scholarly journals SIRT3 Acts as a Positive Autophagy Regulator to Promote Lipid Mobilization in Adipocytes via Activating AMPK

2020 ◽  
Vol 21 (2) ◽  
pp. 372 ◽  
Author(s):  
Tian Zhang ◽  
Jingxin Liu ◽  
Qiang Tong ◽  
Ligen Lin
Keyword(s):  
Lipid Droplets ◽  
Metabolic Dysfunction ◽  
Lipid Mobilization ◽  
Promising Therapeutic Target ◽  
Treatment Of Obesity ◽  
Amp Activated Protein Kinase ◽  
Chaperone Mediated Autophagy ◽  
Perilipin 1 ◽  
Sirt3 Expression ◽  
Excessive Accumulation

Obesity is increasing at an alarming rate worldwide, which is characterized by the excessive accumulation of triglycerides in adipocytes. Emerging evidence has demonstrated that macroautophagy and chaperone-mediated autophagy (CMA) regulate lipid mobilization and play a key role in energy balance. Sirtuin 3 (SIRT3) is an NAD+-dependent deacetylase, which is important in regulating macroautophagy and lipid metabolism. It is still unknown whether SIRT3 modulates macroautophagy and CMA in adipocytes. The current study found that macroautophagy was dynamically regulated during 3T3-L1 adipocyte differentiation, which coincided with SIRT3 expression. In mature adipocytes, overexpression of SIRT3 activated macroautophagy, mainly on lipid droplets (LDs), through activating the AMP-activated protein kinase (AMPK)-unc-51-like kinase 1 (ULK1) pathway, which in turn resulting in smaller LD size and reduced lipid accumulation. Moreover, SIRT3 overexpression induced the formation of perilipin-1 (PLN1)-heat shock cognate 71 kDa protein (HSC70)-lysosome-associated membrane protein 2 (LAMP2) complex, to activate CMA and cause the instability of LDs in adipocytes. In summary, we found SIRT3 is a positive regulator of macroautophagy and CMA in adipocytes, which might be a promising therapeutic target for treatment of obesity and its related metabolic dysfunction.

scholarly journals AMPK as a mediator of hormonal signalling

2009 ◽  
Vol 44 (2) ◽  
pp. 87-97 ◽  
Author(s):  
Chung Thong Lim ◽  
Blerina Kola ◽  
Márta Korbonits
Keyword(s):  
Protein Synthesis ◽  
Fatty Acid ◽  
Metabolic Disorders ◽  
Energy Homeostasis ◽  
Metabolic Effects ◽  
Whole Body ◽  
Acid Oxidation ◽  
Treatment Of Obesity ◽  
Amp Activated Protein Kinase ◽  
Hormonal Signalling

AMP-activated protein kinase (AMPK) is a key molecular player in energy homeostasis at both cellular and whole-body levels. AMPK has been shown to mediate the metabolic effects of hormones such as leptin, ghrelin, adiponectin, glucocorticoids and insulin as well as cannabinoids. Generally, activated AMPK stimulates catabolic pathways (glycolysis, fatty acid oxidation and mitochondrial biogenesis) and inhibits anabolic pathways (gluconeogenesis, glycogen, fatty acid and protein synthesis), and has a direct appetite-regulating effect in the hypothalamus. Drugs that activate AMPK, namely metformin and thiazolidinediones, are often used to treat metabolic disorders. Thus, AMPK is now recognised as a potential target for the treatment of obesity and associated co-morbidities.

scholarly journals Angiotensin AT1 receptor antagonism by losartan stimulates adipocyte browning via induction of apelin

2020 ◽  
Vol 295 (44) ◽  
pp. 14878-14892
Author(s):  
Dong Young Kim ◽  
Mi Jin Choi ◽  
Tae Kyung Ko ◽  
Na Hyun Lee ◽  
Ok-Hee Kim ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Protein Kinase ◽  
Metabolic Disorders ◽  
Angiotensin Ii Receptor ◽  
Adeno Associated Virus ◽  
Receptor Antagonism ◽  
White Adipocytes ◽  
Treatment Of Obesity ◽  
Amp Activated Protein Kinase

