Warren EC, Dooves S, Lugarà E, et al. Decanoic acid inhibits mTORC1 activity independent of glucose and insulin signaling [published online ahead of print, 2020 Sep 2]. Proc Natl Acad Sci U S A. 2020;202008980. doi:10.1073/pnas.2008980117

https://doi.org/10.1073/pnas.2008980117

Abstract

Low-glucose and -insulin conditions, associated with ketogenic diets, can reduce the activity of the mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway, potentially leading to a range of positive medical and health-related effects. Here, we determined whether mTORC1 signaling is also a target for decanoic acid, a key component of the medium-chain triglyceride (MCT) ketogenic diet. Using a tractable model system, Dictyostelium, we show that decanoic acid can decrease mTORC1 activity, under conditions of constant glucose and in the absence of insulin, measured by phosphorylation of eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1). We determine that this effect of decanoic acid is dependent on a ubiquitin regulatory X domain-containing protein, mediating inhibition of a conserved Dictyostelium AAA ATPase, p97, a homolog of the human transitional endoplasmic reticulum ATPase (VCP/p97) protein. We then demonstrate that decanoic acid decreases mTORC1 activity in the absence of insulin and under high-glucose conditions in ex vivo rat hippocampus and in tuberous sclerosis complex (TSC) patient-derived astrocytes. Our data therefore indicate that dietary decanoic acid may provide a new therapeutic approach to down-regulate mTORC1 signaling.

https://www.pnas.org/content/pnas/early/2020/09/01/2008980117.full.pdf

https://preview.redd.it/z4kqflf1dwl51.png?width=404&format=png&auto=webp&s=525b3697dd034337b32ca4772419df501bf7fb37

Significance

The mTORC1 complex provides a critical role in cell function, regulating a variety of processes including growth and autophagy. mTORC1 signaling is hyperactivated in a range of common diseases including cancer, epilepsy, and neurodegenerative disorders. Hence, mTORC1 signaling provides an important target for regulation in many contexts. Here, we show that decanoic acid, a key component of a widely used medicinal diet, reduces mTORC1 activity. We identify this in a tractable model system, and validate it in ex vivo rat brain tissue and in human iPSCderived astrocy

Dabke P, Das AM. Mechanism of Action of Ketogenic Diet Treatment: Impact of Decanoic Acid and Beta-Hydroxybutyrate on Sirtuins and Energy Metabolism in Hippocampal Murine Neurons. Nutrients. 2020;12(8):E2379. Published 2020 Aug 8. doi:10.3390/nu12082379

https://doi.org/10.3390/nu12082379

Abstract

The ketogenic diet (KD), a high-lipid and low-carbohydrate diet, has been used in the treatment of epilepsy, neurodegenerative disorders, inborn errors of metabolism and cancer; however, the exact mechanism/s of its therapeutic effect is not completely known. We hypothesized that sirtuins (SIRT)-a group of seven NAD-dependent enzymes and important regulators of energy metabolism may be altered under KD treatment. HT22 hippocampal murine neurons were incubated with two important KD metabolites-beta-hydroxybutyrate (BHB) (the predominant ketone body) and decanoic acid (C10), both accumulating under KD. Enzyme activity, protein, and gene expressions of SIRT 1-4, enzyme capacities of the mitochondrial respiratory chain complexes (MRC), citrate synthase (CS) and gene expression of monocarboxylate transporters were measured in control (untreated) and KD-treated cells. Incubation with both-BHB and C10 resulted in significant elevation of SIRT1 enzyme activity and an overall upregulation of the MRC. C10 incubation showed prominent increases in maximal activities of complexes I + III and complex IV of the MRC and ratios of their activities to that of CS, pointing towards a more efficient functioning of the mitochondria in C10-treated cells.

https://www.mdpi.com/2072-6643/12/8/2379/pdf

https://preview.redd.it/zvp6vuns1zh51.png?width=880&format=png&auto=webp&s=560d983e095d310a84941112dce3300a16eb13ef

https://preview.redd.it/ho04a07z1zh51.png?width=732&format=png&auto=webp&s=c26b238e7918289a8b8f64321b408c355a64b679

https://preview.redd.it/x3x01n212zh51.png?width=743&format=png&auto=webp&s=885e8009109f99d4b34a147d2434aa74c86a1a4d

https://www.ncbi.nlm.nih.gov/pubmed/31366451

Enderlin J1, Loussouarn A2, Benoist JF3, Dozières-Puyravel B2, Auvin S4.

