scholarly journals FGF2 disruption enhances thermogenesis in brown and beige fat to protect against obesity and hepatic steatosis

2020 ◽  
Author(s):  
Haifang Li ◽  
Xinzhi Zhang ◽  
Cheng Huang ◽  
Huan Liu ◽  
Shuang Liu ◽  
...  
Keyword(s):  
Hepatic Steatosis ◽  
Adrenergic Stimulation ◽  
Erk Phosphorylation ◽  
Beige Adipocytes ◽  
Beige Fat ◽  
Ucp1 Expression ◽  
Cold Challenge ◽  
Potential Strategy ◽  
Pparγ Expression

ABSTRACTSince brown and beige fat expend energy in the form of heat via non-shivering thermogenesis, identifying key regulators of thermogenic functions represents a major goal for development of potential therapeutic avenues for obesity and associated disorders. Here, we identified fibroblast growth factor 2 (FGF2) as a novel thermogenic regulator. FGF2 gene disruption resulted in increased thermogenic capability in both brown and beige fat, which was supported by increased UCP1 expression, enhanced respiratory exchange ratio, and elevated thermogenic potential under cold challenge or β-adrenergic stimulation. Thus, deletion of FGF2 protected mice from high fat-induced obesity and hepatic steatosis. Mechanistically, FGF2 acts in autocrine/paracrine fashions in vitro. Exogenous FGF2 supplementation inhibits both PGC-1α and PPARγ expression through ERK phosphorylation, thereby limiting PGC-1α/PPARγ interactions, and leading to suppression of UCP1 expression and thermogenic activity in brown and beige adipocytes. These findings suggest a viable potential strategy for use of FGF2-selective inhibitors in treatment of combating obesity and related disorders.

scholarly journals Betatrophin knockdown induces beiging and mitochondria biogenesis of white adipocytes

2020 ◽  
Vol 245 (1) ◽  
pp. 93-100 ◽  
Author(s):  
Zhe-Zhen Liao ◽  
Xiao-Yan Qi ◽  
Ya-Di Wang ◽  
Jiao-Yang Li ◽  
Qian-Qian Gu ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Ampk Signaling ◽  
White Adipocytes ◽  
Beige Adipocytes ◽  
Beige Fat ◽  
Mitochondria Biogenesis ◽  
Paracrine Actions ◽  
White Fat

Remodeling of energy-storing white fat into energy-consuming beige fat has led to a promising new approach to alleviate adiposity. Several studies have shown adipokines can induce white adipose tissue (WAT) beiging through autocrine or paracrine actions. Betatrophin, a novel adipokine, has been linked to energy expenditure and lipolysis but not clearly clarified. Here, we using high-fat diet-induced obesity to determine how betatrophin modulate beiging and adiposity. We found that betatrophin-knockdown mice displayed less white fat mass and decreased plasma TG and NEFA levels. Consistently, inhibition of betatrophin leads to the phenotype change of adipocytes characterized by increased mitochondria contents, beige adipocytes and mitochondria biogenesis-specific markers both in vivo and in vitro. Of note, blocking AMP-activated protein kinase (AMPK) signaling pathway is able to abolish enhanced beige-like characteristics in betatrophin-knockdown adipocytes. Collectively, downregulation of betatrophin induces beiging in white adipocytes through activation of AMPK signaling pathway. These processes suggest betatrophin as a latent therapeutic target for obesity.

scholarly journals Bola3 Regulates Beige Adipocyte Thermogenesis via Maintaining Mitochondrial Homeostasis and Lipolysis

2021 ◽  
Vol 11 ◽  
Author(s):  
Ningning Bai ◽  
Jingyuan Ma ◽  
Miriayi Alimujiang ◽  
Jun Xu ◽  
Fan Hu ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Oxidative Capacity ◽  
Mrna Levels ◽  
Cluster Assembly ◽  
Respiratory Chain Complexes ◽  
Beige Adipocyte ◽  
Mitochondrial Homeostasis ◽  
Beige Adipocytes ◽  
Beige Fat

Mitochondrial iron-sulfur (Fe-S) cluster is an important cofactor for the maturation of Fe-S proteins, which are ubiquitously involved in energy metabolism; however, factors facilitating this process in beige fat have not been established. Here, we identified BolA family member 3 (Bola3), as one of 17 mitochondrial Fe-S cluster assembly genes, was the most significant induced gene in the browning program of white adipose tissue. Using lentiviral-delivered shRNA in vitro, we determined that Bola3 deficiency inhibited thermogenesis activity without affecting lipogenesis in differentiated beige adipocytes. The inhibition effect of Bola3 knockdown might be through impairing mitochondrial homeostasis and lipolysis. This was evidenced by the decreased expression of mitochondria related genes and respiratory chain complexes, attenuated mitochondrial formation, reduced mitochondrial maximal respiration and inhibited isoproterenol-stimulated lipolysis. Furthermore, BOLA3 mRNA levels were higher in human deep neck brown fat than in the paired subcutaneous white fat, and were positively correlated with thermogenesis related genes (UCP1, CIDEA, PRDM16, PPARG, COX7A1, and LIPE) expression in human omental adipose depots. This study demonstrates that Bola3 is associated with adipose tissue oxidative capacity both in mice and human, and it plays an indispensable role in beige adipocyte thermogenesis via maintaining mitochondrial homeostasis and adrenergic signaling-induced lipolysis.