Adipocyte browning appears to be a potential therapeutic strategy to combat obesity and related metabolic disorders. Recent studies have shown that apelin, an adipokine, stimulates adipocyte browning and has negative cross-talk with angiotensin II receptor type 1 (AT1 receptor) signaling. Here, we report that losartan, a selective AT1 receptor antagonist, induces browning, as evidenced by an increase in browning marker expression, mitochondrial biogenesis, and oxygen consumption in murine adipocytes. In parallel, losartan up-regulated apelin expression, concomitant with increased phosphorylation of protein kinase B and AMP-activated protein kinase. However, the siRNA-mediated knockdown of apelin expression attenuated losartan-induced browning. Angiotensin II cotreatment also inhibited losartan-induced browning, suggesting that AT1 receptor antagonism-induced activation of apelin signaling may be responsible for adipocyte browning induced by losartan. The in vivo browning effects of losartan were confirmed using both C57BL/6J and ob/ob mice. Furthermore, in vivo apelin knockdown by adeno-associated virus carrying–apelin shRNA significantly inhibited losartan-induced adipocyte browning. In summary, these data suggested that AT1 receptor antagonism by losartan promotes the browning of white adipocytes via the induction of apelin expression. Therefore, apelin modulation may be an effective strategy for the treatment of obesity and its related metabolic disorders.

scholarly journals O-GlcNAc transferase inhibits visceral fat lipolysis and promotes diet-induced obesity

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Yunfan Yang ◽  
Minnie Fu ◽  
Min-Dian Li ◽  
Kaisi Zhang ◽  
Bichen Zhang ◽  
...  
Keyword(s):  
Visceral Fat ◽  
Hexosamine Biosynthetic Pathway ◽  
Visceral Fat Accumulation ◽  
Diet Induced Obesity ◽  
Treatment Of Obesity ◽  
High Level ◽  
Glcnac Transferase ◽  
Metabolically Unhealthy Obesity ◽  
Unique Potential ◽  
Perilipin 1

AbstractExcessive visceral fat accumulation is a primary risk factor for metabolically unhealthy obesity and related diseases. The visceral fat is highly susceptible to the availability of external nutrients. Nutrient flux into the hexosamine biosynthetic pathway leads to protein posttranslational modification by O-linked β-N-acetylglucosamine (O-GlcNAc) moieties. O-GlcNAc transferase (OGT) is responsible for the addition of GlcNAc moieties to target proteins. Here, we report that inducible deletion of adipose OGT causes a rapid visceral fat loss by specifically promoting lipolysis in visceral fat. Mechanistically, visceral fat maintains a high level of O-GlcNAcylation during fasting. Loss of OGT decreases O-GlcNAcylation of lipid droplet-associated perilipin 1 (PLIN1), which leads to elevated PLIN1 phosphorylation and enhanced lipolysis. Moreover, adipose OGT overexpression inhibits lipolysis and promotes diet-induced obesity. These findings establish an essential role for OGT in adipose tissue homeostasis and indicate a unique potential for targeting O-GlcNAc signaling in the treatment of obesity.

scholarly journals Adiponectin Exerts Peripheral Inhibitory Effects on the Mouse Gastric Smooth Muscle through the AMPK Pathway

2020 ◽  
Vol 21 (24) ◽  
pp. 9617
Author(s):  
Eglantina Idrizaj ◽  
Rachele Garella ◽  
Silvia Nistri ◽  
Alfonso Dell’Accio ◽  
Emanuele Cassioli ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Multidisciplinary Approach ◽  
Gastric Fundus ◽  
Inhibitory Effects ◽  
Immunofluorescence Analysis ◽  
Synthesis Inhibitor ◽  
Ampk Signaling ◽  
Gastric Smooth Muscle ◽  
Treatment Of Obesity ◽  
Amp Activated Protein Kinase

Some adipokines, such as adiponectin (ADPN), other than being implicated in the central regulation of feeding behavior, may influence gastric motor responses, which are a source of peripheral signals that also influence food intake. The present study aims to elucidate the signaling pathways through which ADPN exerts its actions in the mouse gastric fundus. To this purpose, we used a multidisciplinary approach. The mechanical results showed that ADPN caused a decay of the strip basal tension, which was abolished by the nitric oxide (NO) synthesis inhibitor, L-NG-nitro arginine (L-NNA). The electrophysiological experiments confirmed that all ADPN effects were abolished by L-NNA, except for the reduction of Ca2+ current, which was instead prevented by the inhibitor of AMP-activated protein kinase (AMPK), dorsomorphin. The activation of the AMPK signaling by ADPN was confirmed by immunofluorescence analysis, which also revealed the ADPN R1 receptor (AdipoR1) expression in glial cells of the myenteric plexus. In conclusion, our results indicate that ADPN exerts an inhibitory action on the gastric smooth muscle by acting on AdipoR1 and involving the AMPK signaling pathway at the peripheral level. These findings provide novel bases for considering AMPK as a possible pharmacologic target for the potential treatment of obesity and eating disorders.

