One of the ways dietary carbohydrate contributes to liver fat is via ChREBP: “carbohydrate-response element binding protein.” It responds to a glucose metabolite and activates transcription of lipogenic genes. Insulin helps. Ketones do the opposite (Nakagawa et al., 2013), by inhibiting the translocation of ChREBP into the nucleus where it does it’s dirty work:
More interestingly, ketones are histone deacetylase inhibitors (HDACi)… this leads to more histone acetylation. Benefits of fasting sans fasting? Modulating of acetylation is a MAJOR regulator of circadian rhythmicity.
Butyrate is another HDACi, so have some fibrous plant foods with your red wine and dark chocolate. Anti-aging (mostly worm studies, but still).
Posted in Advanced nutrition, chocolate, circadian, Dietary fat, fat, insulin, Ketosis, microbiome, wine
Tagged carbs, circadian rhythm, ketones
“Need” is a funny concept. You don’t need to eat seafood. You don’t need an appendix or legs, either.
An article about the Omega-3 Index was published in Whole Foods Magazine. Scanning through the figures, I noticed a few interesting studies.
For example, Association of marine omega-3 fatty acid levels with telomeric aging in patients with coronary heart disease (Farzaneh-Far et al., 2010)
Telomere length is believed to be a biomarker of aging: the shorter your telomeres, the faster you’re aging. In the study, they measured telomere length in white blood cells and EPA+DHA in whole blood at baseline and again 5 years later.
Quartile 1: EPA+DHA = 2.3% of the fatty acids in whole blood.
Quartile 2: 3.3%
Quartile 3: 4.3%
Quartile 4: 7.3%
Potential confounders: quartile 4 was comprised of educated rich white old non-smokers with low levels of inflammation, but the statisticians assure us those variables were controlled for… so there’s that.
I didn’t want to blog about the artificial sweetener study; to be honest, I didn’t even want to read it. I just wanted to report: 1) how many Diet Cokes are we talking about; and 2) when are you going to die.
Artificial sweeteners induce glucose intolerance by altering the gut microbiota (Suez et al., 2014)
Non-caloric artificial sweeteners (NAS) = saccharin, sucralose, and aspartame. Saccharin worked the best (worst) in the mouse study, so they tested it in humans. This was the part I found most relevant: seven healthy volunteers (5 men & 2 women, aged 28-36) who did not typically consume a lot of sweeteners were recruited and given 120 mg saccharin three times per day. 360 mg saccharin is ~10 packets of Sweet’n Low.
Part I: Circadian Mismatch
1. Artificial light at night suppresses melatonin (Lewy et al., 1980); induces “circadian mismatch.”
2. Circadian mismatch is associated with and/or predisposes to breast cancer (eg, He et al., 2014 and Yang et al., 2014).
3. In this epic study, human breast cancer xenografts were exposed to blood taken from healthy, pre-menopausal women during the day (melatonin-depleted), at night (high melatonin), or at night after light exposure (melatonin-depleted) (Blask et al., 2005). They showed that tumors exposed to melatonin-depleted blood exhibited higher proliferative activity than those exposed to melatonin-repleted blood. This has been deemed one of the most “ethical” studies to demonstrate a causal link between circadian mismatch and cancer.
4. And to make matters worse, circadian mismatch also reduces the efficacy of cancer drug therapy (Dauchy et al., 2014). This study showed that, in a rodent model of breast cancer, exposure to light at night (circadian mismatch) enhanced tumor development and induced tamoxifen-resistance, and this was abolished by melatonin replacement.
They also suggested a mechanism: tumors metabolize linoleate into the mitogen 13-HODE. Melatonin suppresses linoleate uptake.
They are conditionally essential at best, only if docosahexaenoic acid (DHA) is lacking. We can’t synthesize omega 3 fatty acids, and indeed they do prevent/cure certain manifestations of “essential fatty acid (EFA) deficiency” (Weise et al., 1958), but DHA can do all that and more. Not that I recommend this, but a diet completely devoid of 18-carbon vege oil fatty acids will not produce EFA deficiency in the presence of DHA. (“vege,” rhymes with “wedge”)
The “parent essential oils” are linoleic acid (LA) and alpha-linolenic acid (ALA). The others, which I think are more important and the truly “essential” ones are eicosapentaenoic acid (EPA), arachidonic acid (AA), but mostly just DHA.
The first manifestation of EFA deficiency is dermatitis (Prottey et al., 1975). Some people say LA is necessary to prevent this, but it would be better phrased as “LA prevents dermatitis;” not “LA is necessary to prevent dermatitis.” All of the evidence suggesting LA is essential is in the context of DHA deficiency.
