scholarly journals Sesamol promotes browning of white adipocytes to ameliorate obesity by inducing mitochondrial biogenesis and inhibition mitophagy via β3-AR/PKA signaling pathway

2021 ◽  
Author(s):  
Cui Lin ◽  
Jihua Chen ◽  
Minmin Hu ◽  
Wenya Zheng ◽  
Ziyu Song ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Protein Kinase ◽  
Total Cholesterol ◽  
Protein Kinase A ◽  
Mitochondrial Biogenesis ◽  
Uncoupling Protein ◽  
Obese Mice ◽  
White Adipocytes ◽  
Beige Adipocytes ◽  
Kinase A

Background: Obesity is defined as an imbalance between energy intake and expenditure, and it is a serious risk factor of non-communicable diseases. Recently many studies have shown that promoting browning of white adipose tissue (WAT) to increase energy consumption has a great therapeutic potential for obesity. Sesamol, a lignan from sesame oil, had shown potential beneficial functions on obesity treatment. Objective: In this study, we used C57BL/6J mice and 3T3-L1 adipocytes to investigate the effects and the fundamental mechanisms of sesamol in enhancing the browning of white adipocytes to ameliorate obesity. Methods: Sixteen-week-old C57BL/6J male mice were fed high-fat diet (HFD) for 8 weeks to establish the obesity models. Half of the obese mice were administered with sesamol (100 mg/kg body weight [b.w.]/day [d] by gavage for another 8 weeks. Triacylglycerol (TG) and total cholesterol assay kits were used to quantify serum TG and total cholesterol (TC). Oil red O staining was used to detect lipid droplet in vitro. Mito-Tracker Green was used to detect the mitochondrial content. Quantitative reverse transcription-polymerase chain reaction (RT-PCR) was used to detect the levels of beige-specific genes. Immunoblotting was used to detect the proteins involved in beige adipocytes formation. Results: Sesamol decreased the content of body fat and suppressed lipid accumulation in HFD-induced obese mice. In addition, sesamol significantly upregulated uncoupling protein-1 (UCP1) protein in adipose tissue. Further research found that sesamol also significantly activated the browning program in mature 3T3-L1 adipocytes, manifested by the increase in beige-specific genes and proteins. Moreover, sesamol greatly increased mitochondrial biogenesis, as proved by the upregulated protein levels of mitochondrial biogenesis, and the inhibition of the proteins associated with mitophagy. Furthermore, β3-adrenergic receptor (β3-AR), protein kinase A-C (PKA-C) and Phospho-protein kinase A (p-PKA) substrate were elevated by sesamol, and these effects were abolished by the pretreatment of antagonists β3-AR. Conclusion: Sesamol promoted browning of white adipocytes by inducing mitochondrial biogenesis and inhibiting mitophagy through the β3-AR/PKA pathway. This preclinical data promised the potential to consider sesamol as a metabolic modulator of HFD-induced obesity.

scholarly journals The Role of Uncoupling Protein 1 in the Metabolism and Adiposity of RIIβ-Protein Kinase A-Deficient Mice

2004 ◽  
Vol 18 (9) ◽  
pp. 2302-2311 ◽  
Author(s):  
Michael A. Nolan ◽  
Maria A. Sikorski ◽  
G. Stanley McKnight
Keyword(s):  
Adipose Tissue ◽  
Oxygen Consumption ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
Uncoupling Protein ◽  
Mrna Level ◽  
Regulatory Subunit ◽  
Uncoupling Protein 1 ◽  
Brown Adipose ◽  
Kinase A

