Fluoxetine ameliorates high-fat diet-induced metabolic abnormalities partially via reduced adipose triglyceride lipase-mediated adipocyte lipolysis

AbstractObesity-related renal lipotoxicity and chronic kidney disease (CKD) are prevalent pathologies with complex aetiologies. One hallmark of renal lipotoxicity is the ectopic accumulation of lipid droplets in kidney podocytes and in proximal tubule cells. Renal lipid droplets are observed in human CKD patients and in high-fat diet rodent models but their precise role remains unclear. Here, we establish a high-fat diet model in Drosophila that recapitulates renal lipid droplets and several other aspects of mammalian CKD. Cell-type specific genetic manipulations show that lipid can overflow from adipose tissue and is taken up by renal cells called nephrocytes. A high-fat diet drives nephrocyte lipid uptake via the multiligand receptor Cubilin, leading to the ectopic accumulation of lipid droplets. These nephrocyte lipid droplets correlate with ER and mitochondrial deficits, as well as with impaired macromolecular endocytosis, a key conserved function of renal cells. Nephrocyte knockdown of diglyceride acyltransferase 1 (DGAT1), overexpression of adipose triglyceride lipase (ATGL) and epistasis tests together reveal that fatty acid flux through the lipid droplet triglyceride compartment protects the ER, mitochondria and endocytosis of renal cells. Strikingly, boosting nephrocyte expression of the lipid droplet resident enzyme ATGL is sufficient to rescue high-fat diet induced defects in renal endocytosis. Moreover, endocytic rescue requires a conserved mitochondrial regulator, peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC1α). This study demonstrates that lipid droplet lipolysis counteracts the harmful effects of a high-fat diet via a mitochondrial pathway that protects renal endocytosis. It also provides a genetic strategy for determining whether lipid droplets in different biological contexts function primarily to release beneficial or to sequester toxic lipids.

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Pharmacological inhibition of adipose triglyceride lipase corrects high-fat diet-induced insulin resistance and hepatosteatosis in mice

Nature Communications ◽

10.1038/ncomms14859 ◽

2017 ◽

Vol 8 (1) ◽

Cited By ~ 64

Author(s):

Martina Schweiger ◽

Matthias Romauch ◽

Renate Schreiber ◽

Gernot F. Grabner ◽

Sabrina Hütter ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

High Fat Diet ◽

Adipose Triglyceride Lipase ◽

High Fat ◽

Alcoholic Fatty Liver ◽

Triglyceride Lipase ◽

Pharmacological Inhibition ◽

Long Term Treatment ◽

Adipose Tissue Lipolysis

Abstract Elevated circulating fatty acids (FAs) contribute to the development of obesity-associated metabolic complications such as insulin resistance (IR) and non-alcoholic fatty liver disease (NAFLD). Hence, reducing adipose tissue lipolysis to diminish the mobilization of FAs and lower their respective plasma concentrations represents a potential treatment strategy to counteract obesity-associated disorders. Here we show that specific inhibition of adipose triglyceride lipase (Atgl) with the chemical inhibitor, Atglistatin, effectively reduces adipose tissue lipolysis, weight gain, IR and NAFLD in mice fed a high-fat diet. Importantly, even long-term treatment does not lead to lipid accumulation in ectopic tissues such as the skeletal muscle or heart. Thus, the severe cardiac steatosis and cardiomyopathy that is observed in genetic models of Atgl deficiency does not occur in Atglistatin-treated mice. Our data validate the pharmacological inhibition of Atgl as a potentially powerful therapeutic strategy to treat obesity and associated metabolic disorders.

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Spred2 Regulates High Fat Diet-Induced Adipose Tissue Inflammation, and Metabolic Abnormalities in Mice

Frontiers in Immunology ◽

10.3389/fimmu.2019.00017 ◽

2019 ◽

Vol 10 ◽

Cited By ~ 5

Author(s):

Takahiro Ohkura ◽

Teizo Yoshimura ◽

Masayoshi Fujisawa ◽

Toshiaki Ohara ◽

Rie Marutani ◽

...

Keyword(s):

Adipose Tissue ◽

High Fat Diet ◽

Metabolic Abnormalities ◽

Adipose Tissue Inflammation ◽

High Fat ◽

Tissue Inflammation

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Magnesium Lithospermate B Attenuates High-Fat Diet-Induced Muscle Atrophy in C57BL/6J Mice

Nutrients ◽

10.3390/nu14010104 ◽

2021 ◽

Vol 14 (1) ◽

pp. 104

Author(s):

Tsun-Li Cheng ◽

Zi-Yun Lin ◽

Keng-Ying Liao ◽

Wei-Chi Huang ◽

Cian-Fen Jhuo ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscle Atrophy ◽

