Time Restricted Feeding

Here’s an interesting study on High Fat diets and Time Restricted Feeding (Sherman H1, Genzer Y, Cohen R, Chapnik N, Madar Z, Froy O. Timed high-fat diet resets circadian metabolism and prevents obesity. FASEB J. 2012 Aug;26(8):3493-502. doi: 10.1096/fj.12-208868. Epub 2012 May 16.). The study

…tested whether long-term (18 wk) clock resetting by RF can attenuate the disruptive effects of diet-induced obesity.

The study looked at:

Analyses included liver clock gene expression, locomotor activity, blood glucose, metabolic markers, lipids, and hormones around the circadian cycle for a more accurate assessment.

Geneticaly, the study claims that:

Compared with mice fed the HF diet ad libitum, the timed HF diet restored the expression phase of the clock genes Clock and Cry1 and phase-advanced Per1, Per2, Cry2, Bmal1, Rorα, and Rev-erbα.

As far as weight goes:

Although timed HF-diet-fed mice consumed the same amount of calories as ad libitum low-fat diet-fed mice, they showed 12% reduced body weight, 21% reduced cholesterol levels, and 1.4-fold increased insulin sensitivity.

So, against a low fat diet the high fat diet did well. So far nothing new from usual. But what the study was concerned with was the Time Restricted Feeding (Intermittent Fasting) aspect. And that’s where the TRF diet did very well.

Compared with the HF diet ad libitum, the timed HF diet led to 18% lower body weight, 30% decreased cholesterol levels, 10% reduced TNF-α levels, and 3.7-fold improved insulin sensitivity. Timed HF-diet-fed mice exhibited a better satiated and less stressed phenotype of 25% lower ghrelin and 53% lower corticosterone levels compared with mice fed the timed low-fat diet. Taken together, our findings suggest that timing can prevent obesity and rectify the harmful effects of a HF diet.

Interesting results.

Here’s a related paper which notes a second study (Timed High Fat Diet Resets Circadian Metabolism and Prevents Obesity).

By an odd coincidence, a similar paper was published in the FASEB J2 about a month later, but the second paper didn’t seem to be aware of the first paper’s publication and didn’t cite it. In fact, the authors of the second paper thought that their paper was the first to be published on the subject of time restricted feeding of a high fat diet. 

Here’s the second paper (Hatori M, Vollmers C, Zarrinpar A, DiTacchio L, Bushong EA, Gill S, Leblanc M, Chaix A, Joens M, Fitzpatrick JA, Ellisman MH, Panda S. Time-restricted feeding without reducing caloric intake prevents metabolic diseases in mice fed a high-fat diet. Cell Metab. 2012 Jun 6;15(6):848-60). Here’s that abstract:

While diet-induced obesity has been exclusively attributed to increased caloric intake from fat, animals fed a high-fat diet (HFD) ad libitum (ad lib) eat frequently throughout day and night, disrupting the normal feeding cycle. To test whether obesity and metabolic diseases result from HFD or disruption of metabolic cycles, we subjected mice to either ad lib or time-restricted feeding (tRF) of a HFD for 8 hr per day. Mice under tRF consume equivalent calories from HFD as those with ad lib access yet are protected against obesity, hyperinsulinemia, hepatic steatosis, and inflammation and have improved motor coordination. The tRF regimen improved CREB, mTOR, and AMPK pathway function and oscillations of the circadian clock and their target genes’ expression. These changes in catabolic and anabolic pathways altered liver metabolome and improved nutrient utilization and energy expenditure. We demonstrate in mice that tRF regimen is a nonpharmacological strategy against obesity and associated diseases.


I was pointed to this by an article by Mark Hyman who claimed about the study that:

Note that the link is not to a human study but to the mouse study above. A tale of mice or men. Someone in a Facebook group pointed me to the study as proof that we can eat fat ad lib. LOL. Proves exactly the opposite.

Fat Stores Where/How?

Peter at the Hyperlipid BLOG has an interesting analysis of an interesting paper on fat storage in mice (On phosphorylating AKT within visceral fat). The study he looks at is (Narita T, Kobayashi M, Itakura K, Itagawa R, Kabaya R, Sudo Y, Okita N, Higami Y. Differential response to caloric restriction of retroperitoneal, epididymal, and subcutaneous adipose tissue depots in rats.  Exp Gerontol. 2018 Apr;104:127-137). The study looked at ad lib feeding of mice and the storage of fat in three White Adipose Tissues (WAT) depots in rats: retroperitoneal (rWAT), epididymal (eWAT) and subcutaneous (sWAT).

