Sustained mitochondrial biogenesis is essential to maintain caloric restriction-induced beige adipocytes

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.

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MiR-494-3p regulates mitochondrial biogenesis and thermogenesis through PGC1-α signalling in beige adipocytes

Scientific Reports ◽

10.1038/s41598-018-33438-3 ◽

2018 ◽

Vol 8 (1) ◽

Cited By ~ 24

Author(s):

Mengistu Lemecha ◽

Katsutaro Morino ◽

Takeshi Imamura ◽

Hirotaka Iwasaki ◽

Natsuko Ohashi ◽

...

Keyword(s):

Mitochondrial Biogenesis ◽

Beige Adipocytes

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Moderate maternal caloric restriction affects mitochondrial biogenesis and redox homeostasis in the pups’ hypothalamus

Free Radical Biology and Medicine ◽

10.1016/j.freeradbiomed.2017.04.111 ◽

2017 ◽

Vol 108 ◽

pp. S26

Author(s):

Vinícius Stone ◽

Pauline Maciel August ◽

Caroline Peres Klein ◽

Mariana Scortegagna Crestani ◽

André Brum Saccomori ◽

...

Keyword(s):

Caloric Restriction ◽

Mitochondrial Biogenesis ◽

Redox Homeostasis

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Caloric Restriction and the Nutrient-Sensing PGC-1αin Mitochondrial Homeostasis: New Perspectives in Neurodegeneration

International Journal of Cell Biology ◽

10.1155/2012/759583 ◽

2012 ◽

Vol 2012 ◽

pp. 1-11 ◽

Cited By ~ 15

Author(s):

Daniele Lettieri Barbato ◽

Sara Baldelli ◽

Beatrice Pagliei ◽

Katia Aquilano ◽

Maria Rosa Ciriolo

Keyword(s):

Neurodegenerative Diseases ◽

Caloric Restriction ◽

Mitochondrial Biogenesis ◽

Dietary Intervention ◽

Current Knowledge ◽

Nutritional Intervention ◽

Nutrient Sensing ◽

Mitochondrial Activity ◽

Beneficial Effects ◽

And Function

Mitochondrial activity progressively declines during ageing and in many neurodegenerative diseases. Caloric restriction (CR) has been suggested as a dietary intervention that is able to postpone the detrimental aspects of aging as it ameliorates mitochondrial performance. This effect is partially due to increased mitochondrial biogenesis. The nutrient-sensing PGC-1αis a transcriptional coactivator that promotes the expression of mitochondrial genes and is induced by CR. It is believed that many of the mitochondrial and metabolic benefits of CR are due to increased PGC-1αactivity. The increase of PGC-1αis also positively linked to neuroprotection and its decrement has been involved in the pathogenesis of many neurodegenerative diseases. This paper aims to summarize the current knowledge about the role of PGC-1αin neuronal homeostasis and the beneficial effects of CR on mitochondrial biogenesis and function. We also discuss how PGC-1α-governed pathways could be used as target for nutritional intervention to prevent neurodegeneration.

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Srebp-1c/Fgf21/Pgc-1α Axis Regulated by Leptin Signaling in Adipocytes—Possible Mechanism of Caloric Restriction-Associated Metabolic Remodeling of White Adipose Tissue

Nutrients ◽

10.3390/nu12072054 ◽

2020 ◽

Vol 12 (7) ◽

pp. 2054

Author(s):

Masaki Kobayashi ◽

Seira Uta ◽

Minami Otsubo ◽

Yusuke Deguchi ◽

Ryoma Tagawa ◽

...

Keyword(s):

Adipose Tissue ◽

Caloric Restriction ◽

White Adipose Tissue ◽

Mitochondrial Biogenesis ◽

Molecular Mechanisms ◽

Whole Body ◽

Fibroblast Growth Factor 21 ◽

Leptin Signaling ◽

Age Related ◽

Metabolic Remodeling

Caloric restriction (CR) improves whole body metabolism, suppresses age-related pathophysiology, and extends lifespan in rodents. Metabolic remodeling, including fatty acid (FA) biosynthesis and mitochondrial biogenesis, in white adipose tissue (WAT) plays an important role in the beneficial effects of CR. We have proposed that CR-induced mitochondrial biogenesis in WAT is mediated by peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), which is transcriptionally regulated by sterol regulatory element-binding protein 1c (SREBP-1c), a master regulator of FA biosynthesis. We have also proposed that the CR-associated upregulation of SREBP-1 and PGC-1α might result from the attenuation of leptin signaling and the upregulation of fibroblast growth factor 21 (FGF21) in WAT. However, the detailed molecular mechanisms remain unclear. Here, we interrogate the regulatory mechanisms involving leptin signaling, SREBP-1c, FGF21, and PGC-1α using Srebp-1c knockout (KO) mice, mouse embryonic fibroblasts, and 3T3-L1 adipocytes, by altering the expression of SREBP-1c or FGF21. We show that a reduction in leptin signaling induces the expression of proteins involved in FA biosynthesis and mitochondrial biogenesis via SREBP-1c in adipocytes. The upregulation of SREBP-1c activates PGC-1α transcription via FGF21, but it is unlikely that the FGF21-associated upregulation of PGC-1α expression is a predominant contributor to mitochondrial biogenesis in adipocytes.

