• Journal of Nutrition and Health
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• 제57권2호
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• pp.171-184
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• 2024

Purpose: Although activating thermogenic adipocytes is a promising strategy to reduce the risk of obesity and related metabolic disorders, emerging evidence suggests that it is difficult to induce adipocyte thermogenesis in obesity. Therefore, this study aimed to investigate the regulation of adipocyte thermogenesis in diet-induced obesity. Methods: Adipose progenitor cells were isolated from the white and brown adipose tissues of control diet (CD) or high-fat diet (HFD) fed mice, and fully differentiated white and brown adipocytes were treated with β-agonists or 18-carbon fatty acids for β-adrenergic activation or peroxisome proliferator-activated receptor (PPAR) activation. Results: Compared to the CD-fed mice, the expression of uncoupling protein 1 (Ucp1) was lower in the white adipose tissue of the HFD-fed mice; however, this was not observed in the brown adipose tissue. The expression of peroxisome proliferator-activated receptor gamma (Pparg) was lower in the brown adipose progenitor cells isolated from HFD-fed mice than in those isolated from the CD-fed mice. Norepinephrine (NE) treatment exerted lesser effect on peroxisome proliferator-activated receptor-γ coactivator (Pgc1a) upregulation in white adipocytes derived from HFD-fed mice than those derived from CD-fed mice. Regardless which 18-carbon fatty acids were treated, the expression levels of thermogenic genes including Ucp1, Pgc1a, and positive regulatory domain zinc finger region protein 16 (Prdm16) were higher in the white adipocytes derived from HFD-fed mice. Oleic acid (OLA) and γ-linolenic acid (GLA) upregulated Pgc1a expression in white adipocytes derived from HFD-fed mice. Brown adipocytes derived from HFD-fed mice had higher expression levels of Pgc1a and Prdm16 compared to their counterparts. Conclusion: These results indicate that diet-induced obesity may downregulate brown adipogenesis and NE-induced thermogenesis in white adipocytes. Also, HFD feeding may induce thermogenic gene expression in white and brown primary adipocytes, and OLA and GLA could augment the expression levels.

• BMB Reports
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• 제54권8호
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• pp.419-424
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• 2021

Cold-induced norepinephrine activates β3-adrenergic receptors (β3-AR) to stimulate the kinase cascade and cAMP-response element-binding protein, leading to the induction of thermogenic gene expression including uncoupling protein 1 (Ucp1). Here, we showed that stimulation of the β3-AR by its agonists isoproterenol and CL316,243 in adipocytes increased the expression of Ucp1 and Heme Oxygenase 1 (Hmox1), the principal Nrf2 target gene, suggesting the functional interaction of Nrf2 with β3-AR signaling. The activation of Nrf2 by tert-butylhydroquinone and reactive oxygen species (ROS) production by glucose oxidase induced both Ucp1 and Hmox1 expression. The increased expression of Ucp1 and Hmox1 was significantly reduced in the presence of a Nrf2 chemical inhibitor or in Nrf2-deleted (knockout) adipocytes. Furthermore, Nrf2 directly activated the Ucp1 promoter, and this required DNA regions located at -3.7 and -2.0 kb of the transcription start site. The CL316,243-induced Ucp1 expression in adipocytes and oxygen consumption in obese mice were partly compromised in the absence of Nrf2 expression. These data provide additional insight into the role of Nrf2 in β3-AR-mediated Ucp1 expression and energy expenditure, further highlighting the utility of Nrf2-mediated thermogenic stimulation as a therapeutic approach to diet-induced obesity.

• BMB Reports
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• 제53권3호
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• pp.142-147
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• 2020

Lipid accumulation in white adipose tissue is the key contributor to the obesity and orchestrates numerous metabolic health problems such as type 2 diabetes, hypertension, atherosclerosis, and cancer. Nonetheless, the prevention and treatment of obesity are still inadequate. Recently, scientists found that brown adipose tissue (BAT) in adult humans has functions that are diametrically opposite to those of white adipose tissue and that BAT holds promise for a new strategy to counteract obesity. In this study, we evaluated the potential of sinapic acid (SA) to promote the thermogenic program and lipolysis in BAT. SA treatment of brown adipocytes induced the expression of brown-adipocyte activation-related genes such as Ucp1, Pgc-1α, and Prdm16. Furthermore, structural analysis and western blot revealed that SA upregulates protein kinase A (PKA) phosphorylation with competitive inhibition by a pan-PKA inhibitor, H89. SA binds to the adenosine triphosphate (ATP) site on the PKA catalytic subunit where H89 binds specifically. PKA-cat-α1 gene-silencing experiments confirmed that SA activates the thermogenic program via a mechanism involving PKA and cyclic AMP response element-binding protein (CREB) signaling. Moreover, SA treatment promoted lipolysis via a PKA/p38-mediated pathway. Our findings may allow us to open a new avenue of strategies against obesity and need further investigation.