scholarly journals Endoplasmic Reticulum Stress Impaired Uncoupling Protein 1 Expression via the Suppression of Peroxisome Proliferator-Activated Receptor γ Binding Activity in Mice Beige Adipocytes

2019 ◽  
Vol 20 (2) ◽  
pp. 274 ◽  
Author(s):  
Ana Yuliana ◽  
Asumi Daijo ◽  
Huei-Fen Jheng ◽  
Jungin Kwon ◽  
Wataru Nomura ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Uncoupling Protein ◽  
Peroxisome Proliferator ◽  
Uncoupling Protein 1 ◽  
Peroxisome Proliferator Activated Receptor ◽  
Beige Adipocytes ◽  
Ucp1 Expression ◽  
Er Homeostasis

Endoplasmic reticulum (ER) homeostasis is critical in maintaining metabolic regulation. Once it is disrupted due to accumulated unfolded proteins, ER homeostasis is restored via activation of the unfolded protein response (UPR); hence, the UPR affects diverse physiological processes. However, how ER stress influences adipocyte functions is not well known. In this study, we investigated the effect of ER stress in thermogenic capacity of mice beige adipocytes. Here, we show that the expression of uncoupling protein 1 (Ucp1) involved in thermoregulation is severely suppressed under ER stress conditions (afflicted by tunicamycin) in inguinal white adipose tissue (IWAT) both in vitro and in vivo. Further investigation showed that extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) were both activated after ER stress stimulation and regulated the mRNA levels of Ucp1 and peroxisome proliferator-activated receptor γ (Pparγ), which is known as a Ucp1 transcriptional activator, in vitro and ex vivo. We also found that Pparγ protein was significantly degraded, reducing its recruitment to the Ucp1 enhancer, thereby downregulating Ucp1 expression. Additionally, only JNK inhibition, but not ERK, rescued the Pparγ protein. These findings provide novel insights into the regulatory effect of ER stress on Ucp1 expression via Pparγ suppression in beige adipocytes.

A compendium of G-protein–coupled receptors and cyclic nucleotide regulation of adipose tissue metabolism and energy expenditure

2020 ◽  
Vol 134 (5) ◽  
pp. 473-512 ◽  
Author(s):  
Ryan P. Ceddia ◽  
Sheila Collins
Keyword(s):  
Adipose Tissue ◽  
Energy Expenditure ◽  
Signaling Pathways ◽  
G Protein ◽  
Uncoupling Protein ◽  
Beige Adipocytes ◽  
Nucleotide Regulation ◽  
Ucp1 Expression ◽  
Thermogenic Adipocytes ◽  
G Protein Coupled

Abstract With the ever-increasing burden of obesity and Type 2 diabetes, it is generally acknowledged that there remains a need for developing new therapeutics. One potential mechanism to combat obesity is to raise energy expenditure via increasing the amount of uncoupled respiration from the mitochondria-rich brown and beige adipocytes. With the recent appreciation of thermogenic adipocytes in humans, much effort is being made to elucidate the signaling pathways that regulate the browning of adipose tissue. In this review, we focus on the ligand–receptor signaling pathways that influence the cyclic nucleotides, cAMP and cGMP, in adipocytes. We chose to focus on G-protein–coupled receptor (GPCR), guanylyl cyclase and phosphodiesterase regulation of adipocytes because they are the targets of a large proportion of all currently available therapeutics. Furthermore, there is a large overlap in their signaling pathways, as signaling events that raise cAMP or cGMP generally increase adipocyte lipolysis and cause changes that are commonly referred to as browning: increasing mitochondrial biogenesis, uncoupling protein 1 (UCP1) expression and respiration.

