Cardiac Nmnat/NAD+/SIR2 pathways activation mediates endurance exercise resistance to heart defects induced by a high-fat diet in aging Drosophila

AbstractEndurance exercise is an important way to resist and treat a high-fat-diet(HFD)-induced heart defects, but the underlying molecular mechanisms are poorly understood. Here, we used Drosophila to identify whether cardiac Nmnat/NAD+/SIR2 pathways activation could mediate endurance exercise resistance to heart defects. The results showed that endurance exercise activated the cardiac Nmnat/NAD+/SIR2/FOXO pathway and Nmnat/NAD+/SIR2/PGC-1α pathway, including up-regulating cardiac Nmnat, SIR2, FOXO, PGC-1α expression, SOD activity, and NAD+ level, and it prevented HFD-induced or cardiac Nmnat knock-down-induced cardiac lipid accumulation, MDA content and fibrillation increase, and fractional shortening decrease. Cardiac Nmnat overexpression activated heart Nmnat/NAD+/SIR2 pathways and resisted HFD-induced cardiac malfunction, but it could not protect against HFD-induced lifespan reduction and locomotor impairment. Exercise improved lifespan and mobility in cardiac Nmnat knockdown flies. Therefore, current results confirmed that cardiac Nmnat/NAD+/SIR2 pathways were important antagonists of HFD-induced heart defects. The cardiac Nmnat/NAD+/SIR2 pathways activation was the important underlying molecular mechanism of endurance exercise and cardiac Nmnat overexpression against heart defects in Drosophila.

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Activation of cardiac Nmnat/NAD+/SIR2 pathways mediates endurance exercise resistance to lipotoxic cardiomyopathy in aging Drosophila

Journal of Experimental Biology ◽

10.1242/jeb.242425 ◽

2021 ◽

Vol 224 (18) ◽

Author(s):

Deng-tai Wen ◽

Lan Zheng ◽

Kai Lu ◽

Wen-qi Hou

Keyword(s):

Endurance Exercise ◽

High Fat Diet ◽

Molecular Mechanisms ◽

Sod Activity ◽

Pathway Activation ◽

Locomotor Impairment ◽

Mda Content ◽

Exercise Induced ◽

Fractional Shortening ◽

Lipotoxic Cardiomyopathy

ABSTRACT Endurance exercise is an important way to resist and treat high-fat diet (HFD)-induced lipotoxic cardiomyopathy, but the underlying molecular mechanisms are poorly understood. Here, we used Drosophila to identify whether cardiac Nmnat/NAD+/SIR2 pathway activation mediates endurance exercise-induced resistance to lipotoxic cardiomyopathy. The results showed that endurance exercise activated the cardiac Nmnat/NAD+/SIR2/FOXO pathway and the Nmnat/NAD+/SIR2/PGC-1α pathway, including up-regulating cardiac Nmnat, SIR2, FOXO and PGC-1α expression, superoxide dismutase (SOD) activity and NAD+ levels, and it prevented HFD-induced or cardiac Nmnat knockdown-induced cardiac lipid accumulation, malondialdehyde (MDA) content and fibrillation increase, and fractional shortening decrease. Cardiac Nmnat overexpression also activated heart Nmnat/NAD+/SIR2 pathways and resisted HFD-induced cardiac malfunction, but it could not protect against HFD-induced lifespan reduction and locomotor impairment. Exercise improved lifespan and mobility in cardiac Nmnat knockdown flies. Therefore, the current results confirm that cardiac Nmnat/NAD+/SIR2 pathways are important antagonists of HFD-induced lipotoxic cardiomyopathy. Cardiac Nmnat/NAD+/SIR2 pathway activation is an important underlying molecular mechanism by which endurance exercise and cardiac Nmnat overexpression give protection against lipotoxic cardiomyopathy in Drosophila.

