP-coupled respiration are not changed. Further, the attenuation of UCP-1 by PRR activation appears to be mediated through downregulation of the UCP-1 promoter activities. Taken together, our results demonstrate the role of selected PRR activation in inducing inflammation and downregulation of UCP-1 expression and mitochondrial respiration in brown adipocytes. Our results uncover novel targets in BAT for obesity treatment and prevention.

scholarly journals New insights into the secretory functions of brown adipose tissue

2019 ◽  
Vol 243 (2) ◽  
pp. R19-R27 ◽  
Author(s):  
Joan Villarroya ◽  
Rubén Cereijo ◽  
Aleix Gavaldà-Navarro ◽  
Marion Peyrou ◽  
Marta Giralt ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Metabolic Diseases ◽  
Brown Adipocyte ◽  
Fibroblast Growth Factor 21 ◽  
Tissue Remodelling ◽  
Brown Adipocytes ◽  
Signalling Molecules ◽  
Brown Adipose

In recent years, an important secretory role of brown adipose tissue (BAT) has emerged, which is consistent, to some extent, with the earlier recognition of the important secretory role of white fat. The so-called brown adipokines or ‘batokines’ may play an autocrine role, which may either be positive or negative, in the thermogenic function of brown adipocytes. Additionally, there is a growing recognition of the signalling molecules released by brown adipocytes that target sympathetic nerve endings (such as neuregulin-4 and S100b protein), vascular cells (e.g., bone morphogenetic protein-8b), and immune cells (e.g., C-X-C motif chemokine ligand-14) to promote the tissue remodelling associated with the adaptive BAT recruitment in response to thermogenic stimuli. Moreover, existing indications of an endocrine role of BAT are being confirmed through the release of brown adipokines acting on other distant tissues and organs; a recent example is the recognition that BAT-secreted fibroblast growth factor-21 and myostatin target the heart and skeletal muscle, respectively. The application of proteomics technologies is aiding the identification of new members of the brown adipocyte secretome, such as the extracellular matrix or complement system components. In summary, BAT can no longer be considered a mere producer of heat in response to environment or dietary challenges; it is also an active secretory tissue releasing brown adipokines with a relevant local and systemic action. The identification of the major brown adipokines and their roles is highly important for the discovery of novel candidates useful in formulating intervention strategies for metabolic diseases.

scholarly journals ASKA technology-based pull-down method reveals a suppressive effect of ASK1 on the inflammatory NOD-RIPK2 pathway in brown adipocytes

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Saki Takayanagi ◽  
Kengo Watanabe ◽  
Takeshi Maruyama ◽  
Motoyuki Ogawa ◽  
Kazuhiro Morishita ◽  
...  
Keyword(s):  
Uncoupling Protein ◽  
Biological Significance ◽  
Suppressive Effect ◽  
Brown Adipocyte ◽  
Brown Adipocytes ◽  
Adipose Tissues ◽  
Signaling Complex ◽  
Brown Adipose ◽  
Immune Pathway

AbstractRecent studies have shown that adipose tissue is an immunological organ. While inflammation in energy-storing white adipose tissues has been the focus of intense research, the regulatory mechanisms of inflammation in heat-producing brown adipose tissues remain largely unknown. We previously identified apoptosis signal-regulating kinase 1 (ASK1) as a critical regulator of brown adipocyte maturation; the PKA-ASK1-p38 axis facilitates uncoupling protein 1 (UCP1) induction cell-autonomously. Here, we show that ASK1 suppresses an innate immune pathway and contributes to maintenance of brown adipocytes. We report a novel chemical pull-down method for endogenous kinases using analog sensitive kinase allele (ASKA) technology and identify an ASK1 interactor in brown adipocytes, receptor-interacting serine/threonine-protein kinase 2 (RIPK2). ASK1 disrupts the RIPK2 signaling complex and inhibits the NOD-RIPK2 pathway to downregulate the production of inflammatory cytokines. As a potential biological significance, an in vitro model for intercellular regulation suggests that ASK1 facilitates the expression of UCP1 through the suppression of inflammatory cytokine production. In parallel to our previous report on the PKA-ASK1-p38 axis, our work raises the possibility of an auxiliary role of ASK1 in brown adipocyte maintenance through neutralizing the thermogenesis-suppressive effect of the NOD-RIPK2 pathway.

scholarly journals Role of β1- and β3-adrenoceptors in the regulation of lipolysis and thermogenesis in rat brown adipocytes

1997 ◽  
Vol 273 (4) ◽  
pp. C1136-C1142 ◽  
Author(s):  
Claude Atgié ◽  
François D’Allaire ◽  
Ludwik J. Bukowiecki
Keyword(s):  
Competitive Inhibition ◽  
Synaptic Cleft ◽  
Minor Role ◽  
Brown Adipocytes ◽  
Respiratory Effects ◽  
High Affinity ◽  
Brown Adipose ◽  
A Minor ◽  
Brl 37344

