Obesity associated pro-fibrotic protein augments fibrosis in heart

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
Y Tsukano ◽  
I Shimizu ◽  
Y Yoshida ◽  
Y Hsiao ◽  
R Ikegami ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Diastolic Dysfunction ◽  
Cardiac Fibrosis ◽  
Sterile Inflammation ◽  
Stressed Condition ◽  
Mice Model ◽  
Dna Microarray Data ◽  
Brown Adipose ◽  
Dietary Obesity ◽  
Fibrotic Disorders

Abstract   Chronic sterile inflammation in visceral fat has causal roles for systemic metabolic disorders in obesity. Inflamed visceral adipose tissue secretes pro-inflammatory adipokines, and this contributes to tissue remodeling under a metabolically stressed condition. Various kinds of white adipokines are broadly studied, however, roles of brown adipose tissue (BAT) derived adipokines (BATokine) remain to be explored. In this project, we tried to characterize pathogenic role of BATokine in obesity related fibrotic disorders, especially focusing on heart failure with preserved ejection fraction (HFpEF). For this purpose, we analyzed two sets of DNA microarray data, and identified an obesity associated pro-fibrotic protein (OAFP) as a possible pathogenic BATokine. Our biobank studies showed OAFP increased in patients with diastolic dysfunction, and E/e' analyzed with cardiac echo increased in direct proportion to circulating OAFP level in humans. We generated dietary obese mice model, and found OAFP increased both in BAT and circulation. We generated a murine systemic or BAT specific OAFP knockout (KO) models, and found that obesity-induced diastolic dysfunction ameliorated in these models. Cardiac fibrosis was also suppressed by genetic depletion of OAFP. We found OAFP increased in circulation in aged humans and mice, and studies in chronologically aged mice showed this molecule increased in BAT with aging. Our results indicate that OAFP is secreted predominantly from BAT, and mediates pathogenic roles by augmenting cardiac fibrosis in dietary obesity or aging. Suppression of OAFP may become a therapy for HFpEF. Funding Acknowledgement Type of funding source: None

Diet, lighting, and food intake affect norepinephrine turnover in dietary obesity

1987 ◽  
Vol 252 (2) ◽  
pp. R402-R408 ◽  
Author(s):  
T. Yoshida ◽  
J. S. Fisler ◽  
M. Fukushima ◽  
G. A. Bray ◽  
R. A. Schemmel
Keyword(s):  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
High Fat Diet ◽  
Brown Fat ◽  
Light Cycle ◽  
High Fat ◽  
Interscapular Brown Adipose Tissue ◽  
Norepinephrine Turnover ◽  
Brown Adipose ◽  
Dietary Obesity

The effects of dietary fat content, lighting cycle, and feeding time on norepinephrine turnover in interscapular brown adipose tissue, heart, and pancreas, and on blood 3-hydroxybutyrate, serum glucose, insulin, and corticosterone have been studied in two strains of rats that differ in their susceptibility to dietary obesity. S 5B/Pl rats, which are resistant to dietary obesity, have a more rapid turnover of norepinephrine in interscapular brown adipose tissue and heart and a greater increase in the concentration of norepinephrine in brown fat when eating a high-fat diet than do Osborne-Mendel rats, which are sensitive to fat-induced obesity. Light cycle and feeding schedule are important modulators of sympathetic activity in heart and pancreas but not in brown fat. Rats of the resistant strain also have higher blood 3-hydroxybutyrate concentrations and lower insulin and corticosterone levels than do rats of the susceptible strain. A high-fat diet increases 3-hydroxybutyrate concentrations and reduces insulin levels in both strains. These studies show, in rats eating a high-fat diet, that differences in norepinephrine turnover, particularly in brown adipose tissue, may play an important role in whether dietary obesity develops and in the manifestations of resistance to this phenomenon observed in the S 5B/Pl rat.