Abstract Mice lacking the RIIβ regulatory subunit of protein kinase A exhibit a 50% reduction in white adipose tissue stores compared with wild-type littermates and are resistant to diet-induced obesity. RIIβ−/− mice also have an increase in resting oxygen consumption along with a 4-fold increase in the brown adipose-specific mitochondrial uncoupling protein 1 (UCP1). In this study, we examined the basis for UCP1 induction and tested the hypothesis that the induced levels of UCP1 in RIIβ null mice are essential for the lean phenotype. The induction of UCP1 occurred at the protein but not the mRNA level and correlated with an increase in mitochondria in brown adipose tissue. Mice lacking both RIIβ and UCP1 (RIIβ−/−/Ucp1−/−) were created, and the key parameters of metabolism and body composition were studied. We discovered that RIIβ−/− mice exhibit nocturnal hyperactivity in addition to the increased oxygen consumption at rest. Disruption of UCP1 in RIIβ−/− mice reduced basal oxygen consumption but did not prevent the nocturnal hyperactivity. The double knockout animals also retained the lean phenotype of the RIIβ null mice, demonstrating that induction of UCP1 and increased resting oxygen consumption is not the cause of leanness in the RIIβ mutant mice.

scholarly journals Mutation of the RIIβ Subunit of Protein Kinase A Differentially Affects Lipolysis but Not Gene Induction in White Adipose Tissue

1999 ◽  
Vol 274 (51) ◽  
pp. 36281-36287 ◽  
Author(s):  
Josep V. Planas ◽  
David E. Cummings ◽  
Rejean L. Idzerda ◽  
G. Stanley McKnight
Keyword(s):  
Adipose Tissue ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
White Adipose Tissue ◽  
Gene Induction ◽  
Kinase A

cAMP-positive regulation of angiotensinogen gene expression and protein secretion in rat adipose tissue

2004 ◽  
Vol 286 (3) ◽  
pp. E434-E438 ◽  
Author(s):  
Valérie Serazin ◽  
Marie-Noelle Dieudonné ◽  
Mireille Morot ◽  
Philippe de Mazancourt ◽  
Yves Giudicelli
Keyword(s):  
Adipose Tissue ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
Protein Secretion ◽  
Intracellular Camp ◽  
Pathological State ◽  
Mrna Levels ◽  
Adrenergic Stimulation ◽  
Rat Adipose Tissue ◽  
Kinase A

The adipose renin-angiotensin system (RAS) has been assigned to participate in the control of adipose tissue development and in the pathogenesis of obesity-related hypertension. In adipose cells, the biological responses to β-adrenergic stimulation are mediated by an increase in intracellular cAMP. Because cAMP is known to promote adipogenesis and because an association exists between body fat mass, hypertension, and increased sympathetic stimulation, we examined the influence of cAMP on angiotensinogen (ATG) expression and secretion in rat adipose tissue. Exposure of primary cultured differentiated preadipocytes to the cAMP analog 8-bromoadenosine 3′,5′-cyclic monophosphate (8-BrcAMP) or cAMP-stimulating agents (forskolin and IBMX) results in a significant increase in ATG mRNA levels. In adipose tissue fragments, 8-BrcAMP also increases ATG mRNA levels and protein secretion, but not in the presence of the protein kinase A inhibitor H89. The addition of isoproterenol, known to stimulate the synthesis of intracellular cAMP via β-adrenoreceptors, had the same stimulatory effect on ATG expression and secretion. These results indicate that cAMP in vitro upregulates ATG expression and secretion in rat adipose tissue via the protein kinase A-dependent pathway. Further studies are required to determine whether this regulatory pathway is activated in human obesity, where increased sympathetic tone is frequently observed, and to elucidate the importance of adipose ATG to the elevated blood pressure observed in this pathological state.

Characterization of RIIβ and D-AKAP1 in differentiated adipocytes

2002 ◽  
Vol 282 (1) ◽  
pp. C205-C212 ◽  
Author(s):  
Archana Chaudhry ◽  
Chen Zhang ◽  
James G. Granneman
Keyword(s):  
Adipose Tissue ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
Immunocytochemical Analysis ◽  
Subcellular Compartments ◽  
Anchoring Proteins ◽  
Mitotracker Red ◽  
Kinase A