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Consumption of a high-fat diet, but not regular endurance exercise training, regulates hypothalamic lipid accumulation in mice

The Journal of Physiology ◽

10.1113/jphysiol.2012.233288 ◽

2012 ◽

Vol 590 (17) ◽

pp. 4377-4389 ◽

Cited By ~ 60

Author(s):

Melissa L. Borg ◽

Simin Fallah Omran ◽

Jacquelyn Weir ◽

Peter J. Meikle ◽

Matthew J. Watt

Keyword(s):

Exercise Training ◽

Endurance Exercise ◽

Lipid Accumulation ◽

High Fat Diet ◽

High Fat ◽

Endurance Exercise Training

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Filbertone Ameliorates Adiposity in Mice Fed a High-Fat Diet via Activation of cAMP Signaling

Nutrients ◽

10.3390/nu11081749 ◽

2019 ◽

Vol 11 (8) ◽

pp. 1749

Author(s):

Youna Moon ◽

Tao Tong ◽

Wesuk Kang ◽

Taesun Park

Keyword(s):

Adipose Tissue ◽

Lipid Accumulation ◽

High Fat Diet ◽

Molecular Mechanisms ◽

Body Weight Gain ◽

Mrna Level ◽

Camp Signaling ◽

High Fat ◽

Necrosis Factor Alpha ◽

Flavor Compound

The aim of this research was to estimate the preventive effects of filbertone, the main flavor compound in hazelnuts, on lipid accumulation in the adipose tissue of mice fed a high-fat diet (HFD) and to reveal the underlying molecular mechanisms. Male C57BL/6N mice were fed chow, a HFD, or a 0.025% filbertone-supplemented HFD for 14 weeks. We found that filbertone supplementation resulted in significant reductions in body weight gain and lipid accumulation in adipose tissue, with parallel improvements in plasma lipid levels (triglycerides, total cholesterol, and free fatty acids) and proinflammatory cytokines (interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α)). Molecular analysis revealed that filbertone treatment led to reprogramming of metabolic signatures in the cyclic adenosine monophosphate (cAMP) pathway. Filbertone supplementation significantly increased the cAMP level and increased downstream protein kinase A catalytic subunit (PKA) signaling in mouse adipose tissue. The mRNA level of adipogenesis-related genes was downregulated in the adipose tissue of filbertone-fed mice compared to control mice fed the HFD alone. Furthermore, filbertone treatment elevated the expression of thermogenic genes in mouse adipose tissue. Filbertone reduced intracellular lipid accumulation and increased the oxygen consumption rate in 3T3-L1 cells and these filbertone-induced changes were abrogated by the adenylate cyclases (ADCY) inhibitor. Taken together, our results suggest that the beneficial effects of filbertone on lipid accumulation may be associated with the activation of cAMP signaling.

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Uridine attenuates obesity, ameliorates hepatic lipid accumulation and modifies the gut microbiota composition in mice fed with a high-fat diet

Food & Function ◽

10.1039/d0fo02533j ◽

2021 ◽

Author(s):

Yilin Liu ◽

Chunyan Xie ◽

Zhenya Zhai ◽

Ze-yuan Deng ◽

Hugo R. De Jonge ◽

...

Keyword(s):

Gut Microbiota ◽

Lipid Accumulation ◽

High Fat Diet ◽

Microbiota Composition ◽

High Fat ◽

Fat Accumulation ◽

Hepatic Lipid ◽

Hepatic Lipid Accumulation ◽

Gut Microbiota Composition

This study aimed to investigate the effect of uridine on obesity, fat accumulation in liver, and gut microbiota composition in high-fat diet-fed mice.

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Baicalin Attenuates High Fat Diet-Induced Obesity and Liver Dysfunction: Dose-Response and Potential Role of CaMKKβ/AMPK/ACC Pathway

Cellular Physiology and Biochemistry ◽

10.1159/000374037 ◽

2015 ◽

Vol 35 (6) ◽

pp. 2349-2359 ◽

Cited By ~ 42

Author(s):

Youli Xi ◽

Miaozong Wu ◽

Hongxia Li ◽

Siqi Dong ◽

Erfei Luo ◽

...