Peter’s interest is in fat storage based on insulin levels. The study compared ad libitum to calorie restricted eating in the mice. Peter concentrated on the ad libitum eating of the mice (not being all that interested in calorie restricted diets). Peter points out that it takes insulin to store fat in subcutaneous tissues but very little insulin to store fat in visceral fat. The study put it this way:

In all WAT depots, CR markedly upregulated the expression of proteins involved in FA biosynthesis in fed rats. In visceral WAT (rWAT and eWAT), hormone-sensitive lipase (lipolytic form) phosphorylation was increased by CR under fed conditions, and decreased by CR under fasted conditions. Conversely, in sWAT, hormone-sensitive lipase phosphorylation was increased by CR under fasted conditions. CR enhanced the effect of feeding on AKT activity in sWAT (indicative of a positive effect on insulin sensitivity) but not in rWAT or eWAT. These data suggest that CR improves lipid metabolism in an insulin signaling-dependent manner in sWAT only.

As Peter puts it:

This looks very much like one of the intrinsic differences between subcutaneous adipocytes and visceral adipocytes is that visceral adipocytes maintain insulin signalling at much lower levels of plasma insulin than do subcutaneous adipocytes. You have to store calories which arrive without insulin somewhere. Looks like this is the place!

I’m still of the opinion that visceral fat is what matters the most in reversal of Type 2 Diabetes. The Low Carb diet gets insulin levels low which reduces fat in general. See this article (A Grand Unified Theory of Polyunsaturated Fatty Acid Misbehaviour in Inflammatory Disease).

This article is actionable as well (Fatty liver and its treatment).

Another Way to Reverse Diabetes

Here’s another way to reverse Type 2 Diabetes (E. L. Lim, K. G. Hollingsworth, B. S. Aribisala, M. J. Chen, J. C. Mathers, R. Taylor. Reversal of type 2 diabetes: normalisation of beta cell function in association with decreased pancreas and liver triacylglycerol. Diabetologia, October 2011, Volume 54, Issue 10, pp 2506–2514). Here were the subjects:

Eleven people with type 2 diabetes (49.5 ± 2.5 years, BMI 33.6 ± 1.2 kg/m2, nine male and two female) were studied before and after 1, 4 and 8 weeks of a 2.5 MJ (600 kcal)/day diet.

Here are the results:

After 1 week of restricted energy intake, fasting plasma glucose normalised in the diabetic group (from 9.2 ± 0.4 to 5.9 ± 0.4 mmol/l; p = 0.003).

Insulin suppression of hepatic glucose output improved from 43 ± 4% to 74 ± 5% (p = 0.003 vs baseline; controls 68 ± 5%).

Hepatic triacylglycerol content fell from 12.8 ± 2.4% in the diabetic group to 2.9 ± 0.2% by week 8 (p = 0.003).

The first-phase insulin response increased during the study period (0.19 ± 0.02 to 0.46 ± 0.07 nmol min−1 m−2p < 0.001) and approached control values (0.62 ± 0.15 nmol min−1 m−2p = 0.42).

Maximal insulin response became supranormal at 8 weeks (1.37 ± 0.27 vs controls 1.15 ± 0.18 nmol min−1 m−2).

Pancreatic triacylglycerol decreased from 8.0 ± 1.6% to 6.2 ± 1.1% (p = 0.03).

Other interesting factoids from the study. In Type 2 diabetics:

Beta cell function declines linearly with time, and after 10 years more than 50% of individuals require insulin therapy.

Here’s the data from the study.

VariableControlsBaselineWeek 1Week 4Week 8
Weight (kg)101.5 ± 3.4103.7 ± 4.599.7 ± 4.5*94.1 ± 4.3 *88.4 ± 4.3*†
BMI (kg/m2)33.4 ± 0.933.6 ± 1.232.3 ± 1.2*30.5 ± 1.2*28.7 ± 1.3*†
Fat mass (kg)36.2 ± 2.739.0 ± 3.536.6 ± 3.6 *31.7 ± 3.7 *26.3 ± 4.0*
ffm (kg)64.7 ± 3.864.7 ± 3.063.2 ± 3.162.4 ± 3.0 *62.1 ± 3.0*
Waist circumference (cm)105.0 ± 1.5107.4 ± 2.2104.4 ± 2.2*99.7 ± 2.4 *94.2 ± 2.5*†
Hip circumference (cm)109.8 ± 2.4109.5 ± 2.9108.3 ± 2.7*105.0 ± 2.6*99.5 ± 2.6*†
WHR0.96 ± 0.020.98 ± 0.020.97 ± 0.020.95 ± 0.010.95 ± 0.01

It is remarkable that the people lost mostly fat. The Fat Free Mass loss was only 2.6kg (about 6 lbs). The fat loss was 10 kg (about 22 lbs). That’s a pretty decent drop.

