Adipocytes initiate an adipose-cerebral-peripheral sympathetic reflex to induce insulin resistance during high-fat feeding

2019 ◽  
Vol 133 (17) ◽  
pp. 1883-1899 ◽  
Author(s):  
Wei Cao ◽  
Meng Shi ◽  
Liling Wu ◽  
Jiaxin Li ◽  
Zhichen Yang ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Glucose Uptake ◽  
White Adipose Tissue ◽  
Salt Intake ◽  
High Salt ◽  
High Fat ◽  
Efferent Nerve ◽  
Salt Loading ◽  
High Salt Intake

Abstract The underlying mechanism by which amassing of white adipose tissue in obesity regulates sympathetic nerve system (SNS) drive to the tissues responsible for glucose disposal, and causes insulin resistance (IR), remains unknown. We tested the hypothesis that high-fat (HF) feeding increases afferent impulses from white adipose tissue that reflexively elevate efferent nerve activity to skeletal muscle (SM) and adipose tissue to impair their local glucose uptake. We also investigated how salt-intake can enhance IR. HF-fed rats received a normal salt (0.4%) or high salt (4%) diet for 3 weeks. High-salt intake in HF fed rats decreased insulin-stimulated 2-deoxyglucose uptake by over 30% in white adipose tissue and SM, exacerbated inflammation, and impaired their insulin signaling and glucose transporter 4 (Glut4) trafficking. Dietary salt in HF fed rats also increased the activity of the adipose-cerebral-muscle renin–angiotensin system (RAS) axes, SNS, and reactive oxygen species (ROS). Insulin sensitivity was reduced by 32% in HF rats during high-salt intake, but was improved by over 62% by interruption of central RAS and SNS drive, and by over 45% by denervation or deafferentation of epididymal fat (all P<0.05). Our study suggest that a HF diet engages a sympathetic reflex from the white adipose tissue that activates adipose-cerebral-muscle RAS/ROS axes and coordinates a reduction in peripheral glucose uptake. These are all enhanced by salt-loading. These findings provide new insight into the role of a reflex initiated in adipose tissue in the regulation of glucose homeostasis during HF feeding that could lead to new therapeutic approaches to IR.

scholarly journals Tofogliflozin Improves Insulin Resistance in Skeletal Muscle and Accelerates Lipolysis in Adipose Tissue in Male Mice

Endocrinology ◽  
2015 ◽  
Vol 157 (3) ◽  
pp. 1029-1042 ◽  
Author(s):  
Atsushi Obata ◽  
Naoto Kubota ◽  
Tetsuya Kubota ◽  
Masahiko Iwamoto ◽  
Hiroyuki Sato ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Glucose Uptake ◽  
White Adipose Tissue ◽  
High Fat Diet ◽  
Molecular Mechanisms ◽  
The Body ◽  
High Fat ◽  
Ad Libitum

Abstract Sodium glucose cotransporter 2 inhibitors have attracted attention as they exert antidiabetic and antiobesity effects. In this study, we investigated the effects of tofogliflozin on glucose homeostasis and its metabolic consequences and clarified the underlying molecular mechanisms. C57BL/6 mice were fed normal chow containing tofogliflozin (0.005%) for 20 weeks or a high-fat diet containing tofogliflozin (0.005%) for 8 weeks ad libitum. In addition, the animals were pair-fed in relation to controls to exclude the influence of increased food intake. Tofogliflozin reduced the body weight gain, mainly because of fat mass reduction associated with a diminished adipocyte size. Glucose tolerance and insulin sensitivity were ameliorated. The serum levels of nonesterified fatty acid and ketone bodies were increased and the respiratory quotient was decreased in the tofogliflozin-treated mice, suggesting the acceleration of lipolysis in the white adipose tissue and hepatic β-oxidation. In fact, the phosphorylation of hormone-sensitive lipase and the adipose triglyceride lipase protein levels in the white adipose tissue as well as the gene expressions related to β-oxidation, such as Cpt1α in the liver, were significantly increased. The hepatic triglyceride contents and the expression levels of lipogenic genes were decreased. Pair-fed mice exhibited almost the same results as mice fed an high-fat diet ad libitum. Moreover, a hyperinsulinemic-euglycemic clamp revealed that tofogliflozin improved insulin resistance by increasing glucose uptake, especially in the skeletal muscle, in pair-fed mice. Taken together, these results suggest tofogliflozin ameliorates insulin resistance and obesity by increasing glucose uptake in skeletal muscle and lipolysis in adipose tissue.