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Caloric restriction reduces sympathetic activity similar to beta-blockers but conveys additional mitochondrio-protective effects in aged myocardium

Scientific Reports ◽

10.1038/s41598-021-81438-7 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Bernd Niemann ◽

Ling Li ◽

Andreas Simm ◽

Nicole Molenda ◽

Jens Kockskämper ◽

...

Keyword(s):

Blood Pressure ◽

Heart Rate ◽

Caloric Restriction ◽

Mitochondrial Biogenesis ◽

Sympathetic Activity ◽

Systolic Function ◽

Beta Blockers ◽

Left Ventricular ◽

Lv Function ◽

Protective Effects

AbstractIncreased activation of sympathetic nervous system contributes to congestive heart failure (CHF) progression, and inhibition of sympathetic overactivation by beta-blockers is successful in CHF patients. Similarly, caloric restriction (CR) reduces sympathetic activity but mediates additional effects. Here, we compared the cardiac effects of CR (− 40% kcal, 3 months) with beta-blocker therapy (BB), diuretic medication (DF) or control diet in 18-months-old Wistar rats. We continuously recorded blood pressure, heart rate, body temperature and activity with telemetric devices and analysed cardiac function, activated signalling cascades and markers of apoptosis and mitochondrial biogenesis. During our study, left ventricular (LV) systolic function improved markedly (CR), mildly (BB) or even deteriorated (DF; control). Diastolic function was preserved by CR and BB but impaired by DF. CR reduced blood pressure identical to DF and BB and heart rate identical to BB. Plasma noradrenaline was decreased by CR and BB but increased by DF. Only CR reduced LV oxidative damage and apoptosis, induced AMPK and Akt phosphorylation and increased mitochondrial biogenesis. Thus, additive to the reduction of sympathetic activity, CR achieves protective effects on mitochondria and improves LV function and ROS damage in aged hearts. CR mechanisms may provide additional therapeutic targets compared to traditional CHF therapy.

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Sinapic Acid Promotes Browning of 3T3-L1 Adipocytes via p38 MAPK/CREB Pathway

BioMed Research International ◽

10.1155/2020/5753623 ◽

2020 ◽

Vol 2020 ◽

pp. 1-8

Author(s):

In-Seon Bae ◽

Sang Hoon Kim

Keyword(s):

Oxidative Phosphorylation ◽

P38 Mapk ◽

Mitochondrial Biogenesis ◽

Uncoupling Protein ◽

Sinapic Acid ◽

Mitogen Activated Protein Kinase ◽

Marker Genes ◽

Peroxisome Proliferator ◽

High Concentration ◽

Beige Adipocytes

Sinapic acid is a plant-derived phenolic compound, which acts as an antioxidant, anticancer, and anti-inflammatory agent. Although sinapic acid is valuable in a variety of therapeutic applications, its role in the improvement of obesity-related metabolic disease is relatively unexplored. Brown-like adipocytes (beige adipocytes) are characterized by a high concentration of mitochondria and high expression of uncoupling protein 1 (UCP1), which has specific functions in energy expenditure and thermogenesis. This study assessed the browning effects of sinapic acid in 3T3-L1 adipocytes. We investigated the expression of beige marker genes in 3T3-L1 adipocytes treated with sinapic acid. Sinapic acid increased the expression of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and UCP1. Sinapic acid also promoted mitochondrial biogenesis by dose-dependently upregulating the oxygen consumption rate and enhancing the expression of representative subunits of oxidative phosphorylation complexes. In addition, treatment with p38 mitogen-activated protein kinase (MAPK) inhibitor and cAMP response element binding (CREB) inhibitor decreased the expressions of genes associated with thermogenesis, mitochondrial biogenesis, and oxidative phosphorylation. In summary, sinapic acid initiates browning 3T3-L1 adipocytes via the p38 MAPK/CREB signaling pathway. Thus, sinapic acid may have potential therapeutic implication in obesity.

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