Low Carb?

This was neither a Low Carb nor Low Fat diet. It was a restricted calorie diet (600 calories a day). The macros were 46.4% carbohydrate, 32.5% protein and 20.1% fat; vitamins, minerals and trace elements; 2.1 MJ/day [510 kcal/day]; Optifast; Nestlé Nutrition, Croydon, UK. This was supplemented with three portions of non-starchy vegetables such that total energy intake was about 2.5 MJ (600 kcal)/day. 

It is remarkable how much fat was lost from the liver in just the first week.

Hepatic triacylglycerol content decreased by 30 ± 5% during week 1 of intervention (p < 0.001), becoming similar to control values (p = 0.75). It continued to decline throughout the intervention period to reach the normal range for non-obese individuals [20] (2.9 ± 0.2%; p = 0.003; Fig. 1), i.e. a total reduction of 70 ± 5%.

Most interestingly, the study after the study noted:

Following the intervention, participants gained 3.1±1.0 kg body weight over 12 weeks, but their HbA1c remained steady while the fat content of both pancreas and liver did not increase.

The conclusion matches my own hypothesis:

The data are consistent with the hypothesis that the abnormalities of insulin secretion and insulin resistance that underlie type 2 diabetes have a single, common aetiology, i.e. excess lipid accumulation in the liver and pancreas.

Ketogenic Infants

From (Settergren G, Lindblad BS, Persson B. Cerebral blood flow and exchange of oxygen, glucose, ketone bodies, lactate, pyruvate and amino acids in infants. Acta Paediatr Scand. 1976 May;65(3):343-53):

Mean values from 12 infants (age 11 days-12 months) were: CBF 69 ml/100 g0min-1; cerebral uptake (in mumoles/100 g-min-1): oxygen 104, glucose 27, acetoacetate 0.9, D-beta-hydroxybutyrate 2.3; cerebral release: lactate 2.4 and pyruvate 0.8. Significant uptake of amino acids was found only for histidine 0.95 and arginine 0.7. Significant correlations between arterial concentration and cerebral exchange were found for: ornithine, arginine, phenylalanine, aspartic acid, serine, glutamine and acetoacetate. CBF and substrate exchange were unrelated to age within the group.

Infants had higher mean CBF and greater uptake of ketone bodies than has been reported in adults.

Blood Sugar Rises

It is common and well documented by Cahill in his landmark studies on starvation that at the start of carbohydrate restriction blood sugar often goes up in the first few days before it starts to drop.

I’ve seen this myself with long fasts (greater than 4 days). The first few days result in your body making a lot of glucose in spite of low carbs in your diet.

It takes several days for your ketone production to kick in. That’s why the body dumps glucose.

I’ve also noticed an association between weight loss and blood sugar. My blood sugar is often up on the day before I drop in weight. In reverse, my blood sugar is lower when my weight goes up.

Native Indian Diet

There’s an interesting book which describes the capture of frontier folks by American Indians in the  frontier era. Often these captives were adopted by their Indian captors to replace family members who had died. In some cases, the captives later refused to return to European American communities when they had the opportunity. There’s a book which collects together many of their experiences (Captured by the Indians: 15 Firsthand Accounts, 1750-1870. Edited by Frederick Drimmer, 1961).

Diet Was Animal-based

The book recounts the diet of the North American Indians and the adaptation of people who were on European diets to the diets of the Indians. The Indians relied largely on animals for their food.

Differences from European Diet

The European captives seem to have suffered the equivalent of the ketogenic flu when they adapted to the Indian diet. They describe a couple of rough days at the start when they abruptly ceased to eat the European diet.

There were definite differences in diet. For example, the Europeans were used to bread at all of their meals but the Indians ate meat alone. From p 27.

This is as simple as the idea that the Indians were largely nomadic in the summer. They built shelters in the winter and stayed at those locations.