scholarly journals High fat and/or high salt intake during pregnancy alters maternal meta-inflammation and offspring growth and metabolic profiles

2014 ◽  
Vol 2 (8) ◽  
pp. e12110 ◽  
Author(s):  
Clare M. Reynolds ◽  
Mark H. Vickers ◽  
Claudia J. Harrison ◽  
Stephanie A. Segovia ◽  
Clint Gray
Keyword(s):  
Salt Intake ◽  
High Salt ◽  
Metabolic Profiles ◽  
High Fat ◽  
High Salt Intake ◽  
Offspring Growth

scholarly journals High-salt intake induced visceral adipose tissue hypoxia and its association with circulating monocyte subsets in humans

Obesity ◽  
2014 ◽  
Vol 22 (6) ◽  
pp. 1470-1476 ◽  
Author(s):  
Xin Zhou ◽  
Fei Yuan ◽  
Wen-Jie Ji ◽  
Zhao-Zeng Guo ◽  
Ling Zhang ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Visceral Adipose Tissue ◽  
Salt Intake ◽  
Tissue Hypoxia ◽  
High Salt ◽  
Monocyte Subsets ◽  
High Salt Intake ◽  
Visceral Adipose

scholarly journals Salt Induces Adipogenesis/Lipogenesis and Inflammatory Adipocytokines Secretion in Adipocytes

2019 ◽  
Vol 20 (1) ◽  
pp. 160 ◽  
Author(s):  
Myoungsook Lee ◽  
Sungbin Richard Sorn ◽  
Yunkyoung Lee ◽  
Inhae Kang
Keyword(s):  
Defense Mechanisms ◽  
Salt Intake ◽  
High Salt ◽  
Mitogen Activated Protein Kinase ◽  
Future Research ◽  
High Dose ◽  
Obesity Prevalence ◽  
Salt Loading ◽  
Lipogenic Genes ◽  
High Salt Intake

It is well known that high salt intake is associated with cardiovascular diseases including hypertension. However, the research on the mechanism of obesity due to high salt intake is rare. To evaluate the roles of salt on obesity prevalence, the gene expression of adipogenesis/lipogenesis and adipocytokines secretion according to adipocyte dysfunction were investigated in salt-loading adipocytes. High salt dose-dependently increased the expression of adipogenic/lipogenic genes, such as PPAR-γ, C/EBPα, SREBP1c, ACC, FAS, and aP2, but decreased the gene of lipolysis like AMPK, ultimately resulting in fat accumulation. With SIK-2 and Na+/K+-ATPase activation, salt increased the metabolites involved in the renin-angiotensin-aldosterone system (RAAS) such as ADD1, CYP11β2, and MCR. Increasing insulin dependent insulin receptor substrate (IRS)-signaling, resulting in the insulin resistance, mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) and Akt-mTOR were activated but AMPK(Thr172) was depressed in salt-loading adipocytes. The expression of pro-inflammatory adipocytokines, TNFα, MCP-1, COX-2, IL-17A, IL-6, leptin, and leptin to adiponectin ratio (LAR) were dose-dependently increased by salt treatment. Using the inhibitors of MAPK/ERK, U0126, we found that the crosstalk among the signaling pathways of MAPK/ERK, Akt-mTOR, and the inflammatory adipogenesis can be the possible mechanism of salt-linked obesity. The possibilities of whether the defense mechanisms against high dose of intracellular salts provoke signaling for adipocytes differentiation or interact with surrounding tissues through other pathways will be explored in future research.

scholarly journals Gdf11 gene transfer prevents high fat diet-induced obesity and improves metabolic homeostasis in obese and STZ-induced diabetic mice

2019 ◽  
Vol 17 (1) ◽  
Author(s):  
Bingxin Lu ◽  
Jianing Zhong ◽  
Jianfei Pan ◽  
Xiaopeng Yuan ◽  
Mingzhi Ren ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Energy Balance ◽  
Glucose Metabolism ◽  
Gene Transfer ◽  
White Adipose Tissue ◽  
High Fat Diet ◽  
Diabetic Mice ◽  
Metabolic Homeostasis ◽  
High Fat