High Fat Diet ◽

Skeletal Muscle Atrophy ◽

Metabolic Abnormalities ◽

High Fat ◽

E3 Ligases ◽

Beneficial Effects ◽

Magnesium Lithospermate B ◽

Tnf Α

Magnesium lithospermate B (MLB) is a primary hydrophilic component of Danshen, the dried root of Salvia miltiorrhiza used in traditional medicine, and its beneficial effects on obesity-associated metabolic abnormalities were reported in our previous study. The present study investigated the anti-muscle atrophy potential of MLB in mice with high-fat diet (HFD)-induced obesity. In addition to metabolic abnormalities, the HFD mice had a net loss of skeletal muscle weight and muscle fibers and high levels of muscle-specific ubiquitin E3 ligases, namely the muscle atrophy F-box (MAFbx) and muscle RING finger protein 1 (MuRF-1). MLB supplementation alleviated those health concerns. Parallel changes were revealed in high circulating tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), skeletal TNF receptor I (TNFRI), nuclear factor-kappa light chain enhancer of activated B cells (NF-κB), p65 phosphorylation, and Forkhead box protein O1 (FoxO1) as well as low skeletal phosphoinositide 3-kinase (PI3K) and protein kinase B (Akt) phosphorylation. The study revealed that MLB prevented obesity-associated skeletal muscle atrophy, likely through the inhibition of MAFbx/MuRF-1-mediated muscular degradation. The activation of the PI3K-Akt-FoxO1 pathway and inhibition of the TNF-α/TNFRI/NF-κB pathway were assumed to be beneficial effects of MLB.

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Adipose Triglyceride Lipase-Null Mice Are Resistant to High-Fat Diet–Induced Insulin Resistance Despite Reduced Energy Expenditure and Ectopic Lipid Accumulation

Endocrinology ◽

10.1210/en.2010-0661 ◽

2011 ◽

Vol 152 (1) ◽

pp. 48-58 ◽

Cited By ~ 74

Author(s):

Andrew J. Hoy ◽

Clinton R. Bruce ◽

Sarah M. Turpin ◽

Alexander J. Morris ◽

Mark A. Febbraio ◽

...

Keyword(s):

Insulin Resistance ◽

Fatty Acids ◽

Insulin Sensitivity ◽

Energy Expenditure ◽

Glucose Tolerance ◽

Lipid Accumulation ◽

High Fat Diet ◽

Adipose Triglyceride Lipase ◽

Wild Type ◽

High Fat

Abstract Adipose triglyceride lipase (ATGL) null (−/−) mice store vast amounts of triacylglycerol in key glucoregulatory tissues yet exhibit enhanced insulin sensitivity and glucose tolerance. The mechanisms underpinning these divergent observations are unknown but may relate to the reduced availability of circulating fatty acids. The aim of this study was to determine whether the enhancements in insulin stimulated glucose metabolism in ATGL−/− mice persist when challenged with a high-fat diet. ATGL−/− mice fed a low-fat diet exhibit improved whole-body insulin sensitivity and glucose tolerance compared with wild-type mice. Wild-type mice became hyperlipidemic and insulin-resistant when challenged with a high-fat diet (HFD, 60% fat) for 4 wk. ATGL−/− mice fed a HFD had elevated circulating fatty acids but had reduced fasting glycemia compared to pre–high-fat diet levels and were refractory to glucose intolerance and insulin resistance. This protection from high-fat diet–induced metabolic perturbations was associated with a preference for fatty acid utilization but reduced energy expenditure and no change in markers of mitochondrial capacity or density. The protection from high-fat diet–induced insulin resistance in ATGL−/− mice was due to increased cardiac and liver insulin-stimulated glucose clearance despite increased lipid content in these tissues. Additionally, there was no difference in skeletal muscle insulin-stimulated glucose disposal, but there was a reduction observed in brown adipose tissue. Overall, these results show that ATGL−/− mice are protected from HFD-induced insulin resistance and reveal a tissue specific disparity between lipid accumulation and insulin sensitivity.

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Rhinacanthus nasutus leaf improves metabolic abnormalities in high-fat diet-induced obese mice

Asian Pacific Journal of Tropical Biomedicine ◽

10.1016/j.apjtb.2015.10.004 ◽

2016 ◽

Vol 6 (1) ◽

pp. 1-7 ◽

Cited By ~ 6

Author(s):

Supaporn Wannasiri ◽

Pritsana Piyabhan ◽

Jarinyaporn Naowaboot

Keyword(s):

High Fat Diet ◽

Metabolic Abnormalities ◽

Obese Mice ◽

High Fat ◽

Rhinacanthus Nasutus

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Low molecular weight chitosan oligosaccharides (LMW-COSs) prevent obesity-related metabolic abnormalities in association with the modification of gut microbiota in high-fat diet (HFD)-fed mice

Food & Function ◽

10.1039/d0fo01871f ◽

2020 ◽

Vol 11 (11) ◽

pp. 9947-9959

Author(s):

Ningning He ◽

Shuo Wang ◽

Zhiyuan Lv ◽

Wandong Zhao ◽

Shangyong Li

Keyword(s):

Molecular Weight ◽

Inflammatory Response ◽

Gut Microbiota ◽

High Fat Diet ◽

Metabolic Parameters ◽

Low Molecular Weight ◽

Metabolic Abnormalities ◽

High Fat ◽

Chitosan Oligosaccharides ◽

Low Molecular Weight Chitosan

Enzymatic LMW-COSs ameliorate obesity and obesity-related metabolic abnormalities. The overall change in gut microbiota was associated with metabolic parameters and its prebiotic functions by regulating gut microbiota and inflammatory response.

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