Keyword(s):

Protein Kinase ◽

Fatty Liver ◽

High Fat Diet ◽

Molecular Mechanisms ◽

Liver Steatosis ◽

Serum Levels ◽

Whole Body ◽

Therapeutic Effects ◽

High Fat ◽

Dependent Protein

Background/Aims: Obesity-associated fatty liver disease affects millions of individuals. This study aimed to evaluate the therapeutic effects of baicalin to treat obesity and fatty liver in high fat diet-induced obese mice, and to study the potential molecular mechanisms. Methods: High fat diet-induced obese animals were treated with different doses of baicalin (100, 200 and 400 mg/kg/d). Whole body, fat pad and liver were weighed. Hyperlipidemia, liver steatosis, liver function, and hepatic Ca2+/CaM-dependent protein kinase kinase β (CaMKKβ) / AMP-activated protein kinase (AMPK) / acetyl-CoA carboxylase (ACC) were further evaluated. Results: Baicalin significantly decreased liver, epididymal fat and body weights in high fat diet-fed mice, which were associated with decreased serum levels of triglycerides, total cholesterol, LDL, alanine transaminase and aspartate transaminase, but increased serum HDL level. Pathological analysis revealed baicalin dose-dependently decreased the degree of hepatic steatosis, with predominantly diminished macrovesicular steatosis at lower dose but both macrovesicular and microvesicular steatoses at higher dose of baicalin. Baicalin dose-dependently inhibited hepatic CaMKKβ/AMPK/ACC pathway. Conclusion: These data suggest that baicalin up to 400 mg/kg/d is safe and able to decrease the degree of obesity and fatty liver diseases. Hepatic CaMKKβ/AMPK/ACC pathway may mediate the therapeutic effects of baicalin in high fat diet animal model.

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Abstract 037: Role of Pro-opiomelanocortin (POMC) Specific PTP1B in Differential Regulation of Blood Pressure, Liver Lipid Accumulation and Glucose Tolerance in Response to a High Fat Diet

Hypertension ◽

10.1161/hyp.68.suppl_1.037 ◽

2016 ◽

Vol 68 (suppl_1) ◽

Author(s):

Nicola Aberdein ◽

Jussara M do Carmo ◽

Zhen Wang ◽

Taolin Fang ◽

Cecilia P de Lara ◽

...

Keyword(s):

Blood Pressure ◽

Glucose Tolerance ◽

Fat Mass ◽

Lipid Accumulation ◽

High Fat Diet ◽

Acute Stress ◽

Liver Lipid ◽

Liver Weight ◽

Metabolic Effects ◽

High Fat

Obese subjects are often resistant to leptin’s metabolic effects although blood pressure (BP) and sympathetic nervous system responses appear to be preserved. Protein tyrosine phosphatase 1B (PTP1B), a negative regulator of leptin signaling, may play a role in promoting this selective leptin resistance and causing metabolic dysfunction in obesity. Our previous studies suggest that the chronic BP responses to leptin are mediated via activation of pro-opiomelanocortin (POMC) neurons. The goal of this study was to determine if PTP1B in POMC neurons differentially controls metabolic functions and BP in mice fed a high fat diet (HFD). Male mice with POMC specific PTP1B deletion (POMC/PTP1B -/- ) and littermate controls (PTP1B flox/flox ) were fed a HFD from 6 to 22 wks of age. Baseline BP after 16 weeks of a HFD (95±2 vs. 95±3 mmHg) and BP responses to acute stress (Δ32±0 vs. Δ32±6 mmHg), measured by telemetry, were not different in POMC/PTP1B -/- compared to control mice, respectively. Heart rate (HR) was not different in POMC/PTP1B -/- and control mice during acute stress (699±4 vs. 697±15 bpm, respectively). Total body weight (TBW) and fat mass were reduced at 20 weeks of age in POMC/PTP1B -/- compared to controls (36.7±0.1 vs. 42.0±1 g TBW and 12.7±0.4 vs. 16.1±1.0 g fat mass, respectively). Liver weight of POMC/PTP1B -/- mice was less than in controls, and this was evident even when liver weight was normalized as % of TBW (4.5±0.2 vs. 5.0±0.2 %). POMC/PTP1B -/- males had reduced liver lipid accumulation compared to controls as measured by EchoMRI (0.08±0.03 vs. 0.15±0.03 g/g liver weight). Glucose tolerance was also improved by 46% in POMC/PTP1B -/- compared to controls as measured by AUC, 25856±1683 vs. 47267±5616 mg/dLx120min, respectively. These findings indicate that PTP1B signaling in POMC neurons plays a crucial role in regulating liver lipid accumulation and glucose tolerance but does not appear to mediate changes in BP or BP responses to acute stress in mice fed a high HFD (supported by NHLBI-PO1HL51971 and NIGMS P20GM104357)