Technically, we can convert a bit of ALA to DHA, estrogen helps, testosterone doesn’t (women have better conversion rates)… and I’d speculate that the reverse is probably easier (DHA –> ALA).
Is it possible to improve the amplitude and resiliency of your circadian rhythms? Is this desirable? Yes and yes, I think.
Introducing, the aMUPA mice (Froy et al., 2006). What you need to know about ‘em: they have very robust circadian rhythms. How is this assessed? Take some mice acclimated to their normal 12 hour light-dark cycle (LD) and place them in constant darkness (DD). Then take liver biopsies and measure circadian genes to see how well they still oscillate throughout the dark day; this is also known as the free-running clock, and it craps out differently in different tissues depending on a variety of factors. Most of the time, however, it’ll run for a few days in the absence of light. Circadian meal timing also helps to hasten re-entrainment.
Note in the figure below: 1) there are two distinct lines of aMUPA mice; and 2) both exhibit a greater amplitude in circadian oscillations during free-running, or DD conditions.
Posted in Advanced nutrition, angiotensin, circadian, diet, Energy balance, insulin, muscle, sleep
Tagged body composition, calories proper, circadian rhythm, energy balance, melatonin, mortality, nutrition, sleep
I got a laugh out of this one; not for the actual content, but because of how the authors worded their findings. They sure love their fishies.
We have two very closely related fish, both Mexican tetra, Astyanax mexicanus, one with eyes who lives on the surface, and another who’s blind and lives in dark caves (“Pachon”). It’s thought that they were the same species one day; divergent evolution.
The blind ones are circadian arrhythmic (Moran et al., 2014). Surface-dwellers are more active during the day than night (blue line, left figure below), and their free-running circadian clock maintains this in the absence of photic input (blue line, right figure). The blind ones, on the other hand, exhibit no circadian rhythm in the light or dark (orange lines):
Cave-dwellers are circadian arrhythmic. This is both in their natural photoperiod (ie, darkness) and in light-dark conditions (which is technically an environmental mismatch, but since they’re eyeless, it doesn’t really matter).
Don’t exacerbate afternoon diabetes with afternoon carbs.
As discussed previously [at length], insulin sensitivity in skeletal muscle follows a circadian pattern: starts out high in the morning and wanes throughout the day.
Diurnal variation in oral glucose tolerance: blood sugar and plasma insulin levels, morning, afternoon and evening (Jarrett et al., 1972)
Diurnal variation in glucose tolerance and insulin secretion in man (Carroll and Nestel, 1973)
Circadian variation of the blood glucose, plasma insulin and human growth hormone levels in response to an oral glucose load in normal subjects (Aparicio et al., 1974)
And insulin sensitivity of adipose tissue goes in the opposite direction: starts out low, and increases as the day progresses.
Diurnal variations in peripheral insulin resistance and plasma NEFA: a possible link? (Morgan et al., 1999)
The studies were standardized for a period of fasting, pre-test meal, and exercise… Following insulin, NEFA fell more slowly in the morning (149 uM/15 min) than in the evening (491 uM/15 min).
Diurnal variation in glucose tolerance: associated changes in plasma insulin, growth hormone, and non-esterified fatty acids (Zimmet et al., 1974)
Adipose tissue insulin sensitivity is greater in the evening. FFA are higher, and get shut down more rapidly, after a carb meal in the evening.
Summary: to minimize blood glucose excursions and proclivity for fat storage, eat more calories earlier in the day; this is circadian nutrient timing. And according to the Alves study, a low-carb protein-rich dinner best preserves lean tissue during weight loss.
Posted in Advanced nutrition, circadian, clamp, diet, Energy balance, insulin, Ketosis, melatonin, Protein
Tagged body composition, calories proper, carbs, circadian rhythm, energy expenditure, insulin, ketosis, melatonin, nutrition, protein
This is where the magic happens.
Rat pups, fed a flaxseed oil-based ketogenic diet from weaning onward – note the drop-off in ketones after 2 weeks (Likhodii et al., 2002):
What happened on day 17?
Patient history: these rats have been “low carb” their whole lives.
Side note: flaxseed oil is very ketogenic! (Likhodii et al., 2000):
Flaxseed oil-based ketogenic diet produced higher ketones than 48h fasting; the same can’t be said for butter or lard. PUFAs in general are more ketogenic than saturated fats in humans, too (eg, Fuehrlein et al., 2004):
Crisco keto (adult rats) (Rho et al., 1999):
suspect those two rogue peaks were experiment days…
Posted in Advanced nutrition, circadian, diet, Dietary fat, Exercise, insulin, Ketosis, Protein
Tagged Atkins, body composition, carbs, energy expenditure, fat, insulin, ketogenic, ketosis, protein