Abstract

Recently, decanoic acid (C10), a medium-chain fatty acid, was shown to be a direct inhibitor of the AMPA receptor. Accordingly, C10 has been suggested as a potential anticonvulsant factor in the ketogenic diet (KD) or the medium-chain triglyceride KD. Here, we tested whether C10 serum levels correlate with the response to KD in five children (1.5 ± 0.6 years of age) with epilepsy. The serum levels of C10 were measured before and after KD initiation (n=2 at one month, n=3 at three months, and n=1 at six months after initiation) by gas chromatography-mass spectrometry. After three months on KD, two patients were found to be responders. The mean serum level before KD initiation was 63.2 μM. Only one patient, who was a non-responder, showed an increase (5%) in C10 serum level after a month of KD. The remaining four patients (two responders) showed a decrease in the C10 level from -5.3% to -75.5%. Our preliminary data show that KD does not lead to an increase in C10 serum levels, suggesting that increased concentration of C10 might not be directly involved in the anticonvulsant effects of classic KD.

https://www.ncbi.nlm.nih.gov/pubmed/28682459
>Abstract
OBJECTIVE: The medium-chain triglyceride (MCT) ketogenic diet contains both octanoic (C8) and decanoic (C10) acids. The diet is an effective treatment for pharmacoresistant epilepsy. Although the exact mechanism for its efficacy is not known, it is emerging that C10, but not C8, interacts with targets that can explain antiseizure effects, for example, peroxisome proliferator-activated receptor-γ (eliciting mitochondrial biogenesis and increased antioxidant status) and the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor. For such effects to occur, significant concentrations of C10 are likely to be required in the brain.
METHODS: To investigate how this might occur, we measured the β-oxidation rate of 13 C-labeled C8 and C10 in neuronal SH-SY5Y cells using isotope-ratio mass spectrometry. The effects of carnitine palmitoyltransferase I (CPT1) inhibition, with the CPT1 inhibitor etomoxir, on C8 and C10 β-oxidation were also investigated.
RESULTS:
Both fatty acids were catabolized, as judged by 13 CO2 release. However, C10 was β-oxidized at a significantly lower rate, 20% that of C8. This difference was explained by a clear dependence of C10 on CPT1 activity, which is low in neurons, whereas 66% of C8 β-oxidation was independent of CPT1. In addition, C10 β-oxidation was decreased further in the presence of C8.
SIGNIFICANCE:
It is concluded that, because CPT1 is poorly expressed in the brain, C10 is relatively spared from β-oxidation and can accumulate. This is further facilitated by the presence of C8 in the MCT ketogenic diet, which has a sparing effect upon C10 β-oxidation.

http://brain.oxfordjournals.org/content/early/2015/11/24/brain.awv325

Seizure control by decanoic acid through direct AMPA receptor inhibition (CC) Pishan Chang, Katrin Augustin, Kim Boddum, Sophie Williams, Min Sun, John A. Terschak, Jörg D. Hardege, Philip E. Chen, Matthew C. Walker, Robin S. B. Williams DOI: http://dx.doi.org/10.1093/brain/awv325 awv325 First published online: 25 November 2015 >Summary > The medium chain triglyceride ketogenic diet is an established treatment for drug-resistant epilepsy that increases plasma levels of decanoic acid and ketones. Recently, decanoic acid has been shown to provide seizure control in vivo, yet its mechanism of action remains unclear. Here we show that decanoic acid, but not the ketones β-hydroxybutryate or acetone, shows antiseizure activity in two acute ex vivo rat hippocampal slice models of epileptiform activity. To search for a mechanism of decanoic acid, we show it has a strong inhibitory effect on excitatory, but not inhibitory, neurotransmission in hippocampal slices. Using heterologous expression of excitatory ionotropic glutamate receptor AMPA subunits in Xenopus oocytes, we show that this effect is through direct AMPA receptor inhibition, a target shared by a recently introduced epilepsy treatment perampanel. Decanoic acid acts as a non-competitive antagonist at therapeutically relevant concentrations, in a voltage- and subunit-dependent manner, and this is sufficient to explain its antiseizure effects. This inhibitory effect is likely to be caused by binding to sites on the M3 helix of the AMPA-GluA2 transmembrane domain; independent from the binding site of perampanel. Together our results indicate that the direct inhibition of excitatory neurotransmission by decanoic acid in the brain contributes to the anti-convulsant effect of the medium chain triglyceride ketogenic diet.

