scholarly journals Evidence that C/EBP-β LAP Increases Fat Metabolism and Protects Against Diet-Induced Obesity in Response to mTOR Inhibition

2021 ◽  
Vol 2 ◽  
Author(s):  
Alessandro Bitto ◽  
Nicole Tatom ◽  
Thomas Krivak ◽  
Peter Grotz ◽  
Matt Kaeberlein
Keyword(s):  
Fat Metabolism ◽  
Mtor Inhibition ◽  
Lipid Catabolism ◽  
Diet Induced Obesity ◽  
Age Related ◽  
Antiretroviral Drug ◽  
Mtorc1 Signaling ◽  
Obesity In Mice ◽  
Common Risk Factors ◽  
Novel Drug

Aging and obesity are common risk factors for numerous chronic pathologies, and the compounding effects of old age and increased adiposity pose a serious threat to public health. Starting from the assumption that aging and obesity may have shared underpinnings, we investigated the antiobesogenic potential of a successful longevity intervention, the mTORC1 inhibitor rapamycin. We find that rapamycin prevents diet-induced obesity in mice and increases the activity of C/EBP-β LAP, a transcription factor that regulates the metabolic shift to lipid catabolism observed in response to calorie restriction. Independent activation of C/EBP-β LAP with the antiretroviral drug adefovir dipivoxil recapitulates the anti-obesogenic effects of rapamycin without reducing signaling through mTORC1 and increases markers of fat catabolism in the liver. Our findings support a model that C/EBP-β LAP acts downstream of mTORC1 signaling to regulate fat metabolism and identifies a novel drug that may be exploited to treat obesity and decrease the incidence of age-related disease.

Resistance to Diet-Induced Obesity in Mice Lacking OPA1 in Adipose Tissue Occurs Independently of Fat-Derived FGF-21 and BAT Function

Diabetes ◽  
2018 ◽  
Vol 67 (Supplement 1) ◽  
pp. 276-LB ◽  
Author(s):  
RENATA PEREIRA ◽  
ANGELA C. OLVERA ◽  
ALEX A. MARTI ◽  
RANA HEWEZI ◽  
WILLIAM A. BUI TRAN ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Diet Induced Obesity ◽  
Obesity In Mice

scholarly journals Effects of stem cells from inducible brown adipose tissue on diet-induced obesity in mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Enrique Calvo ◽  
Noelia Keiran ◽  
Catalina Núñez-Roa ◽  
Elsa Maymó-Masip ◽  
Miriam Ejarque ◽  
...  
Keyword(s):  
Stem Cells ◽  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Therapeutic Option ◽  
Metabolic Activation ◽  
Diet Induced Obesity ◽  
Brown Adipose ◽  
Obesity In Mice ◽  
Treatment Of Obesity ◽  
Visceral Adipose

AbstractAdipose-derived mesenchymal stem cells (ASCs) are a promising option for the treatment of obesity and its metabolic co-morbidities. Despite the recent identification of brown adipose tissue (BAT) as a potential target in the management of obesity, the use of ASCs isolated from BAT as a therapy for patients with obesity has not yet been explored. Metabolic activation of BAT has been shown to have not only thermogenic effects, but it also triggers the secretion of factors that confer protection against obesity. Herein, we isolated and characterized ASCs from the visceral adipose tissue surrounding a pheochromocytoma (IB-hASCs), a model of inducible BAT in humans. We then compared the anti-obesity properties of IB-hASCs and human ASCs isolated from visceral white adipose tissue (W-hASCs) in a murine model of diet-induced obesity. We found that both ASC therapies mitigated the metabolic abnormalities of obesity to a similar extent, including reducing weight gain and improving glucose tolerance. However, infusion of IB-hASCs was superior to W-hASCs in suppressing lipogenic and inflammatory markers, as well as preserving insulin secretion. Our findings provide evidence for the metabolic benefits of visceral ASC infusion and support further studies on IB-hASCs as a therapeutic option for obesity-related comorbidities.

scholarly journals Zebrafish Model in Ophthalmology to Study Disease Mechanism and Drug Discovery

