In previous installments, we’ve proven the following:
- A calorie is not a calorie when you eat it at a different time of day.
- A calorie is not a calorie when you eat it in a differently processed form.
- A calorie is not a calorie when you eat it as a wholly different food.
- A calorie is not a calorie when you eat it as protein, instead of carbohydrate or fat.
- A calorie is not a calorie when you change the type of fat, or when you substitute it for sugar.
- A calorie is not a calorie at the low end of the carbohydrate curve (< 10%).
- Controlled weight-loss studies do not produce results consistent with “calorie math”.
- Even if all calories were equal (and we’ve proven they’re not), the errors in estimating our true “calorie” intake exceed the changes calculated by the 3500-calorie rule (“calorie math”) by approximately two orders of magnitude.
What’s More Important: Losing Weight, or Not Gaining It?
It’s instructive to keep in mind that these two questions are not the same—and as such, they may have different answers:
- What diet will help me lose weight most easily and efficiently?
- What diet will stop me from gaining weight most easily and efficiently?
As we saw in Part II, the entire obesity crisis in America resulted from the average American gaining roughly one pound per year. So instead of asking “How can we lose weight?” it’s perhaps more important to ask “How can we avoid gaining weight in the first place?”
The first question is answered by underfeeding studies: the second question is answered by overfeeding studies. I’ll return to this important distinction later in this series.
Intermittent Fasting, Time-Restricted Feeding, and “High-Fat Diets”
Cell Metab. 2012 Jun 6;15(6):848-60. doi: 10.1016/j.cmet.2012.04.019. Epub 2012 May 17.
Time-restricted feeding without reducing caloric intake prevents metabolic diseases in mice fed a high-fat diet.
Hatori M, Vollmers C, Zarrinpar A, DiTacchio L, Bushong EA, Gill S, Leblanc M, Chaix A, Joens M, Fitzpatrick JA, Ellisman MH, Panda S.
“Mice under tRF consume equivalent calories from HFD as those with ad lib access, yet are protected against obesity, hyperinsulinemia, hepatic steatosis, inflammation, and have improved motor coordination.”
Experimental setup: Half the mice were fed standard chow, half were fed the standard “high-fat diet”. Each half was subdivided into ad libitum-fed mice, who had 24/7 access to food, and time-restricted mice, who only had access to food for eight hours out of 24.
I use scare quotes around “high-fat diet” for several reasons, many alluded to in the previous installment.
First, the “high-fat diet” contains 20% purified sugars.
Second, unlike the standard chow diet, which contains actual food similar to the natural diet of seed-eating, primarily herbivorous mice (the primary ingredients are “ground corn, dehulled soybean meal, dried beet pulp, fish meal, ground oats”), the “high-fat diet” consists entirely of purified laboratory ingredients (the primary ingredients are “lard, casein, maltodextrin, sucrose, powdered cellulose, soybean oil”), none of which occur in or resemble the natural diet of mice. (PDF of ingredients for chow diet, high-fat diet.)
Result: instead of speaking of a “chow diet” and a “high-fat diet”, it’s more appropriate to speak of a species-appropriate diet, or “natural diet”, and a species-inappropriate diet, or “industrial diet”.
Returning to the study, we have four groups of mice: natural/ad-lib (“NA”), natural/time-restricted (“NT”), industrial/ad-lib (“FA”), industrial/time-restricted (“FT”).
First, we find that despite the radically different diets and restricted feeding windows, all four groups consumed almost exactly the same number of “calories”:
Interestingly, both time-restricted groups (NT and FT) were more active than the ad-lib groups (NA and FA):
However, only one of the groups got fat: the group which ate the industrial diet ad libitum.
The extra weight was almost entirely fat mass:
Just to make the point clear, the researchers even included pictures of a representative FA and FT mouse:
Remember, both mice not only ate the same diet—they consumed the same number of “calories” each day.
How about that?
There is much more fascinating data in this paper: at the risk of overquoting, here are some passages of interest. (Emphasis mine.)