https://doi.org/10.1038/s41598-021-86468-9

https://pubmed.ncbi.nlm.nih.gov/33772066

Abstract

Octanoic acid is a medium-chained saturated fatty acid found abundantly in the ketogenic dietary supplements containing medium chained triglycerides (MCT) along with decanoic acid. The MCT ketogenic diet is commonly consumed for weight loss but has also showcased neuroprotective potential against neurodegenerative disorders. However, recent clinical findings have reported a critical disadvantage with the long-term consumption of ketogenic diet i.e. bone loss. The following study was employed to investigate whether the two major components of MCT diet also possess bone loss potential as observed with classical ketogenic diet. Swiss albino mice aged between 10 and 12 weeks, were divided into 3 treatment groups that were administered with oral suspensions of octanoic acid, decanoic acid and a combination of both for 4 weeks. Bone specific markers, microarchitectural parameters, using micro computed tomography, and biomechanical strength were analyzed. Remarkably deleterious alterations in the trabecular bone microarchitecture, and on bone markers were observed in the octanoic acid treated groups. Our results suggest significant negative effects on bone health by octanoic acid. These findings require further investigation and validation in order to provide significant clinically relevant data to possibly modify dietary composition of the MCT ketogenic diet.

------------------------------------------ Info ------------------------------------------

Open Access: True

Authors: Shreshta Jain - Reena Rai - Divya Singh - Divya Vohora -

Additional links:

https://doi.org/10.1038/s41598-021-86468-9

------------------------------------------ Extra ------------------------------------------

I got some extra info because the situation on bone health was unclear to me. Here's the response I got to the study on my questions:

>This was an interesting and I hazard to say “dodgy” paper. I am not the biggest fan of mice studies as it is, although we have to work with what we can, there just needs to be a better way to design model studies, as so many of the genetics in these mice are so messed up, that they are far from representative of natural physiology and even natural pathophysiology in action. 
>
>Things of note that

Just putting this out there to check for some shared experiences in this area.

I've been working on a GC method to analyze fatty acid content in samples that involves converting them to methyl esters with a BF3 solution in methanol, and what I thought would be a fairly straightforward part of the development has been giving me trouble. Using a test compound, decanoic acid, I'm struggling to see anything above ~60% recovery as the methyl ester after trying a few different approaches to extracting my product into hexane and injecting.

It feels like I'm hitting a ceiling, seeing this same ~60% result a few times now. Am I dealing with some inevitable loss due to an equilibrium or something? I extract into hexane after letting the reaction go for an hour at 60 C, which should be overkill according to the literature.

Happy to hear any thoughts on this!

https://www.tdx.cat/bitstream/handle/10803/284040/Thesis%20Yanine%20Arrieta.pdf?sequence=1

Conclusion: the packed column spirits won all the sensory comparisons.

Summary

"The obtained results have shown that packed column distillation improves the aromatic profile of less aromatic pear varieties, such as Blanquilla and Conference, thus making possible to obtain similar distillates as with the Bartlett pear, a more aromatic variety.

Regarding kiwi distillates, the products obtained with the packed column have been better appreciated by consumers, featuring aromatic profiles with higher concentration of positive aromas, and less negative aromas. With respect to grape pomace distillates, the trend has been similar to fruit distillates. Finally, it is worth to remark the greater yield obtained in recovered ethanol, thus allowing an increased productivity by means of packed column distillation."

Exerpts

"The higher floral character in column distillates might be also due to the fact that the sum of monoterpenols concentrations was higher for distillates produced with the column compared to those produced in the alembic (see table 5). Like in the C6-C12 ethyl esters case, the reflux column recovers more these aroma compounds in the heart cut."

"Results obtained in this study show that the distillation system has a stronger influence than the yeast strain on the floral and fruity character of the kiwi distillates. Compared with alembic spirits, the packed column spirits presented higher amounts of compounds associated with favourable aromas (floral and fruity), such as C6-C10 esters and monoterpenols, and lower amounts of compounds associated with organoleptic defects (pungent), such as ethyl acetate and methyl acetate. Moreover, the distillates obtained with the packed column were preferred by a consumer panel and higher ethanol recoveries were achieved."

