scholarly journals Sympathetic Transmitters Controlling Thermogenic Efficacy of Brown Adipocytes by Modulating Mitochondrial Complex V

2017 ◽  
Author(s):  
Tao-Rong Xie ◽  
Chun-Feng Liu ◽  
Jian-Sheng Kang
Keyword(s):  
Atpase Activity ◽  
Proton Leak ◽  
Mitochondrial Complex ◽  
Brown Adipocytes ◽  
Proton Atpase ◽  
Obesity Intervention ◽  
Obesity And Diabetes ◽  
Brown Adipose ◽  
Key Factor ◽  
New Strategies

ABSTRACTObesity is epidemic worldwide as the results of excessive energy intake or inefficient energy expenditure. It is promising to utilize the thermogenic function of brown adipose tissue for obesity intervention. However, the mechanisms controlling the efficacy of norepinephrine-induced thermogenesis in brown adipocytes remain elusive. Here, we demonstrate that the proton ATPase activity of mitochondrial complex V is a key factor, which antagonizes proton leak by UCP1 and determines the efficacy of norepinephrine-induced thermogenesis in brown adipocytes. Furthermore, to avoid unnecessary and undesired heat production, we reveal that ATP as a sympathetic cotransmitter is necessary for the high efficacy and specificity of norepinephrine-induced thermogenesis in brown adipocytes by upregulating the ATP synthase activity of complex V. Thus, we demonstrate the modulation mechanism of thermogenic efficacy in brown adipocytes. These findings imply new strategies for efficiently utilizing brown adipocytes thermogenic capacity, and therapeutic targets for the treatments of obesity and diabetes.Highlights1. Norepinephrine (NE) induces heterogeneous responses in brown adipocytes2. NE activates the H+-ATPase activity of mitochondrial complex V3. Mitochondrial complex V is a key factor in NE-induced thermogenic efficacy4. ATP as a sympathetic cotransmitter enhances the NE-induced thermogenic efficacy

scholarly journals Regulation of Cidea protein stability by the ubiquitin-mediated proteasomal degradation pathway

2007 ◽  
Vol 408 (2) ◽  
pp. 259-266 ◽  
Author(s):  
Siu Chiu Chan ◽  
Sheng-Cai Lin ◽  
Peng Li
Keyword(s):  
Protein Stability ◽  
Mutational Analysis ◽  
Critical Role ◽  
Proteasome Inhibitors ◽  
Degradation Pathway ◽  
Post Translational Modification ◽  
Brown Adipocytes ◽  
Obesity And Diabetes ◽  
Brown Adipose ◽  
Lysine Residues

Cidea, one of three members of the CIDE (cell-death-inducing DNA-fragmentation-factor-45-like effector) family of proteins, is highly enriched in brown adipose tissue, in which it plays a critical role in adaptive thermogenesis and fat accumulation. Cidea-null mice have increased energy expenditure with resistance to high-fat-diet-induced obesity and diabetes. However, little is known as to how the Cidea protein is regulated. In the present study we show that Cidea is a short-lived protein as measured by cycloheximide-based protein chase experiments in different cell lines or in differentiated brown adipocytes. Proteasome inhibitors specifically increased the stability of both transfected and endogenous Cidea protein. Furthermore, Cidea protein was found to be polyubiquitinated when overexpressed in different culture cells as well as in differentiated mature brown adipocytes. Extensive mutational analysis of individual lysine residues revealed that ubiquitinated lysine residues are located in the N-terminal region of Cidea, as alteration of these lysine residues to alanine (N-5KA mutant) renders Cidea much more stable when compared with wild-type or C-terminal lysine-less mutant (C-5KA). Furthermore, K23 (Lys23) within the N-terminus of the Cidea was identified as the major contributor to its polyubiquitination signal and the protein instability. Taken together, the results of our study demonstrated that the ubiquitin–proteasome system confers an important post-translational modification that controls the protein stability of Cidea.

