Palmitic acid stimulates energy metabolism and inhibits insulin/PI3K/AKT signaling in differentiated human neuroblastoma cells: The role of mTOR activation and mitochondrial ROS production

Calvo-Ochoa, Erika; Sánchez-Alegría, Karina; Gómez-Inclán, Cecilia; Ferrera, Patricia; Arias, Clorinda

doi:10.1016/j.neuint.2017.09.008

Cited by 40 publications

(53 citation statements)

References 53 publications

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“…To assess whether PA induces Ca 2+ entry by any of these mechanisms, we first tested whether PA is metabolized by the mitochondria and thereby increases intraneuronal ATP levels. We have previously reported that both insulin and PA treatment increased the metabolic activity of differentiated MSN cells, as observed by the increase in MTT reduction by mitochondrial dehydrogenases 20 . Here, we found that both insulin and PA increased ATP levels 6 minutes and 1 hour after exposure.…”

Section: Resultssupporting

confidence: 71%

“…However, we found that the ATP produced by differentiated human neuroblastoma cells after PA exposure was totally blocked by the CPT1‐specific inhibitor etomoxir, which prevents the transport of activated fatty acids into the mitochondrial matrix for further metabolization. In previous works, we have also demonstrated that in both, cultured hippocampal neurons and differentiated human MSN cells, PA exposure reduces the NAD/NADH ratio and increases MTT reduction, which also indicates that PA is able to stimulate oxidative metabolism in neurons 20,31 . Although the role of fatty acid β‐oxidation as a sensor mechanism of nutrient availability in hypothalamic neurons is well known, 61 the present results suggest that neurons exposed to high concentrations of free fatty acids, as can occur in diabetic and obese subjects, 44 may undergone detrimental effects with respect the lack of insulin sensitivity and Ca 2+ dyshomeostasis.…”

Section: Discussionsupporting

confidence: 67%

“…The modulating effects of PA on intracellular signaling pathways and transcription factors, along with its use as energy supply or precursor for the synthesis of ceramides, and the production of inflammatory mediators have been implicated in the development of insulin resistance 20,31,53‐56 …”

Section: Discussionmentioning

confidence: 99%

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Palmitic acid induces insulin resistance by a mechanism associated with energy metabolism and calcium entry in neuronal cells

et al. 2021

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Palmitic acid (PA) is a saturated fatty acid whose high consumption has been largely associated with the development of different metabolic alterations, such as insulin resistance, metabolic syndrome, and type 2 diabetes. Particularly in the brain, insulin signaling disruption has been linked to cognitive decline and is considered a risk factor for Alzheimer's disease. Cumulative evidence has demonstrated the participation of PA in the molecular cascade underlying cellular insulin resistance in peripheral tissues, but its role in the development of neuronal insulin resistance and the mechanisms involved are not fully understood. It has generally been accepted that the brain does not utilize fatty acids as a primary energy source, but recent evidence shows that neurons possess the machinery for fatty acid β‐oxidation. However, it is still unclear under what conditions neurons use fatty acids as energy substrates and the implications of their oxidative metabolism in modifying insulin‐stimulated effects. In the present work, we have found that neurons differentiated from human neuroblastoma MSN exposed to high but nontoxic concentrations of PA generate ATP through mitochondrial metabolism, which is associated with an increase in the cytosolic Ca2+ and diminished insulin signaling in neurons. These findings reveal a novel mechanism by which saturated fatty acids produce Ca2+ entry and insulin resistance that may play a causal role in increasing neuronal vulnerability associated with metabolic diseases.