2021 ◽  
Vol 14 (8) ◽  
pp. 716
Author(s):  
Yiwen Hong ◽  
Yan Luo
Keyword(s):  
Drug Discovery ◽  
Behavioral Assessment ◽  
Age Related Macular Degeneration ◽  
Disease Mechanism ◽  
Zebrafish Model ◽  
Age Related ◽  
Eye Disorders ◽  
Vertebrate Model ◽  
Drug Treatments ◽  
Novel Drug

Visual impairment and blindness are common and seriously affect people’s work and quality of life in the world. Therefore, the effective therapies for eye diseases are of high priority. Zebrafish (Danio rerio) is an alternative vertebrate model as a useful tool for the mechanism elucidation and drug discovery of various eye disorders, such as cataracts, glaucoma, diabetic retinopathy, age-related macular degeneration, photoreceptor degeneration, etc. The genetic and embryonic accessibility of zebrafish in combination with a behavioral assessment of visual function has made it a very popular model in ophthalmology. Zebrafish has also been widely used in ocular drug discovery, such as the screening of new anti-angiogenic compounds or neuroprotective drugs, and the oculotoxicity test. In this review, we summarized the applications of zebrafish as the models of eye disorders to study disease mechanism and investigate novel drug treatments.

scholarly journals CIB2 regulates mTORC1 signaling and is essential for autophagy and visual function

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Saumil Sethna ◽  
Patrick A. Scott ◽  
Arnaud P. J. Giese ◽  
Todd Duncan ◽  
Xiaoying Jian ◽  
...  
Keyword(s):  
Visual Function ◽  
Molecular Mechanisms ◽  
Neurodegenerative Disorder ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Negative Regulator ◽  
Age Related Macular Degeneration ◽  
Age Related ◽  
Mtorc1 Signaling ◽  
Marked Accumulation

AbstractAge-related macular degeneration (AMD) is a multifactorial neurodegenerative disorder. Although molecular mechanisms remain elusive, deficits in autophagy have been associated with AMD. Here we show that deficiency of calcium and integrin binding protein 2 (CIB2) in mice, leads to age-related pathologies, including sub-retinal pigment epithelium (RPE) deposits, marked accumulation of drusen markers APOE, C3, Aβ, and esterified cholesterol, and impaired visual function, which can be rescued using exogenous retinoids. Cib2 mutant mice exhibit reduced lysosomal capacity and autophagic clearance, and increased mTORC1 signaling—a negative regulator of autophagy. We observe concordant molecular deficits in dry-AMD RPE/choroid post-mortem human tissues. Mechanistically, CIB2 negatively regulates mTORC1 by preferentially binding to ‘nucleotide empty’ or inactive GDP-loaded Rheb. Upregulated mTORC1 signaling has been implicated in lymphangioleiomyomatosis (LAM) cancer. Over-expressing CIB2 in LAM patient-derived fibroblasts downregulates hyperactive mTORC1 signaling. Thus, our findings have significant implications for treatment of AMD and other mTORC1 hyperactivity-associated disorders.

An ursolic acid-enriched Cynomorium songarium extract attenuates high fat diet-induced obesity in mice possibly through mitochondrial uncoupling

2014 ◽  
Vol 9 ◽  
pp. 211-224 ◽  
Author(s):  
Jihang Chen ◽  
Hoi Shan Wong ◽  
Hoi Yan Leung ◽  
Pou Kuan Leong ◽  
Wing Man Chan ◽  
...  
Keyword(s):  
Ursolic Acid ◽  
High Fat Diet ◽  
High Fat ◽  
Mitochondrial Uncoupling ◽  
Diet Induced Obesity ◽  
Obesity In Mice

scholarly journals TAMI-35. AUTOPHAGY MEDIATED LIPID CATABOLISM FACILITATES GLIOMA PROGRESSION TO OVERCOME BIOENERGETIC CRISIS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii220-ii220
Author(s):  
Chenran Wang ◽  
Michael Haas ◽  
Syn Yeo ◽  
Ritama Paul ◽  
Fuchun Yang ◽  
...  
Keyword(s):  
Tumor Progression ◽  
Cancer Cells ◽  
Strong Association ◽  
Glioma Cells ◽  
Acid Oxidation ◽  
Mrna Levels ◽  
Atp Production ◽  
Lipid Catabolism ◽  
Mtorc1 Signaling