"In column distillations, PC1 was also characterized by higher levels of ethyl esters such as ethyl-2-trans-4-cis- decadienoate (0.992), ethyl decanoate (0.990), and ethyl dodecanoate (0.987). The recovery of these compounds in the heart fraction was always more effective in column distillations."

"In contrast, for the column-distilled spirits, no significant differences were found. This could be due to the fact that the spirits distilled in the column had a significantly higher concentration of favorab

I would have a daughter

The funeral director was asking us what we think Mum should wear in her casket.

Mum always loved to wear sarongs (fabric wraps that go around the torso and drape downward a bit like a long skirt would), so my uncle suggested that she wear a sarong in there.

The funeral director looked a bit confused, as did some of our family members, to which my uncle added:

"What's sarong with that?"

I started laughing like an idiot. He was proud of it too. The funeral director was rather shocked. We assured her, and our more proper relatives, that Mum would've absolutely loved the joke (which is very true).

His delivery was perfect. I'll never forget the risk he took. We sometimes recall the moment as a way help cushion the blows of the grieving process.

--Edit-- I appreciate the condolences. I'm doing well and the worst is behind me and my family. But thanks :)

--Edit-- Massive thanks for all the awards and kind words. And the puns! Love 'em.

But Bill kept the Windows

True story; it even happened last night. My 5-year-old son walks up behind me and out of the blue says, "hey."

I turn to him and say, "yeah, kiddo? What's up?"

He responds, "it's dead grass."

I'm really confused and trying to figure out what's wrong and what he wants from me. "What? There's dead grass? What's wrong with that?"

.

.

.

He says, totally straight-faced, "hay is dead grass," and runs off.

And then you will all be sorry.

No it doesn't.

Now it’s syncing.

He replied, "Well, stop going to those places then!"

I will find you. You have my Word.

She said how do you know he was headed to work?

“thank you for your cervix.”

Made me smile

Mods said I'm a cereal reposter...

But now I stand corrected.

Wait. Sorry, wrong sub.

Theoretical Fizz-ics

Because you can’t ‘C’ in the dark

I said, “That makes two of us.”

so I had to ground him.

He's doing better currently.

And conducting himself properly.

https://www.pnas.org/content/early/2020/09/01/2008980117

Decanoic acid inhibits mTORC1 activity independent of glucose and insulin signaling

Significance

The mTORC1 complex provides a critical role in cell function, regulating a variety of processes including growth and autophagy. mTORC1 signaling is hyperactivated in a range of common diseases including cancer, epilepsy, and neurodegenerative disorders. Hence, mTORC1 signaling provides an important target for regulation in many contexts. Here, we show that decanoic acid, a key component of a widely used medicinal diet, reduces mTORC1 activity. We identify this in a tractable model system, and validate it in ex vivo rat brain tissue and in human iPSC-derived astrocytes from patients with a clinically relevant disease. Thus, we provide insight into an easily accessible therapeutic approach for a range of diseases.

Abstract

Low-glucose and -insulin conditions, associated with ketogenic diets, can reduce the activity of the mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway, potentially leading to a range of positive medical and health-related effects. Here, we determined whether mTORC1 signaling is also a target for decanoic acid, a key component of the medium-chain triglyceride (MCT) ketogenic diet. Using a tractable model system, Dictyostelium, we show that decanoic acid can decrease mTORC1 activity, under conditions of constant glucose and in the absence of insulin, measured by phosphorylation of eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1). We determine that this effect of decanoic acid is dependent on a ubiquitin regulatory X domain-containing protein, mediating inhibition of a conserved Dictyostelium AAA ATPase, p97, a homolog of the human transitional endoplasmic reticulum ATPase (VCP/p97) protein. We then demonstrate that decanoic acid decreases mTORC1 activity in the absence of insulin and under high-glucose conditions in ex vivo rat hippocampus and in tuberous sclerosis complex (TSC) patient-derived astrocytes. Our data therefore indicate that dietary decanoic acid may provide a new therapeutic approach to down-regulate mTORC1 signaling.

https://preview.redd.it/uw0bnel3mio51.png?width=1280&format=png&auto=webp&s=03f62fdd33c1ad84cd43431e86c1b20bd0ebb647

Seems the full article is free. I might have to read it after work.

Source: P.D. Mangan [https://twitter.com/