Ventromedial hypothalamic knife-cut lesions in rats resistant to dietary obesity

1984 ◽  
Vol 246 (6) ◽  
pp. R943-R948 ◽  
Author(s):  
J. Oku ◽  
G. A. Bray ◽  
J. S. Fisler ◽  
R. Schemmel
Keyword(s):  
Body Weight ◽  
Adipose Tissue ◽  
Food Intake ◽  
High Fat Diet ◽  
Corn Oil ◽  
High Fat ◽  
Interscapular Brown Adipose Tissue ◽  
Brown Adipose ◽  
Dietary Obesity

The effects of ventromedial hypothalamic (VMH) knife-cut lesions on food intake and body weight of S 5B/Pl rats, which are normally resistant to obesity when eating a high-fat diet, were examined in two experiments. In the first experiment body weight increased only slightly after VMH knife-cut lesions when animals were fed pelleted laboratory chow or a 10% corn oil diet. When eating the 30% corn oil diet, however, body weight increased in the VMH knife-cut rats. In the second experiment VMH knife-cut lesions produced a small weight gain in rats fed the 10% fat diet; this manipulation also increased food intake and disrupted the normal diurnal feeding pattern. Changes in the weight of the liver, interscapular brown adipose tissue, and white adipose tissue paralleled the changes in body weight. Plasma insulin increased in the rats eating the 30% corn oil diet ad libitum but not in the VMH-lesioned animals pair fed to the sham-operated rats. Incorporation of 3H from 3H2O into lipid was significantly increased in white fat of animals with VMH knife cuts. Similar results were obtained from incubation of adipose tissue in vitro with insulin and radioactively labeled glucose. These studies show that hypothalamic knife-cut lesions can remove the resistance of the S 5B/Pl rats to obesity when they are fed a high-fat diet.

Individual severity of dietary obesity in unselected Wistar rats: relationship with hyperphagia

2000 ◽  
Vol 279 (2) ◽  
pp. E340-E347 ◽  
Author(s):  
Joanne A. Harrold ◽  
Peter S. Widdowson ◽  
John C. Clapham ◽  
Gareth Williams
Keyword(s):  
Adipose Tissue ◽  
Energy Intake ◽  
Rectal Temperature ◽  
Wistar Rats ◽  
Gastrocnemius Muscle ◽  
Mrna Levels ◽  
Brown Adipose ◽  
Significant Difference ◽  
Dietary Obesity ◽  
Palatable Diet

We investigated the relative importance of overeating, thermogenesis, and uncoupling protein (UCP) expression in determining the severity of obesity in male Wistar rats fed a highly palatable diet. After 2 wk of feeding, body weight did not differ significantly from controls (248 ± 4 vs. 229 ± 3 g; P > 0.3), but rectal temperature, brown adipose tissue (BAT) mass, UCP3 expression in gastrocnemius muscle, and UCP2 expression in white adipose tissue (WAT) were all elevated in diet-fed animals. In a further study, rats fed a palatable diet for 8 wk exhibited higher energy intake and rectal temperature than controls. Dietary-obese rats were divided into high (427–490 g; n = 8) and low (313–410 g; n = 10) weight gainers. The high gainers ate significantly more than the low gainers, and energy intake was positively correlated with weight gain ( r 2 = 0.72, P < 0.01). UCP2 and UCP3 mRNA levels in gastrocnemius muscle were significantly increased above lean controls in all diet-fed animals, whereas UCPs in WAT and BAT did not differ significantly from controls. Whereas rats fed palatable food exhibited a thermogenic response, there was no significant difference in core temperature between high and low gain groups (37.5 ± 0.1 vs. 37.6 ± 0.1°C; P > 0.5). We conclude that a higher energy intake is the critical factor determining susceptibility to dietary obesity in unselected Wistar rats.

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.