To evaluate the physiological functions of β1-, β2-, and β3-adrenoceptors (ARs) in brown adipose tissue, the lipolytic and respiratory effects of various adrenergic agonists and antagonists were studied in rat brown adipocytes. The β-agonists stimulated both lipolysis and respiration (8–10 times above basal levels), with the following order of potency (concentration eliciting 50% of maximum response): CL-316243 (β3) > BRL-37344 (β3) > isoproterenol (mainly β1/β2) > norepinephrine (NE; mainly β1/β2) > epinephrine (mainly β1/β2) ≫ dobutamine (β1) ≫ procaterol (β2). Schild plot coefficients of competitive inhibition experiments using ICI-89406 (β1 antagonist) revealed that more than one type of receptor mediates NE action. It is concluded from our results that 1) NE, at low plasma levels (1–25 nM), stimulates lipolysis and respiration mainly through β1-ARs, 2) NE, at higher levels, stimulates lipolysis and respiration via both β1- and β3-ARs, 3) β2-ARs play only a minor role, and 4) β3-ARs may represent the physiological receptors for the high NE concentrations in the synaptic cleft, where the high-affinity β1-ARs are presumably desensitized. It is also suggested that lipolysis represents the flux-generating step regulating mitochondrial respiration.

scholarly journals Phosphocholine accumulation and PHOSPHO1 depletion promote adipose tissue thermogenesis

2020 ◽  
Vol 117 (26) ◽  
pp. 15055-15065 ◽  
Author(s):  
Mengxi Jiang ◽  
Tony E. Chavarria ◽  
Bingbing Yuan ◽  
Harvey F. Lodish ◽  
Nai-Jia Huang
Keyword(s):  
Adipose Tissue ◽  
Negative Regulator ◽  
Brown Adipocytes ◽  
Diet Induced Obesity ◽  
The Metabolic Syndrome ◽  
Brown Adipose ◽  
Cold Tolerant ◽  
Functional Relevance ◽  
Hydrolysis Of

Phosphocholine phosphatase-1 (PHOSPHO1) is a phosphocholine phosphatase that catalyzes the hydrolysis of phosphocholine (PC) to choline. Here we demonstrate that the PHOSPHO1 transcript is highly enriched in mature brown adipose tissue (BAT) and is further induced by cold and isoproterenol treatments of BAT and primary brown adipocytes. In defining the functional relevance of PHOPSPHO1 in BAT thermogenesis and energy metabolism, we show that PHOSPHO1 knockout mice are cold-tolerant, with higher expression of thermogenic genes in BAT, and are protected from high-fat diet-induced obesity and development of insulin resistance. Treatment of mice with the PHOSPHO1 substrate phosphocholine is sufficient to induce cold tolerance, thermogenic gene expression, and allied metabolic benefits. Our results reveal a role of PHOSPHO1 as a negative regulator of BAT thermogenesis, and inhibition of PHOSPHO1 or enhancement of phosphocholine represent innovative approaches to manage the metabolic syndrome.

scholarly journals Dopamine directly increases mitochondrial mass and thermogenesis in brown adipocytes

2017 ◽  
Vol 58 (2) ◽  
pp. 57-66 ◽  
Author(s):  
Rose Kohlie ◽  
Nina Perwitz ◽  
Julia Resch ◽  
Sebastian M Schmid ◽  
Hendrik Lehnert ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Energy Homeostasis ◽  
Uncoupling Protein ◽  
Brown Adipocyte ◽  
Peroxisome Proliferator ◽  
Cellular Mechanisms ◽  
Brown Adipocytes ◽  
Peroxisome Proliferator Activated Receptor ◽  
Mitochondrial Mass ◽  
Brown Adipose

Brown adipose tissue (BAT) is key to energy homeostasis. By virtue of its thermogenic potential, it may dissipate excessive energy, regulate body weight and increase insulin sensitivity. Catecholamines are critically involved in the regulation of BAT thermogenesis, yet research has focussed on the effects of noradrenaline and adrenaline. Some evidence suggests a role of dopamine (DA) in BAT thermogenesis, but the cellular mechanisms involved have not been addressed. We employed our extensively characterised murine brown adipocyte cells. D1-like and D2-like receptors were detectable at the protein level. Stimulation with DA caused an increase in cAMP concentrations. Oxygen consumption rates (OCR), mitochondrial membrane potential (Δψm) and uncoupling protein 1 (UCP1) levels increased after 24 h of treatment with either DA or a D1-like specific receptor agonist. A D1-like receptor antagonist abolished the DA-mediated effect on OCR, Δψm and UCP1. DA induced the release of fatty acids, which did not additionally alter DA-mediated increases of OCR. Mitochondrial mass (as determined by (i) CCCP- and oligomycin-mediated effects on OCR and (ii) immunoblot analysis of mitochondrial proteins) also increased within 24 h. This was accompanied by an increase in peroxisome proliferator-activated receptor gamma co-activator 1 alpha protein levels. Also, DA caused an increase in p38 MAPK phosphorylation and pharmacological inhibition of p38 MAPK abolished the DA-mediated effect on Δψm. In summary, our study is the first to reveal direct D1-like receptor and p38 MAPK-mediated increases of thermogenesis and mitochondrial mass in brown adipocytes. These results expand our understanding of catecholaminergic effects on BAT thermogenesis.

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