scholarly journals Characterization and Functions of Protease-Activated Receptor 2 in Obesity, Diabetes, and Metabolic Syndrome: A Systematic Review

2016 ◽  
Vol 2016 ◽  
pp. 1-16 ◽  
Author(s):  
Satomi Kagota ◽  
Kana Maruyama ◽  
John J. McGuire
Keyword(s):  
Systematic Review ◽  
Metabolic Syndrome ◽  
Endothelial Dysfunction ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Cell Surface Receptor ◽  
Metabolic Dysfunction ◽  
The Face ◽  
Surface Receptor ◽  
Treatment Of Obesity

Proteinase-activated receptor 2 (PAR2) is a cell surface receptor activated by serine proteinases or specific synthetic compounds. Interest in PAR2 as a pharmaceutical target for various diseases is increasing. Here we asked two questions relevant to endothelial dysfunction and diabetes: How is PAR2 function affected in blood vessels? What role does PAR2 have in promoting obesity, diabetes, and/or metabolic syndrome, specifically via the endothelium and adipose tissues? We conducted a systematic review of the published literature in PubMed and Scopus (July 2015; search terms: par2, par-2, f2lr1, adipose, obesity, diabetes, and metabolic syndrome). Seven studies focused on PAR2 and vascular function. The obesity, diabetes, or metabolic syndrome animal models differed amongst studies, but each reported that PAR2-mediated vasodilator actions were preserved in the face of endothelial dysfunction. The remaining studies focused on nonvascular functions and provided evidence supporting the concept that PAR2 activation promoted obesity. Key studies showed that PAR2 activation regulated cellular metabolism, and PAR2 antagonists inhibited adipose gain and metabolic dysfunction in rats. We conclude that PAR2 antagonists for treatment of obesity indeed show early promise as a therapeutic strategy; however, endothelial-specific PAR2 functions, which may offset mechanisms that produce vascular dysfunction in diabetes, warrant additional study.

scholarly journals OPA1-anchored PKA phosphorylates perilipin 1 on S522 and S497 in adipocytes differentiated from human adipose stem cells

2018 ◽  
Vol 29 (12) ◽  
pp. 1487-1501 ◽  
Author(s):  
Marie Rogne ◽  
Dinh-Toi Chu ◽  
Thomas M. Küntziger ◽  
Maria-Niki Mylonakou ◽  
Philippe Collas ◽  
...  
Keyword(s):  
Stem Cells ◽  
Lipid Droplets ◽  
Protein Targeting ◽  
Adipose Stem Cells ◽  
Adrenergic Control ◽  
Anchoring Protein ◽  
Adipocytic Differentiation ◽  
First Time ◽  
Human Adipose Stem Cells ◽  
Perilipin 1

Optic atrophy 1 (OPA1) is the A-kinase anchoring protein targeting the pool of protein kinase A (PKA) responsible for perilipin 1 phosphorylation, a gatekeeper for lipolysis. However, the involvement of OPA1-bound PKA in the downstream regulation of lipolysis is unknown. Here we show up-regulation and relocation of OPA1 from mitochondria to lipid droplets during adipocytic differentiation of human adipose stem cells. We employed various biochemical and immunological approaches to demonstrate that OPA1-bound PKA phosphorylates perilipin 1 at S522 and S497 on lipolytic stimulation. We show that the first 30 amino acids of OPA1 are essential for its lipid droplet localization as is OMA1-dependent processing. Finally, our results indicate that presence of OPA1 is necessary for lipolytic phosphorylation of downstream targets. Our results show for the first time, to our knowledge, how OPA1 mediates adrenergic control of lipolysis in human adipocytes by regulating phosphorylation of perilipin 1.

scholarly journals LIPID DROPLET SIGNALING IN METABOLIC HEALTH AND AGING

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. 456-456
Author(s):  
Charles Najt
Keyword(s):  
Fatty Acid ◽  
Energy Metabolism ◽  
Lipid Droplets ◽  
Metabolic Dysfunction ◽  
Critical Pathways ◽  
Cellular Energy ◽  
Cellular Energy Metabolism ◽  
Eicosanoid Production ◽  
Key Players