Abstract Activation of mTORC1 plays a significant role in cancer development and progression. However, the metabolic mechanisms to sustain mTORC1 activation in stressed cancer cells are still underappreciated. Autophagy, one downstream process of mTORC1, is proposed to be suppressed under the condition of mTORC1 hyper-activation. Interestingly, we recently revealed higher autophagy activity in various Tsc-deficient tumor cells with mTORC1 hyper-activity. Nevertheless, the functions and mechanisms of autophagy in regulating mTORC1 in cancer cells are not well understood. In this study, we revealed a strong association of altered mRNA levels in mTORC1 upstream and downstream genes with poor prognosis of glioma patients. Our metabolic and molecular studies indicated that autophagy mediated lipid catabolism was essential to sustain mTORC1 activity in glioma cells under energy stresses. We found that autophagy inhibitors or fatty acid oxidation (FAO) inhibition in combination with 2-Deoxy-D-glucose (2DG) decreased oxidative phosphorylation, ATP production, mTORC1 activity, and survival of glioma cells in vitro. Consistently, the combination of chloroquine (CQ) or FAO inhibitors with 2DG effectively suppressed the progression of xenografted glioma with mTORC1 hyperactivation in mice. This study established a novel autophagy/lipid degradation/FAO/ATP pathway that maintains high mTORC1 signaling and tumor progression in brain cancer cells under energy stresses. The requirement of lipophagy in brain cancers may provide an opportunity to develop new molecular therapeutic targets to counteract mTORC1 for tumor progression.

scholarly journals Peroxisome Proliferator-Activated Receptors-Alpha and Gamma Are Targets to Treat Offspring from Maternal Diet-Induced Obesity in Mice

PLoS ONE ◽  
2013 ◽  
Vol 8 (5) ◽  
pp. e64258 ◽  
Author(s):  
D'Angelo Carlo Magliano ◽  
Thereza Cristina Lonzetti Bargut ◽  
Simone Nunes de Carvalho ◽  
Marcia Barbosa Aguila ◽  
Carlos Alberto Mandarim-de-Lacerda ◽  
...  
Keyword(s):  
Maternal Diet ◽  
Peroxisome Proliferator ◽  
Diet Induced Obesity ◽  
Obesity In Mice ◽  
Peroxisome Proliferator Activated Receptors

scholarly journals NPY Deficiency Prevents Postmenopausal Adiposity by Augmenting Estradiol-Mediated Browning

2018 ◽  
Vol 75 (6) ◽  
pp. 1042-1049
Author(s):  
Seongjoon Park ◽  
Erkhembayar Nayantai ◽  
Toshimitsu Komatsu ◽  
Hiroko Hayashi ◽  
Ryoichi Mori ◽  
...  
Keyword(s):  
Body Weight ◽  
Adipose Tissue ◽  
Fat Metabolism ◽  
Male Mice ◽  
Wild Type ◽  
Male And Female ◽  
Female Mice ◽  
Age Related ◽  
Promising Target ◽  
Intracellular Mechanism

Abstract The orexigenic hormone neuropeptide Y (NPY) plays a pivotal role in the peripheral regulation of fat metabolism. However, the mechanisms underlying the effects of sex on NPY function have not been extensively analyzed. In this study, we examined the effects of NPY deficiency on fat metabolism in male and female mice. Body weight was slightly decreased, whereas white adipose tissue (WAT) mass was significantly decreased as the thermogenic program was upregulated in NPY-/- female mice compared with that in wild-type mice; these factors were not altered in response to NPY deficiency in male mice. Moreover, lack of NPY resulted in an increase in luteinizing hormone (LH) expression in the pituitary gland, with concomitant activation of the estradiol-mediated thermogenic program in inguinal WAT, and alleviated age-related modification of adiposity in female mice. Taken together, these data revealed a novel intracellular mechanism of NPY in the regulation of fat metabolism and highlighted the sexual dimorphism of NPY as a promising target for drug development to reduce postmenopausal adiposity.

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