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 Novel Browning Agents, Mechanisms, and Therapeutic Potentials of Brown Adipose Tissue

2016 ◽  
Vol 2016 ◽  
pp. 1-15 ◽  
Author(s):  
Umesh D. Wankhade ◽  
Michael Shen ◽  
Hariom Yadav ◽  
Keshari M. Thakali
Keyword(s):  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Energy Homeostasis ◽  
Therapeutic Potential ◽  
Uncoupling Protein ◽  
Brown Adipocytes ◽  
Atp Production ◽  
Obesity And Diabetes ◽  
Brown Adipose ◽  
Beige Adipocytes

Nonshivering thermogenesis is the process of biological heat production in mammals and is primarily mediated by brown adipose tissue (BAT). Through ubiquitous expression of uncoupling protein 1 (Ucp1) on the mitochondrial inner membrane, BAT displays uncoupling of fuel combustion and ATP production in order to dissipate energy as heat. Because of its crucial role in regulating energy homeostasis, ongoing exploration of BAT has emphasized its therapeutic potential in addressing the global epidemics of obesity and diabetes. The recent appreciation that adult humans possess functional BAT strengthens this prospect. Furthermore, it has been identified that there are both classical brown adipocytes residing in dedicated BAT depots and “beige” adipocytes residing in white adipose tissue depots that can acquire BAT-like characteristics in response to environmental cues. This review aims to provide a brief overview of BAT research and summarize recent findings concerning the physiological, cellular, and developmental characteristics of brown adipocytes. In addition, some key genetic, molecular, and pharmacologic targets of BAT/Beige cells that have been reported to have therapeutic potential to combat obesity will be discussed.

Norepinephrine- and insulin-resistant glucose transport in brown adipocytes from diabetic SHR/N-cp rats

1993 ◽  
Vol 265 (3) ◽  
pp. R577-R583
Author(s):  
A. Marette ◽  
P. Mauriege ◽  
J. P. Despres ◽  
O. L. Tulp ◽  
L. J. Bukowiecki
Keyword(s):  
Glucose Metabolism ◽  
Glucose Transport ◽  
Insulin Receptors ◽  
Brown Adipocytes ◽  
Spontaneously Hypertensive ◽  
Insulin Resistant ◽  
Metabolic Defects ◽  
Obesity And Diabetes ◽  
Brown Adipose ◽  
Insulin Responsiveness

The effects of norepinephrine and insulin on glucose transport were investigated in brown adipocytes isolated from obese nondiabetic Lister and Albany (LA/N-cp strain) rats (O-LA), obese diabetic spontaneously hypertensive (SHR/N-cp strain) rats (O-SHR), and from their lean (L) controls to test whether the decreased calorigenic response to norepinephrine of O-SHR adipocytes was specifically associated with alterations in glucose metabolism. Norepinephrine and insulin independently stimulated glucose transport in L-LA, O-LA, and L-SHR brown adipocytes, but their stimulatory effects were markedly reduced in O-SHR cells. Both insulin responsiveness and the total number of insulin receptors were significantly decreased in O-SHR adipocytes but not in O-LA cells. The number of high-affinity beta 1/beta 2-adrenoceptors was significantly increased (+70%) in O-LA adipocytes but was similar in L-SHR and O-SHR cells. These results indicate that 1) major metabolic defects are present in brown adipose tissue (BAT) of O-SHR but not of O-LA, although these two strains are homozygous for the cp allele, 2) postreceptor defects are predominantly involved in O-SHR adipocyte refractoriness to norepinephrine, and 3) a reduced mitochondrial content may represent the principal metabolic alteration explaining the decreased effects of norepinephrine on both thermogenesis and glucose transport. It is postulated that the marked insulin resistance of O-SHR leads to a decreased mitochondriogenesis in BAT, resulting in a diminished tissue thermogenic capacity and reduced glucose metabolism, thereby contributing to obesity and diabetes.

scholarly journals Arsenite exposure suppresses adipogenesis, mitochondrial biogenesis and thermogenesis via autophagy inhibition in brown adipose tissue