Abstract Lipid droplets (LDs) are neutral lipid rich organelles involved in lipid storage, fatty acid trafficking, and signaling. Emerging evidence from our laboratory and others suggests that the specific LD resident proteins couple/uncouple cells and tissues from inflammation and metabolic dysfunction. However, the mechanism by which LD proteins influences these critical pathways remains unknown. We will present data delving into the role of LD proteins Perilipin (PLIN) 2 and 5 in balancing cellular energy metabolism, mitochondrial function, and inflammation. Data will be presented defining novel mechanisms through which PLIN2 orchestrates eicosanoid production as a means to promote inflammation. We will contrast these findings to PLIN5, which uncouples LD accumulation from metabolic dysfunction and inflammation, in part due to its promotion of SIRT1 signaling. Overall, these studies will highlight a crucial role of LD metabolism and signaling in regulating cellular energy homeostatic processes known to be key players in governing healthspan.

scholarly journals Fluvastatin Sodium Ameliorates Obesity through Brown Fat Activation

2019 ◽  
Vol 20 (7) ◽  
pp. 1622 ◽  
Author(s):  
Na Yin ◽  
Hanlin Zhang ◽  
Rongcai Ye ◽  
Meng Dong ◽  
Jun Lin ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Large Scale ◽  
Body Weight Gain ◽  
Uncoupling Protein ◽  
Mice Model ◽  
Subcutaneous White Adipose Tissue ◽  
Promising Therapeutic Target ◽  
Brown Adipose ◽  
Treatment Of Obesity ◽  
Coa Reductase

Brown adipose tissue (BAT), an organ that burns energy through uncoupling thermogenesis, is a promising therapeutic target for obesity. However, there are still no safe anti-obesity drugs that target BAT in the market. In the current study, we performed large scale screening of 636 compounds which were approved by Food and Drug Administration (FDA) to find drugs that could significantly increase uncoupling protein 1 (UCP1) mRNA expression by real-time PCR. Among those UCP1 activators, most of them were antibiotics or carcinogenic compounds. We paid particular attention to fluvastatin sodium (FS), because as an inhibitor of the cellular hydroxymethyl glutaryl coenzyme A (HMG-CoA) reductase, FS has already been approved for treatment of hypercholesteremia. We found that in the cellular levels, FS treatment significantly increased UCP1 expression and BAT activity in human brown adipocytes. Consistently, the expression of oxidative phosphorylation-related genes was significantly increased upon FS treatment without differences in adipogenic gene expression. Furthermore, FS treatment resisted to high-fat diet (HFD)-induced body weight gain by activating BAT in the mice model. In addition, administration of FS significantly increased energy expenditure, improved glucose homeostasis and ameliorated hepatic steatosis. Furthermore, we reveal that FS induced browning in subcutaneous white adipose tissue (sWAT) known to have a beneficial effect on energy metabolism. Taken together, our results clearly demonstrate that as an effective BAT activator, FS may have great potential for treatment of obesity and related metabolic disorders.

scholarly journals KDM4B protects against obesity and metabolic dysfunction

2018 ◽  
Vol 115 (24) ◽  
pp. E5566-E5575 ◽  
Author(s):  
Yingduan Cheng ◽  
Quan Yuan ◽  
Laurent Vergnes ◽  
Xin Rong ◽  
Ji Youn Youn ◽  
...  
Keyword(s):  
Critical Role ◽  
Metabolic Dysfunction ◽  
Adipose Tissues ◽  
Adaptive Thermogenesis ◽  
Metabolic Genes ◽  
Liver And Pancreas ◽  
Normal Body Weight ◽  
Treatment Of Obesity ◽  
Lysine Demethylase

Although significant progress has been made in understanding epigenetic regulation of in vitro adipogenesis, the physiological functions of epigenetic regulators in metabolism and their roles in obesity remain largely elusive. Here, we report that KDM4B (lysine demethylase 4B) in adipose tissues plays a critical role in energy balance, oxidation, lipolysis, and thermogenesis. Loss of KDM4B in mice resulted in obesity associated with reduced energy expenditure and impaired adaptive thermogenesis. Obesity in KDM4B-deficient mice was accompanied by hyperlipidemia, insulin resistance, and pathological changes in the liver and pancreas. Adipocyte-specific deletion of Kdm4b revealed that the adipose tissues were the main sites for KDM4B antiobesity effects. KDM4B directly controlled the expression of multiple metabolic genes, including Ppargc1a and Ppara. Collectively, our studies identify KDM4B as an essential epigenetic factor for the regulation of metabolic health and maintaining normal body weight in mice. KDM4B may provide a therapeutic target for treatment of obesity.

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