Abstract Background The growth differentiation factor 11 (GDF11) was shown to reverse age-related hypertrophy on cardiomyocytes and considered as anti-aging rejuvenation factor. The role of GDF11 in regulating metabolic homeostasis is unclear. In this study, we investigated the functions of GDF11 in regulating metabolic homeostasis and energy balance. Methods Using a hydrodynamic injection approach, plasmids carrying a mouse Gdf11 gene were delivered into mice and generated the sustained Gdf11 expression in the liver and its protein level in the blood. High fat diet (HFD)-induced obesity was employed to examine the impacts of Gdf11 gene transfer on HFD-induced adiposity, hyperglycemia, insulin resistance, and hepatic lipid accumulation. The impacts of GDF11 on metabolic homeostasis of obese and diabetic mice were examined using HFD-induced obese and STZ-induced diabetic models. Results Gdf11 gene transfer alleviates HFD-induced obesity, hyperglycemia, insulin resistance, and fatty liver development. In obese and STZ-induced diabetic mice, Gdf11 gene transfer restores glucose metabolism and improves insulin resistance. Mechanism study reveals that Gdf11 gene transfer increases the energy expenditure of mice, upregulates the expression of genes responsible for thermoregulation in brown adipose tissue, downregulates the expression of inflammatory genes in white adipose tissue and those involved in hepatic lipid and glucose metabolism. Overexpression of GDF11 also activates TGF-β/Smad2, PI3K/AKT/FoxO1, and AMPK signaling pathways in white adipose tissue. Conclusions These results demonstrate that GDF11 plays an important role in regulating metabolic homeostasis and energy balance and could be a target for pharmacological intervention to treat metabolic disease.

scholarly journals High-Salt Intake Ameliorates Hyperglycemia and Insulin Resistance in WBN/Kob-Leprfa/fa Rats: A New Model of Type 2 Diabetes Mellitus

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Yoshiichi Takagi ◽  
Taichi Sugimoto ◽  
Masaya Kobayashi ◽  
Mitsuyuki Shirai ◽  
Fumitoshi Asai
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Glucose Homeostasis ◽  
Salt Intake ◽  
Urine Volume ◽  
High Salt ◽  
High Salt Intake

High-salt intake is a major risk factor for developing hypertension in type 2 diabetes mellitus, but its effects on glucose homeostasis are controversial. We previously found that high-salt intake induces severe hypertension in WBN/Kob diabetic fatty (WBKDF) rats. In the present study, we examined the effects of a high-salt intake on glucose homeostasis in WBKDF rats. Male WBKDF rats and age-matched Wistar rats at 6 weeks of age were each divided into two groups and fed either a normal-sodium (NS, 0.26%) diet or high-sodium (HS, 8%) diet for 7 weeks. Systolic blood pressure and urine volume were increased in WBKDF-HS and Wistar-HS. Body weight gain and food consumption were comparable between NS and HS in both strains. Plasma and urine glucose levels were significantly increased in WBKDF-NS but not in WBKDF-HS. HOMA-IR in WBKDF-HS was significantly lower compared with that in WBKDF-NS. The high plasma adiponectin level in WBKDF-NS compared with that in Wistar-NS was further enhanced in WBKDF-HS. Glycogen deposits and fat droplets in the livers of WBKDF-HS were reduced compared with those of WBKDF-NS. The present study demonstrated that HS intake ameliorated hyperglycemia and insulin resistance in WBKDF rats, which may be due to increased plasma levels of adiponectin.

scholarly journals Deletion of the gene encoding G0/G1 switch protein 2 (G0s2) alleviates high-fat-diet-induced weight gain and insulin resistance, and promotes browning of white adipose tissue in mice

Diabetologia ◽  
2014 ◽  
Vol 58 (1) ◽  
pp. 149-157 ◽  
Author(s):  
Wissal El-Assaad ◽  
Karim El-Kouhen ◽  
Amro H. Mohammad ◽  
Jieyi Yang ◽  
Masahiro Morita ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Weight Gain ◽  
White Adipose Tissue ◽  
High Fat Diet ◽  
High Fat ◽  
Gene Encoding

scholarly journals Thromboxane A2 Receptor Antagonist (ONO-8809) Attenuates the Renal Disorders Caused by Salt-Overload in Stroke-Prone Spontaneously Hypertensive Rats