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Effects of Endurance Exercise and High-Fat Diet on Insulin Resistance and Ceramide Contents of Skeletal Muscle in Sprague-Dawley Rats

Korean Diabetes Journal ◽

10.4093/kdj.2010.34.4.244 ◽

2010 ◽

Vol 34 (4) ◽

pp. 244 ◽

Cited By ~ 9

Author(s):

Hyun Lyung Jung ◽

Ho Youl Kang

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Endurance Exercise ◽

High Fat Diet ◽

Sprague Dawley ◽

High Fat ◽

Sprague Dawley Rats

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Fisetin attenuates high fat diet-triggered hepatic lipid accumulation: A mechanism involving liver inflammation overload associated TACE/TNF-α pathway

Journal of Functional Foods ◽

10.1016/j.jff.2018.12.007 ◽

2019 ◽

Vol 53 ◽

pp. 7-21 ◽

Cited By ~ 9

Author(s):

Xu Minxuan ◽

Yan Sun ◽

Xianling Dai ◽

Jianxia Zhan ◽

Tingting Long ◽

...

Keyword(s):

Lipid Accumulation ◽

High Fat Diet ◽

Liver Inflammation ◽

High Fat ◽

Hepatic Lipid ◽

Hepatic Lipid Accumulation ◽

Tnf Α

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Hepatic Lipid Accumulation Induced by a High-fat Diet Is Regulated by Nrf2 Through Multiple Pathways

10.21203/rs.3.rs-775710/v1 ◽

2021 ◽

Author(s):

sheng Qiu ◽

Zerong Liang ◽

Qinan Wu ◽

Miao Wang ◽

Mengliu Yang ◽

...

Keyword(s):

Lipid Metabolism ◽

Lipid Accumulation ◽

High Fat Diet ◽

Underlying Mechanism ◽

Luciferase Assay ◽

High Fat ◽

Hepatic Lipid ◽

Hepatic Lipid Accumulation

Abstract BackgroundNuclear factor erythroid 2-related factor 2 (Nrf2) is reportedly involved in hepatic lipid metabolism, but the results are contradictory and the underlying mechanism thus remains unclear. Herein we focused on elucidating the effects of Nrf2 on hepatic adipogenesis and on determining the possible underlying mechanism. We established a metabolic associated fatty liver disease (MAFLD) model in high fat diet (HFD) fed Nrf2 knockout (Nrf2 KO) mice; further, a cell model of lipid accumulation was established using mouse primary hepatocytes (MPHs) treated with free fatty acids (FAs). Using these models, we investigated the relationship between Nrf2 and autophagy and its role in the development of MAFLD.ResultsWe observed that Nrf2 expression levels were up-regulated in patients with MAFLD and diet-induced obese mice. Nrf2 deficiency led to hepatic lipid accumulation in vivo and in vitro, in addition to, promoting lipogenesis mainly by increasing SREBP-1 activity. Moreover, Nrf2 deficiency attenuated autophagic flux and inhibited the fusion of autophagosomes and lysosomes in vivo and in vitro. Weakened autophagy caused reduced lipolysis in the liver. Importantly, Chromatin immunoprecipitation-qPCR (ChIP-qPCR) and dual-luciferase assay results proved that Nrf2 bound to LAMP1 promoter and regulated its transcriptional activity. We accordingly report that Nrf2-LAMP1 interaction has an indispensable role in Nrf2-regulated hepatosteatosis. ConclusionsThese data collectively confirm that Nrf2 deficiency promotes hepatosteatosis by enhancing SREBP-1 activity and attenuating autophagy. To conclude, our data reveal a novel multi-pathway effect of Nrf2 on lipid metabolism in the liver, and we believe that multi-target intervention of Nrf2 signaling is a promising new strategy for the prevention and treatment of MAFLD.

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