Adipocyte deletion of HuR induces spontaneous cardiac hypertrophy and fibrosis

2021 ◽  
Author(s):  
Adrienne R. Guarnieri ◽  
Sarah R. Anthony ◽  
Anamarie Gozdiff ◽  
Lisa C. Green ◽  
Salma M. Fleifil ◽  
...  
Keyword(s):  
Gene Expression ◽  
Adipose Tissue ◽  
Cardiac Fibrosis ◽  
Serum Levels ◽  
Tissue Homeostasis ◽  
Cardiometabolic Health ◽  
Specific Gene ◽  
Rna Seq ◽  
Tissue Specific ◽  
Brown Adipose

Adipose tissue homeostasis plays a central role in cardiovascular physiology, and the presence of thermogenically active brown adipose tissue (BAT) has recently been associated with cardiometabolic health. We have previously shown that adipose tissue-specific deletion of HuR (Adipo-HuR-/-) reduces BAT-mediated adaptive thermogenesis, and the goal of this work was to identify the cardiovascular impacts of Adipo-HuR-/-. We found that Adipo-HuR-/- mice exhibit a hypercontractile phenotype that is accompanied by increased left ventricle wall thickness and hypertrophic gene expression. Furthermore, hearts from Adipo-HuR-/- display increased fibrosis via picrosirius red staining and periostin expression. To identify underlying mechanisms, we applied both RNA-seq and weighted gene co-expression network analysis (WGCNA) across both cardiac and adipose tissue to define HuR-dependent changes in gene expression as well as significant relationships between adipose tissue gene expression and cardiac fibrosis. RNA-seq results demonstrated a significant increase in pro-inflammatory gene expression in both cardiac and subcutaneous white adipose tissue (scWAT) from Adipo-HuR-/- mice that is accompanied by an increase in serum levels of both TNF-ᵯC; and IL-6. In addition to inflammation-related genes, WGCNA identified a significant enrichment in extracellular vesicle-mediated transport and exosome-associated genes in scWAT whose expression most significantly associated with degree of cardiac fibrosis observed in Adipo-HuR-/- mice, implicating these processes as a likely adipose-to-cardiac paracrine mechanism. These results are significant in that they demonstrate the spontaneous onset of cardiovascular pathology in an adipose tissue-specific gene deletion model and contribute to our understanding of how disruptions in adipose tissue homeostasis may mediate cardiovascular disease.

P2591Circulating pro fibrotic protein promotes fibrosis in liver and heart

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
Y Tsukano ◽  
I Shimizu ◽  
Y Yoshida ◽  
R Ikegami ◽  
Y Hayashi ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Cardiac Fibrosis ◽  
Peptide Vaccine ◽  
Transcript Level ◽  
Mice Model ◽  
Nash Model ◽  
Age Related ◽  
Brown Adipose ◽  
Micro Array

Abstract Analyzing two sets of DNA micro array data with bioinformatics, we identified a secreted form pro-fibrotic protein (sPFP) expressed in dysfunctional brown adipose tissue (BAT) in mice. Testing our biobank samples, we found this protein increased in plasma of non-alcoholic steatohepatitis (NASH) patients or aged individuals. We generated a murine obese NASH model by imposing a high fat diet in C57BL/6NCr mice for 9–10 months since 4 weeks of age, and found that sPFP is produced predominantly by BAT. In this model, we also found that sPFP increased in plasma. We generated a murine systemic sPFP knockout (KO) model and found that liver fibrosis ameliorated in sPFP-KO model. We also suppressed circulating sPFP with a peptide vaccine targeting this molecule, and found that sPFP vaccination therapy inhibited liver fibrosis. Next, we generated sPFP gain of function (GOF) model by the administration of plasmid encoding sPFP into skeletal muscle. Liver fibrosis augmented in sPFP-GOF model, and these results suggested that sPFP has causal role for the progression of fibrotic response in liver. In the obese NASH model, we found that cardiac fibrosis also developed and it ameliorated in sPFP-KO model, indicating that sPFP may have pathological roles for heart failure with preserved ejection fraction (HFpEF) related with age-related disorders. In addition to an increase in circulating sPFP in aged individuals, we found that sPFP increased in BAT of chronological aged mice model. In vitro studies with differentiated brown adipocytes showed that c-Fos upregulated sPFP in transcript level. Our results suggest that sPFP contributes for the progression of fibrotic responses in obese or aged models. Inhibition of sPFP may become a therapy for NASH or HFpEF.