Other food they ate included:

  • boiled venison (p. 33)
  • buffalo (p. 34)
  • deer, bear, racoon (p. 38)
  • wildcat (p. 40)
  • fox (p. 41)
  • hickory nuts (p. 37)
  • hawthorn seeds (p. 37)
  • green corn (pp. 33, 41)

There are some very specific details such as this account of cooking a bear (p. 39).

See this article for more information on the dietary habits of American Indians (Guts and Grease: The Diet of Native Americans).

Consumption of Carbohydrates

For carbohydrates the women among the Indians tapped trees for sap and then concentrated the sap by heating it in bronze pots. They would dip their meat in the syrup. Here is the account of how they made syrup.

I wonder if the Indians had bronze kettles prior to the European arrival? Wikipedia indicates that there was no bronze objections created in North America prior to the European arrival. For more information on this subject see (Introduction to Contact and Precontact Period Copper & Brass Metalwork).

The Indians seemed to be aware that they needed both fat and carbohydrates to gain needed weight. There is plenty of evidence in the book that the Indians had extended times without any food (p. 40).

Hunting Methods

There is an account of how they would run down horses by chasing after them for miles (p. 42). It was easier to track them when there was a little snow on the ground.

Defined Gender Roles

Women took care of the corn and men hunted. There is an account of where the men would mock their European captives who helped the women with the corn (p. 43).

Revisiting the “Alpert” Number

I think that the Alpert number may not be right if you are on a Low Carbohydrate diet.

The Alpert number is the maximum rate of fat oxidation from a relatively moderately active person (Hypophagia – How much fat can I lose in a day?). It occurred to me that I can check this number from my own VO2max test.

  • Looking at the REE at rest (REE from VO2max) it shows 2.16 kCal/min.
  • From my Bod Pod results (Overshot My Recomp Goals – Part 1) my fat mass is 12.3 lbs.
  • Multiplying my fat mass times the Alpert number is 381.3 kCals/day. That’s 15.88 kCal/hr or 0.26 kCal/min.

Yet, my REE was 2.1 kCal/min  at and RER of 0.73 (90% fat) which is 1.9 kCal/min from fat oxidation. Flipping the number around that’s 1.9 times 60 times 24 = 2736 kCal per day from fat.

The smallest number I saw in the resting period was 1.209 kCal/min or 1740 kCal/day. dividing 1740 number by my fat weight in lbs is 141 kCal per lb of fat mass. That’s quite a bit more than the Alpert number.

The Minnesota Starvation (Ancel Keys) data was the basis of the Alpert number. Perhaps the difference is in the idea that I am not actually in starvation? And the Minnesota Starvation subjects were fed carbohydrates in their diet.

The Alpert number pretty closely matches my own experiences in Protein Sparing dieting.

Blood Sugar and Fasting

A while back, I noticed that my Blood Sugar peaks around the second day of extended fasting. George Cahill did the seminal work measuring blood markers during starvation (Cahill, George. Fuel Metabolism in Starvation.). Here’s an interesting chart from that study that explains the sources of glucose during starvation.

This demonstrates the increase in blood sugar around day 2-3. Diabetics are particularly adept at GNG. Eventually though, even that reduces as the body becomes physiologically Insulin Resistant.

The chart can provide some idea of what happens in a ketogenic diet. Although someone on a ketogenic diet is eating enough food, their exogenous glucose is greatly reduced due to the low carbohydrate content of the diet. Glycogen stores lower next. When the glycogen stores get low the body then upregulates Glyconeogenesis (GNG).

This could also explain why when I see an increase in blood sugars on one morning I often see a drop in weight the following morning. The body is signalling that it is switching fuel to up-regulated GNG due to dropped Glycogen stores. Although these two sources are of the same magnitude in Cahill’s chart above they could well be less equally matched in a diabetic. It is possible that GNG in a diabetic outpaces the ability to pull from Glycogen stores.


Hyperinsulemia and Weight Loss

Interesting line of evidence as to why insulinemia may cause obesity (rather than the reverse). The evidence is based on a 5-6 week long water-only fast (Fasting insulin and weight loss on a water fast). In the study referenced, the fasting insulin of the individuals was measured as they progressed on the fast.

On a water fast the higher your starting weight (surrogate for “fed” fasting insulin, remote surrogate for “starvation” fasting insulin), the less weight you lose over 5-6 weeks.

Elevated insulin is associated with obesity BECAUSE it inhibits lipolysis.