• Journal of Ginseng Research
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• 제43권4호
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• pp.589-599
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• 2019

Background: Panax ginseng Meyer is known as a conventional herbal medicine, and ginsenoside Rg1, a steroid glycoside, is one of its components. Although Rg1 has been proved to have an antiobesity effect, the mechanism of this effect and whether it involves adipose browning have not been elucidated. Methods: 3T3-L1 and subcutaneous white adipocytes from mice were used to access the thermogenic effect of Rg1. Adipose mitochondria and uncoupling protein 1 (UCP1) expression were analyzed by immunofluorescence. Protein level and mRNA of UCP1 were also evaluated by Western blotting and realtime polymerase chain reaction, respectively. Results: Rg1 dramatically enhanced expression of brown adipocyte-especific markers, such as UCP1 and fatty acid oxidation genes, including carnitine palmitoyltransferase 1. In addition, it modulated lipid metabolism, activated 5' adenosine monophosphate (AMP)-activated protein kinase, and promoted lipid droplet dispersion. Conclusions: Rg1 increases UCP1 expression and mitochondrial biogenesis in 3T3-L1 and subcutaneous white adipose cells isolated from C57BL/6 mice. We suggest that Rg1 exerts its antiobesity effects by promoting adipocyte browning through activation of the AMP-activated protein kinase pathway.

• Molecules and Cells
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• 제41권10호
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• pp.900-908
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• 2018

Insulin resistance is closely associated with metabolic diseases such as type 2 diabetes, dyslipidemia, hypertension and atherosclerosis. Thiazolidinediones (TZDs) have been developed to ameliorate insulin resistance by activation of peroxisome proliferator-activated receptor (PPAR) ${\gamma}$. Although TZDs are synthetic ligands for $PPAR{\gamma}$, metabolic outcomes of each TZD are different. Moreover, there are lack of head-to-head comparative studies among TZDs in the aspect of metabolic outcomes. In this study, we analyzed the effects of three TZDs, including lobeglitazone (Lobe), rosiglitazone (Rosi), and pioglitazone (Pio) on metabolic and thermogenic regulation. In adipocytes, Lobe more potently stimulated adipogenesis and insulin-dependent glucose uptake than Rosi and Pio. In the presence of pro-inflammatory stimuli, Lobe efficiently suppressed expressions of pro-inflammatory genes in macrophages and adipocytes. In obese and diabetic db/db mice, Lobe effectively promoted insulin-stimulated glucose uptake and suppressed pro-inflammatory responses in epididymal white adipose tissue (EAT), leading to improve glucose intolerance. Compared to other two TZDs, Lobe enhanced beige adipocyte formation and thermogenic gene expression in inguinal white adipose tissue (IAT) of lean mice, which would be attributable to cold-induced thermogenesis. Collectively, these comparison data suggest that Lobe could relieve insulin resistance and enhance thermogenesis at low-concentration conditions where Rosi and Pio are less effective.

• Journal of Applied Biological Chemistry
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• 제66권
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• pp.186-196
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• 2023

Dyglomera^® is an aqueous ethanol extract derived from the fruit and pods of Dichrostachys glomerata. A previous study has revealed that Dyglomera regulates adipogenesis and lipolysis by modulating AMP-activated protein kinase (AMPK) phosphorylation and increased expression levels of lipolysis-related proteins in white adipose tissue of high fat diet-induced mice and 3T3-L1 adipocyte cells. To further investigate mechanisms of Dyglomera, additional studies were performed using 3T3-L1 cells. Results revealed that Dyglomera downregulated adipogenesis by inhibiting the protein kinase B/mammalian target of rapamycin signaling pathway and reconfirmed that it downregulated gene expression levels of proliferator-activated receptor (PPAR)-γ, CCAAT enhancer binding protein α, sterol-regulation element-binding protein-1c. Dyglomera also reduced adipokines such as tumor necrosis factor alpha, interleukin-1β, and interleukin 6 by regulating leptin expression. Moreover, Dyglomera promoted beige-and-brown adipocyte-related phenotypes and regulated metabolism by increasing mitochondrial number and expression levels of genes such as T-box protein 1, transmembrane protein 26, PR domain 16, and cluster of differentiation 40 as well as thermogenic factors such as uncoupling protein 1, proliferator-activated receptor-gamma co-activator-1α, Sirtuin 1, and PPARα through AMPK activation. Thus, Dyglomera not only can inhibit adipogenesis, but also can promote lipolysis and thermogenesis and regulate metabolism by affecting adipokine secretion from 3T3-L1 adipocytes.