Brown fat thermogenesis in a rat model of dietary obesity

1987 ◽  
Vol 253 (5) ◽  
pp. R756-R762 ◽  
Author(s):  
J. S. Fisler ◽  
J. R. Lupien ◽  
R. D. Wood ◽  
G. A. Bray ◽  
R. A. Schemmel
Keyword(s):  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
High Fat Diet ◽  
Brown Fat ◽  
Cafeteria Diet ◽  
High Fat ◽  
Interscapular Brown Adipose Tissue ◽  
Low Fat Diet ◽  
Brown Adipose ◽  
Dietary Obesity

The effects of chronic feeding of a high-fat diet or a cafeteria-type diet on weight gain and thermogenesis in brown adipose tissue as measured by the binding of a purine nucleotide (guanosine 5'-diphosphate, GDP) to mitochondria of brown adipose tissue have been studied in two strains of rats that differ in their susceptibility to dietary obesity. S 5B/Pl rats, which are resistant to developing obesity when eating a high-fat diet or drinking sucrose solutions, have greater specific GDP binding in interscapular brown adipose tissue (IBAT) than do Osborne-Mendel rats, which are sensitive to fat-induced obesity. A high-fat diet, fed isoenergetically to the low-fat diet, did not increase the growth of IBAT and decreased specific GDP binding in both strains. Feeding a cafeteria diet resulted in obesity and increased mass and protein content of the IBAT in both strains of rats. However, specific GDP binding increased in response to cafeteria feeding only in the Osborne-Mendel rats. These studies show that thermogenesis, as measured by GDP binding to mitochondria in brown adipose tissue, is suppressed by both isoenergetic and ad libitum feeding of a high-fat diet. The higher basal GDP binding in the brown fat of the S 5B/Pl rats suggests that higher thermogenesis of this tissue contributes to the resistance of this strain to fat-induced obesity. The inability of S 5B/Pl rats to further increase thermogenesis when eating a cafeteria diet may contribute to their becoming obese.

Dietary obesity: brown fat denervation fails to alter development or recovery

1986 ◽  
Vol 250 (6) ◽  
pp. R1108-R1116 ◽  
Author(s):  
J. E. Cox ◽  
J. F. Lorden
Keyword(s):  
Weight Loss ◽  
Adipose Tissue ◽  
Weight Gain ◽  
Sympathetic Activation ◽  
Sprague Dawley ◽  
Experimental Conditions ◽  
Sprague Dawley Rats ◽  
Brown Adipose ◽  
Obese Rats ◽  
Dietary Obesity

We assessed the effect of scapular brown adipose tissue (BAT) denervation on dietary obesity in adult female Sprague-Dawley rats. In rats maintained for 32 days on an obesity-inducing regimen, BAT denervation produced significant reductions in food intake (83.4 vs. 94.4 kcal/day), weight gain (66.0 vs. 103.5 g), and carcass fat (19.3 vs. 27.6%). A subgroup of denervates consuming as many calories as controls (94.1 kcal/day) failed to gain more weight (92.2 g) or accumulate more fat (25.4%) than controls. In rats developing obesity for 32 days followed by 8 days on laboratory chow, weight change was unaffected by denervation during either weight gain (89.4 vs. 87.1 g for controls) or weight loss (21.2 vs. 22.1 g) phases, as was carcass fat (21.0 vs. 20.4%). BAT norepinephrine utilization was unchanged in nondenervated obese rats and those recovering from obesity. We did not, therefore, find evidence that under these experimental conditions sympathetic activation of BAT countered obesity during overconsumption or contributed to recovery from obesity.

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