1703-P: Altered UCP1 Expression in ADSC-Derived Beige Adipocytes Determines Mitochondrial ROS Production in T2DM Patients

Diabetes ◽  
2020 ◽  
Vol 69 (Supplement 1) ◽  
pp. 1703-P
Author(s):  
SVETLANA MICHURINA ◽  
IURII STAFEEV ◽  
IGOR SKLYANIK ◽  
EKATERINA SHESTAKOVA ◽  
ANATOLIY YURASOV ◽  
...  
Keyword(s):  
Ros Production ◽  
Mitochondrial Ros ◽  
Beige Adipocytes ◽  
Ucp1 Expression

scholarly journals Beige adipocytes mediate the neuroprotective and anti-inflammatory effects of subcutaneous fat in obese mice

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
De-Huang Guo ◽  
Masaki Yamamoto ◽  
Caterina M. Hernandez ◽  
Hesam Khodadadi ◽  
Babak Baban ◽  
...  
Keyword(s):  
Subcutaneous Fat ◽  
Visceral Obesity ◽  
Interleukin 4 ◽  
Hippocampal Synaptic Plasticity ◽  
Beige Adipocytes ◽  
Beige Fat ◽  
Dietary Obesity ◽  
Anti Inflammatory ◽  
Subcutaneous Adiposity ◽  
The Relationship

AbstractVisceral obesity increases risk of cognitive decline in humans, but subcutaneous adiposity does not. Here, we report that beige adipocytes are indispensable for the neuroprotective and anti-inflammatory effects of subcutaneous fat. Mice lacking functional beige fat exhibit accelerated cognitive dysfunction and microglial activation with dietary obesity. Subcutaneous fat transplantation also protects against chronic obesity in wildtype mice via beige fat-dependent mechanisms. Beige adipocytes restore hippocampal synaptic plasticity following transplantation, and these effects require the anti-inflammatory cytokine interleukin-4 (IL4). After observing beige fat-mediated induction of IL4 in meningeal T-cells, we investigated the contributions of peripheral lymphocytes in donor fat. There was no sign of donor-derived lymphocyte trafficking between fat and brain, but recipient-derived lymphocytes were required for the effects of transplantation on cognition and microglial morphology. These findings indicate that beige adipocytes oppose obesity-induced cognitive impairment, with a potential role for IL4 in the relationship between beige fat and brain function.

scholarly journals E3 ubiquitin ligase Grail promotes hepatic steatosis through Sirt1 inhibition

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Pei-Yao Liu ◽  
Cheng-Cheung Chen ◽  
Chia-Ying Chin ◽  
Te-Jung Liu ◽  
Wen-Chiuan Tsai ◽  
...  
Keyword(s):  
Hepatic Steatosis ◽  
Lipid Accumulation ◽  
Acid Synthesis ◽  
Sirtuin 1 ◽  
Nonalcoholic Fatty Liver ◽  
Expression Of Genes ◽  
Hepatic Fat ◽  
Underlying Mechanisms

AbstractIn obese adults, nonalcoholic fatty liver disease (NAFLD) is accompanied by multiple metabolic dysfunctions. Although upregulated hepatic fatty acid synthesis has been identified as a crucial mediator of NAFLD development, the underlying mechanisms are yet to be elucidated. In this study, we reported upregulated expression of gene related to anergy in lymphocytes (GRAIL) in the livers of humans and mice with hepatic steatosis. Grail ablation markedly alleviated the high-fat diet-induced hepatic fat accumulation and expression of genes related to the lipid metabolism, in vitro and in vivo. Conversely, overexpression of GRAIL exacerbated lipid accumulation and enhanced the expression of lipid metabolic genes in mice and liver cells. Our results demonstrated that Grail regulated the lipid accumulation in hepatic steatosis via interaction with sirtuin 1. Thus, Grail poses as a significant molecular regulator in the development of NAFLD.

scholarly journals Selective Targeting of Breast Cancer by Tafuramycin a Using SMA-Nanoassemblies

Molecules ◽  
2021 ◽  
Vol 26 (12) ◽  
pp. 3532
Author(s):  
Ibrahim M. El-Deeb ◽  
Valeria Pittala ◽  
Diab Eltayeb ◽  
Khaled Greish
Keyword(s):  
Breast Cancer ◽  
Progesterone Receptors ◽  
In Vivo Studies ◽  
Chemotherapy Agent ◽  
Anticancer Effects ◽  
Tumor Tissues ◽  
Potential Strategy ◽  
Tumor Accumulation

Triple-negative breast cancer (TNBC) is a heterogeneous subtype of tumors that tests negative for estrogen receptors, progesterone receptors, and excess HER2 protein. The mainstay of treatment remains chemotherapy, but the therapeutic outcome remains inadequate. This paper investigates the potential of a duocarmycin derivative, tafuramycin A (TFA), as a new and more effective chemotherapy agent in TNBC treatment. To this extent, we optimized the chemical synthesis of TFA, and we encapsulated TFA in a micellar system to reduce side effects and increase tumor accumulation. In vitro and in vivo studies suggest that both TFA and SMA–TFA possess high anticancer effects in TNBC models. Finally, the encapsulation of TFA offered a preferential avenue to tumor accumulation by increasing its concentration at the tumor tissues by around four times in comparison with the free drug. Overall, the results provide a new potential strategy useful for TNBC treatment.

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