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Jiyoung Bae ◽  
Yura Jang ◽  
Heejeong Kim ◽  
Kalika Mahato ◽  
Cameron Schaecher ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Mitochondrial Biogenesis ◽  
Metabolic Disorders ◽  
High Dose ◽  
Brown Adipocytes ◽  
Treatment And Prevention ◽  
Obesity And Diabetes ◽  
Brown Adipose ◽  
Contaminated Drinking Water

Abstract Arsenite, a trivalent form of arsenic, is an element that occurs naturally in the environment. Humans are exposed to high dose of arsenite through consuming arsenite-contaminated drinking water and food, and the arsenite can accumulate in the human tissues. Arsenite induces oxidative stress, which is linked to metabolic disorders such as obesity and diabetes. Brown adipocytes dissipating energy as heat have emerging roles for obesity treatment and prevention. Therefore, understanding the pathophysiological role of brown adipocytes can provide effective strategies delineating the link between arsenite exposure and metabolic disorders. Our study revealed that arsenite significantly reduced differentiation of murine brown adipocytes and mitochondrial biogenesis and respiration, leading to attenuated thermogenesis via decreasing UCP1 expression. Oral administration of arsenite in mice resulted in heavy accumulation in brown adipose tissue and suppression of lipogenesis, mitochondrial biogenesis and thermogenesis. Mechanistically, arsenite exposure significantly inhibited autophagy necessary for homeostasis of brown adipose tissue through suppression of Sestrin2 and ULK1. These results clearly confirm the emerging mechanisms underlying the implications of arsenite exposure in metabolic disorders.

scholarly journals Interleukin-10 Attenuates Liver Fibrosis Exacerbated by Thermoneutrality

2021 ◽  
Vol 8 ◽  
Author(s):  
Ha Thi Nga ◽  
Ji Sun Moon ◽  
Jingwen Tian ◽  
Ho Yeop Lee ◽  
Seok-Hwan Kim ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Cultured Cells ◽  
Smooth Muscle Actin ◽  
Interleukin 10 ◽  
Conditioned Media ◽  
Alpha Smooth Muscle Actin ◽  
Brown Adipocytes ◽  
Secreted Factors ◽  
Brown Adipose ◽  
Key Factor

Background: Crosstalk between brown adipose tissue (BAT) and the liver is receiving increasing attention. This study investigated the effect of BAT dysfunction by thermoneutral (TN) housing on liver fibrosis in mice and examined the effect of secreted factors from brown adipocytes on the activation of hepatic stellate cells (HSCs).Methods: The carbon tetrachloride (CCl4)-induced liver fibrosis mouse model was used to evaluate fibrotic changes in the livers of mice housed under standard and TN conditions. The effect of BAT on the activation of HSCs was examined using cultured cells treated with conditioned media from brown adipocytes.Results: Under TN conditions, mice with CCl4-induced liver fibrosis exhibited increased liver injury, collagen deposition, and alpha smooth muscle actin (α-SMA) expression in the liver compared with mice maintained at room temperature. The numbers of liver-infiltrating immune cells and T cells producing IL-17A and IFN-γ were also significantly increased in the livers of mice housed under TN conditions. Treatment of HSCs with conditioned media from brown adipocytes markedly attenuated HSC activation, as shown by down-regulated α-SMA expression at day 4, day 7 and day 10 of culture. At thermoneutrality, with CCl4 administration, IL-10-deficient mice exhibited more severe liver fibrosis than wild-type mice. Interestingly, conditioned media from IL-10-deficient brown adipocytes could up-regulate the expression of α-SMA and induce HSCs activation.Conclusions: BAT inactivation by thermoneutrality contributes to the activation of pro-inflammatory and pro-fibrotic pathways in mice with CCl4-induced liver fibrosis. Normal brown adipocytes secreted factors that impair the activation of HSCs, while this protective effect was lost in IL-10-deficient brown adipocytes. Thus, the BAT–liver axis may serve as a potential therapeutic target for liver fibrosis, and IL-10 may be a key factor regulating the activation of HSCs by BAT.

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.

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 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.

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