A-kinase anchoring proteins (AKAPs) have been proposed to regulate cAMP-dependent signaling in the cell by targeting RII subunits of protein kinase A (PKA) to specific subcellular compartments. RIIβ is the predominant PKA subtype in adipose tissue. In gel overlay assays of C3H/10T1/2 adipocytes and adipose tissue, RIIβ bound to several proteins including a prominent 132-kDa band, which was strongly induced upon differentiation of C3H/10T1/2 cells into adipocytes. Immunoblotting and nuclease protection analysis of C3H/10T1/2 cellular extracts identified this band as D-AKAP1/S-AKAP84, a putative AKAP. Immunocytochemical analysis of C3H/10T1/2 adipocytes revealed that most of D-AKAP1/S-AKAP84, but not RIIβ, was colocalized with a mitochondrial-selective dye, MitoTracker red. These findings were further confirmed in studies where D-AKAP1/ S-AKAP84, but not RIIβ, were localized in purified mitochondria made from C3H/10T1/2 adipocytes. Moreover, D-AKAP1, which is upregulated after differentiation, did not recruit RIIβto membrane fractions enriched in mitochondria. These results demonstrate that D-AKAP1/S-AKAP84 does not interact with PKA in differentiated C3H/10T1/2 adipocytes under the conditions tested.

scholarly journals The Gintonin-Enriched Fraction of Ginseng Regulates Lipid Metabolism and Browning via the cAMP-Protein Kinase a Signaling Pathway in Mice White Adipocytes

Biomolecules ◽  
2020 ◽  
Vol 10 (7) ◽  
pp. 1048
Author(s):  
Kippeum Lee ◽  
Heegu Jin ◽  
Sungwoo Chei ◽  
Hyun-Ji Oh ◽  
Sun-Hye Choi ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Fat Metabolism ◽  
Health Concern ◽  
Potential Treatment ◽  
Preventive Effect ◽  
Immunofluorescence Analysis ◽  
Major Health ◽  
White Adipocytes ◽  
Kinase A

Obesity is a major health concern and is becoming an increasingly serious societal problem worldwide. The browning of white adipocytes has received considerable attention because of its potential protective effect against obesity-related metabolic disease. The gintonin-enriched fraction (GEF) is a non-saponin, glycolipoprotein component of ginseng that is known to have neuroprotective and anti-inflammatory effects. However, the anti-obesity and browning effects of GEF have not been explored to date. Therefore, we aimed to determine whether GEF has a preventive effect against obesity. We differentiated 3T3-L1 cells and mouse primary subcutaneous adipocytes for 8 days in the presence or absence of GEF, and then measured the expression of intermediates in signaling pathways that regulate triglyceride (TG) synthesis and browning by Western blotting and immunofluorescence analysis. We found that GEF reduced lipid accumulation by reducing the expression of pro-adipogenic and lipogenic factors, and increased lipolysis and thermogenesis, which may be mediated by an increase in the phosphorylation of protein kinase A. These findings suggest that GEF may induce fat metabolism and energy expenditure in white adipocytes and therefore may represent a potential treatment for obesity.

scholarly journals Protein Kinase A Regulatory Subunits in Human Adipose Tissue: Decreased R2B Expression and Activity in Adipocytes From Obese Subjects

Diabetes ◽  
2008 ◽  
Vol 58 (3) ◽  
pp. 620-626 ◽  
Author(s):  
G. Mantovani ◽  
S. Bondioni ◽  
L. Alberti ◽  
L. Gilardini ◽  
C. Invitti ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
Human Adipose Tissue ◽  
Regulatory Subunits ◽  
Obese Subjects ◽  
Expression And Activity ◽  
Kinase A

Leptin-induced nitric oxide production in white adipocytes is mediated through PKA and MAP kinase activation

2005 ◽  
Vol 289 (2) ◽  
pp. C379-C387 ◽  
Author(s):  
Nadia Mehebik ◽  
Anne-Marie Jaubert ◽  
Dominique Sabourault ◽  
Yves Giudicelli ◽  
Catherine Ribière
Keyword(s):  
Nitric Oxide ◽  
Adipose Tissue ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
Protein Phosphatase ◽  
Plasma Levels ◽  
Mitogen Activated Protein Kinase ◽  
No Production ◽  
Tyrosine Kinase 2 ◽  
Kinase A