2021 ◽  
Author(s):  
Yusuke Nagatani ◽  
Toshihide Higashino ◽  
Kosho Kinoshita ◽  
Hideaki Higashino
Keyword(s):  
Gene Expression ◽  
Spontaneously Hypertensive Rats ◽  
Salt Intake ◽  
Thromboxane A2 ◽  
High Salt ◽  
Hypertensive Rats ◽  
Salt Loading ◽  
Spontaneously Hypertensive ◽  
Oxidative Stresses ◽  
High Salt Intake

Background. Epidemiological and clinical studies demonstrated that excessive salt intake causes severe hypertension and exacerbated organ derangement such as chronic kidney disease (CKD). In this study, we focused on evaluating histological and gene-expression findings in the kidney using stroke-prone spontaneously hypertensive rats (SHRSP) with high-salt intake and thromboxane A2/ prostaglandin H2 receptor (TPR) blocker ONO-8809. Methods. SHRSP aged 6 weeks were divided into three groups eating normal chow containing 0.4% NaCl, 2.0%NaCl, or 2.0%NaCl +ONO-8809 (0.6mg/kg p.o. daily). Histological analyses with immunohistochemistry and a gene-expression assay with a DNA kidney microarray were performed after 8 weeks. Results. The following changes were observed with high-salt intake. Glomerular sclerotic changes were remarkably observed in the juxtaglomerular cortex areas. ED1, MCP-1, nitrotyrosine, and HIF-1&alpha; staining areas were increased in the glomeruli and interstitial portion. Tbxa2r which encodes TPR, Prcp, and Car7 were significantly underexpressed in the kidney. The plasma 8-isoprostane level was significantly elevated, and was attenuated with ONO-8809 treatment. Conclusion. TXA2 and oxidative stresses exaggerated renal dysfunction in salt-loading SHRSP, and ONO-8809 as a TPR blocker suppressed these changes. Therefore, ONO-8809 is a candidate drug to prevent CKD for hypertensive patients associated with high-salt intake.

Dissociation between right atrial pressure and plasma atrial natriuretic factor following prolonged high salt intake

1990 ◽  
Vol 68 (3) ◽  
pp. 408-412
Author(s):  
Jiri Widimsky Jr. ◽  
Otto Kuchel ◽  
Waldemar Debinski ◽  
Gaétan Thibault
Keyword(s):  
Atrial Natriuretic Factor ◽  
Salt Intake ◽  
High Salt ◽  
Atrial Pressure ◽  
Right Atrial ◽  
Right Atrial Pressure ◽  
Salt Loading ◽  
Natriuretic Factor ◽  
High Salt Intake ◽  
Atrial Natriuretic

The influence of prolonged high salt intake on intravascular volume, right atrial pressure, plasma atrial natriuretic factor, and extra-atrial tissue (lung, kidney, and liver) COOH- and NH2-terminal atrial natriuretic factor content was investigated in normotensive rats. Despite prolonged high salt (8% NaCl) intake for 5 weeks, total intravascular volume was not impaired. However, right atrial pressure was increased by 54% (p < 0.01) after salt loading. Although this increment in right atrial pressure should favor atrial natriuretic factor release after NaCl intake, plasma atrial natriuretic factor (COOH-terminal) concentrations markedly decreased from 97.8 ± 27 to 38.9 ± 8 pg/mL. Sodium and circulatory homeostasis was, however, well preserved. The lungs contained the highest levels of COOH- and NH2-terminal atrial natriuretic factor. Salt loading resulted in increased concentrations of low as well as high molecular weight atrial natriuretic factor in the lung but not in the kidney or the liver. Our study indicates a limited role of atrial natriuretic factor in adaptation to prolonged salt consumption in rats. Dissociation between right atrial pressure and plasma atrial natriuretic factor after salt intake implicates other factors regulating circulating peptide levels. Prolonged salt intake increases lung generation of atrial natriuretic factor.Key words: atrial natriuretic factor, volume, atrial pressure, high salt diet.

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