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Section: Resultssupporting

confidence: 71%

Section: Discussionsupporting

confidence: 67%

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Palmitic acid induces insulin resistance by a mechanism associated with energy metabolism and calcium entry in neuronal cells

et al. 2021

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“…Our current results showed that Scu reduced mTOR phosphorylation at Ser2448 in PA‐induced HepG2 cells. mTOR activation requires phosphorylation at Ser2448 by insulin (Calvo‐Ochoa, Sánchez‐Alegría, Gómez‐Inclán, Ferrera, & Arias, ). The results demonstrate that upon insulin stimulation, Scu significantly suppressed mTOR phosphorylation in PA‐induced HepG2 cells and the liver of the HFD‐induced mice.…”

Section: Discussionmentioning

confidence: 99%

Scutellarin, a modulator of mTOR, attenuates hepatic insulin resistance by regulating hepatocyte lipid metabolism via SREBP‐1c suppression

Luan

Huo

Zhao

et al. 2019

Phytotherapy Research

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High levels of consumption of saturated lipids have been largely associated with the increasing prevalence of metabolic diseases. In particular, saturated fatty acids such as palmitic acid (PA) have been implicated in the development of insulin resistance (IR).Scutellarin (Scu) is one of the effective traditional Chinese medicines considered beneficial for liver diseases and diabetes. In this study, we investigated the effect of Scu on IR and lipid metabolism disorders in vitro and in high fat diet (HFD)-fed mice. In vitro, we found that Scu decreased insulin-dependent lipid accumulation and the mRNA expression of CD36, Fasn, and ACC in PA-treated HepG2 cells. Additionally, Scu upregulated Akt phosphorylation and improved the insulin signalling pathway. Moreover, Scu downregulated mammalian target of rapamycin (mTOR) phosphorylation and the n-SREBP-1c protein level and also reduced lipid accumulation via the mTORdependent pathway, as confirmed by the molecular docking of Scu to mTOR. In HFDfed C57BL/6 mice, Scu improved oral glucose tolerance, pyruvate tolerance and the IR index and also increased the Akt phosphorylation level. Moreover, Scu reduced hepatocyte steatosis, decreased lipid accumulation and triglyceride levels, inhibited mTOR phosphorylation, and decreased the SREBP-1c level in the liver. Taken together, these findings suggest that Scu ameliorates hepatic IR by regulating hepatocyte lipid metabolism via the mTOR-dependent pathway through SREBP-1c suppression. K E Y W O R D Shepatic insulin resistance, lipid accumulation, mTOR, n-SREBP-1c

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“…These results could help explain why that happens! Other studies done by us and by other scientists have found that a type of fat called saturated fats, which is very abundant in processed foods, can directly damage neurons by changing the way they use energy and by increasing molecules that cause stress and inflammation [5,6]. All these amazing scientific studies back up what your parents and doctors always tell you: eating a nutritious, balanced diet low in processed foods and sugar is very important for staying healthy, strong, and smart!…”

Section: Our Conclusion: a Nutritious Balanced Diet Is Fundamental mentioning

confidence: 99%

Food for Thought: What Happens to the Brain When We Eat Foods High in Fat and Sugar?

Calvo-Ochoa¹,

Arias²

2019

Front. Young Minds

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Have you ever wondered how different foods in your diet affect your brain? The brain is an extraordinary organ in charge of an astounding number of functions in your body. This is why the brain requires highquality nutrients found in the food you eat. But what happens to your brain when you eat processed foods high in fat and sugar? To answer this question, we fed rats a diet high in fat and sugar and then studied its effects in a part of the brain important for memory and learning, known as the hippocampus. Surprisingly, we found out that eating foods high in fat and sugar, even for short periods of time, produces several harmful changes in the hippocampus. We think that these changes could have a negative impact on memory and learning.

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Palmitic acid stimulates energy metabolism and inhibits insulin/PI3K/AKT signaling in differentiated human neuroblastoma cells: The role of mTOR activation and mitochondrial ROS production

Cited by 40 publications

References 53 publications

Palmitic acid induces insulin resistance by a mechanism associated with energy metabolism and calcium entry in neuronal cells

Palmitic acid induces insulin resistance by a mechanism associated with energy metabolism and calcium entry in neuronal cells

Scutellarin, a modulator of mTOR, attenuates hepatic insulin resistance by regulating hepatocyte lipid metabolism via SREBP‐1c suppression

Food for Thought: What Happens to the Brain When We Eat Foods High in Fat and Sugar?

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