Leptin injection increases plasma levels of nitrites and/or nitrates, an index of nitric oxide (NO) production. Because plasma levels of NO are correlated with fat mass and because adipose tissue is the main source of leptin, it seems that adipose tissue plays a major role in NO release induced by leptin. Adipocytes express both leptin receptors and nitric oxide synthase (NOS; including the endothelial isoform, NOS III, and the inducible isoform, NOS II). In this study, we have demonstrated that physiological concentrations of leptin stimulate NOS activity in adipocytes. This effect of leptin is abolished by 1) AG490, an inhibitor of Janus tyrosine kinase 2/signal transducer and activator of transcription 3; 2) U0126, an inhibitor of mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (p42/p44 MAPK); and 3) N-[2-( p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide (H-89) or Rp diastereomer of adenosine 3′,5′-cyclic phosphorothioate, two inhibitors of protein kinase A, but not by wortmannin, an inhibitor of phosphatidylinositol 3-kinase. Immunoblotting studies have shown that leptin fails to activate Akt but increases p42/p44 MAPK phosphorylation, an effect that is prevented by U0126 but not by H-89. Furthermore, leptin induces NOS III phosphorylation at Ser1179and Thr497, but not when adipocytes are pretreated with H-89 or U0126. Finally, stimulation of adipocyte NOS activity by leptin is either unaltered when protein phosphatase 2A is inhibited by 1 nM okadaic acid or completely abolished when protein phosphatase 1 (PP1) activity is inhibited by 3 nM tautomycin, which supports a crucial role for PP1 in mediating this effect of leptin. On the whole, these experiments demonstrate that NOS activity is a novel target for leptin in adipocytes and that the leptin-induced NOS activity is at least in part the result of NOS III phosphorylations via both protein kinase A and p42/p44 MAPK activation. More generally, this study also leads to the hypothesis of NO as a potentially important factor for leptin signaling in adipocytes.

scholarly journals D-Mannitol Induces a Brown Fat-like Phenotype via a β3-Adrenergic Receptor-Dependent Mechanism

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 768
Author(s):  
Hui-Jeon Jeon ◽  
Dong Kyu Choi ◽  
JaeHeon Choi ◽  
Seul Lee ◽  
Heejin Lee ◽  
...  
Keyword(s):  
Body Weight ◽  
Adipose Tissue ◽  
Lipid Metabolism ◽  
Protein Kinase ◽  
White Adipose Tissue ◽  
Adrenergic Receptor ◽  
Uncoupling Protein ◽  
The Body ◽  
Brown Fat ◽  
White Adipocytes

The presence of brown adipocytes within white adipose tissue is associated with phenotypes that exhibit improved metabolism and proper body weight maintenance. Therefore, a variety of dietary agents that facilitate the browning of white adipocytes have been investigated. In this study, we screened a natural product library comprising 133 compounds with the potential to promote the browning of white adipocytes, and found that D-mannitol induces the browning of 3T3-L1 adipocytes by enhancing the expression of brown fat-specific genes and proteins, and upregulating lipid metabolism markers. D-mannitol also increased the phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase 1 (ACC), suggesting a possible role in lipolysis and fat oxidation. Moreover, an increase in the expression of genes associated with D-mannitol-induced browning was strongly correlated with the activation of the β3-adrenergic receptor as well as AMPK, protein kinase A (PKA), and PPARγ coactivator 1α (PGC1α). D-mannitol effectively reduced the body weight of mice fed a high-fat diet, and increased the expression of β1-oxidation and energy expenditure markers, such as Cidea, carnitine palmityl transferase 1 (CPT1), uncoupling protein 1 (UCP1), PGC1α, and acyl-coenzyme A oxidase (ACOX1) in the inguinal white adipose tissue. Our findings suggest that D-mannitol plays a dual regulatory role by inducing the generation of a brown fat-like phenotype and enhancing lipid metabolism. These results indicate that D-mannitol can function as an anti-obesity supplement.

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