Mice fed normal chow or high fat diet under a tRF regimen (NT and FT) improved diurnal rhythms in their RER compared to their ad lib fed counterparts, with higher RER during feeding and reduced RER during fasting, indicative of increased glycolysis and fat oxidation respectively (Figure 1C).
Despite equivalent energy intake from the same nutrient source, FT mice were protected against excessive body weight gain that afflicted FA mice (Figures 1J, 1K and S1), suggesting that the temporal feeding pattern reprograms the molecular mechanisms of energy metabolism and body weight regulation.
mTOR induces the expression of glucose-6-phosphate dehydrogenase (G6pdx) (Duvel et al., 2010), whose protein product is the rate limiting enzyme of the PPC and is activated by accumulation of its substrate G6-P. In turn, the PPC is a major source of NADPH which reduces glutathione. In the livers of mice under tRF, induced expression of G6pdx along with elevated G6-Pled to increased activity of the PPC as measured by higher levels of PPC intermediates and of reduced glutathione (Figures 3D, 3E and S3).
FT mice were also protected from the hepatomegaly and elevated serum alanine aminotransferase (ALT) levels that are associated with obesity-induced hepatic steatosis (Figures 4J and 4K). […] Livers from the FT mice did not have the profound increase in intracellular fat deposits, reduced mitochondrial density and reduced endoplasmic reticulum that were characteristic of the liver samples from the FA mice (Figures 5C, 5D and Table S2).
The tRF regimen temporally reprograms glucose metabolism away from gluconeogenesis towards glycolysis, reduced glutathione and anabolic pathways. Accordingly, FT mice did not display the hallmarks associated with glucose intolerance found in diet-induced obesity, instead showing glucose tolerance and insulin levels comparable to the control NA mice (Figures 3I and 3J). The overall improvement in metabolic state also paralleled improved motor coordination in the mice under tRF paradigms (Figure 3K).
Elevated β-oxidation and reduced fatty acid synthesis in the liver coupled with increased BAT energy expenditure observed in the FT mice prevented the adipocyte hypertrophy common to BAT and white adipose tissue (WAT) derived from the FA mice (Figures 6F and 6G). Furthermore, inflammation marked by extensive infiltration of macrophages and expression of proinflammatory genes, including TNFα, IL6 and CXCL2 that are generally found in the WAT of the FA mice, were attenuated in the FT mice (Figure 6H). Even in mice fed normal diet, tRF reduced the expression of inflammatory cytokines in the WAT. In summary, the tRF paradigm affected multiple tissues and improved whole body energy homeostasis, and reduced inflammation.
A Bonus Observation
Tucked into the corner of Figure 4, we see a curious graph: the FT mice (industrial “high-fat” diet, time-restricted) performed best of all the groups on the accelerating Rotarod test.
“What’s a Rotarod?” you ask.
(Perhaps the fact that ketones are the preferred fuel of the brain and heart isn’t just a biochemical curiosity.)
Takeaways: Intermittent Fasting
First, it’s clear that a calorie is not a calorie when you’re intermittent fasting.
However, the most interesting part, to me, is the difference between the natural and industrial diet groups. 16/8 intermittent fasting was only mildly beneficial to the mice eating a natural diet. However, the mice fed an industrial diet ad libitum (“FA”) were not only obese—they were in terrible metabolic shape, with fatty liver and impaired glucose metabolism. In contrast, the time-restricted industrial diet mice (“FT”) were, for the most part, just as healthy as the mice fed a natural diet.
Tentative takeaway: The less species-appropriate your diet is, the more difference intermittent fasting makes to your health and bodyweight.
This doesn’t mean you can eat all the junk food you want so long as you fast afterward! For instance, nothing about IF will stop gluten grains from causing intestinal permeability (see Fasano 2011). However, it seems that IF may be able to increase your tolerance for dietary patterns that would otherwise be unhealthy for you, cause weight gain, or both.
Also, I can’t resist the observation that most agrarian religions prescribe a significant amount of fasting. John Durant has speculated that this is a disease-fighting measure, but it may well be a general health measure that helps compensate for the inferior agrarian diet.
Live in freedom, live in beauty.
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