Fuel Metabolism In Starvation

(Bart) #1

This is a very well written paper talking about fuel metabolism in starvation. It starts out with sort of a background story on the author but then goes into the history of the research regarding ketones and insulin, fasting studies and much more. It is a very easy paper to read and understand compared to most papers. I think many of you will enjoy it. I will also attach the pdf in case people are interested.

Fuel Metabolism in Starvation.pdf (570.1 KB)

(Michael - When reality fails to meet expectations, the problem is not reality.) #2

Resurrecting this topic because I just read it! Included the following link in another topic and thought it deserved it’s own. Sure enough, it already has its own and I hope folks will read this, it’s a keto gold mine - especially starting at the bottom of page 5.

from page 11:

This brings us to the evolutionary history of β-hydroxybutyrate (βOHB) and
the role of various energy sources required for life. Most bacteria use poly-β-
hydroxybutyrate as an energy store; coliforms are an exception. In some proto-
zoans, up to 90% of dry weight is poly-βOHB. Even archaea use it for energy
storage, which suggests it has been around for well over 2—3 billion years. It is
possible that its selection was aided by the periods of low environmental oxygen
that occurred during the Archaean, Proterozoic, and Palaeozoic eras. Poly-βOHB
is stored as several large granules in the cytoplasm, therefore having very little
osmotic effect. This is in contrast to the two other fundamental archaeal energy
stores, polypyrophosphate (38) and various polysaccharides (14). Both of these
require much hydration, with 2—4 grams of water stored in cells along with each
gram of glycogen (19). Polypyrophosphate for energy storage disappeared with
the prokaryotes. However, we have retained poly-βOHB, but apparently not for
energy. It is a component of cell walls and, in one case, a component of a Ca2+
channel (57). This is the only example of a nonprotein ion channel so far reported.
It is also present in low concentrations in blood serum, and altered levels have
been reported in diabetic animals (58). I should point out that I have been unable
to find evidence of triglyceride in prokaryotes!

(Michael - When reality fails to meet expectations, the problem is not reality.) #3

Returning to fasting man, brain use of βOHB, by displacing glucose as its major fuel, has allowed man to survive lengthy periods of starvation. But more importantly, it has permitted brain to become the most significant component in human evolution. Other secondary adaptations had to be made, particularly in reproduction. The mega brain of H. sapiens and the recent antecedents such as neanderthalensis, erectus, and habilis posed a problem in getting the big head through the pelvic canal, particularly with bipedalism, as the hominoids became hominids, some 7 mya. Bipedalism necessitated narrowing of the pelvic canal for optimal mobility. Speed necessitates limbs close together, whereas limbs far apart result in waddling, i.e., greyhounds versus bulldogs, deer versus turtles, pheasants versus ducks. We are the only primate born facing backward and, more importantly, born obese. Obstetric problems in primates other than humans are essentially unknown (60).

Not well known, however, is the metabolism of the human newborn, which is essentially ketotic. Blood glucose levels fall strikingly in the neonate, and concentrations of βOHB may rise to 2—3 mM. The newborn human brain consumes 60%—70% of total metabolism at birth, nearly half via β-hydroxybutyrate. Fitting in with this pattern is maternal colostrum. It contains much triglyceride and protein, but little lactose, starting man’s entry into society on an Atkins diet (Figure 6)! Lactose gradually increases during the first two to three days of lactation (46), during which time ketosis disappears. Also, humans are born a few months premature compared with our primate cousins. And, again, we are the only primate born fat, probably to furnish the caloric bank for our big brains. We are also the only primate with significant neonatal brain injury (20) due to extreme sensitivity to hypoxia/ischemia (78). Again, this is a penalty for having a big brain!

(Michael - When reality fails to meet expectations, the problem is not reality.) #4


Veech and colleagues discovered that administering β-hydroxybutyrate to the perfused rat heart in place of glucose increased work output but decreased oxygen consumption (35). Henry Lardy (41), in the 1940s, showed that bull sperm motility was increased in vitro by β-hydroxybutyrate as compared with 15 other substrates but with a decrease in oxygen consumption, similar to the perfused heart. One then has to consider β-hydroxybutyrate as a unique nutritional compound (Table 1).1 It has equally balanced hydrophilic and hydrophobic characteristics, and therefore is neither fat nor carbohydrate. Again, it is an archaic molecule. Does it have any therapeutic value as either a nutraceutical or a pharmaceutical agent? Veech et al. addressed this question in 2001 (80) and again more recently in 2004 (79). A more simplistic paper for physicians was also published (12). One can posit a number of uses, including in obstetrical problems whereby the infant might be supported by βOHB during difficult labor, the agent being infused into the mother. It readily crosses the placenta. Next, the fact that nature delayed the synthesis of adequate lactose for the first day or so suggests βOHB might be of help in any newborn, particularly if small for gestational age. It has already been used in children with congenital disorders in fat oxidation or ketone production with some dramatic success (54, 75). As mentioned above, its use in drug-resistant childhood epilepsy to displace the ketogenic diet awaits the availability of orally absorbable esters. The sodium salt has been given to children without apparent
problems, but the amount needed to get the blood level into the therapeutic range for epileptic children challenges the capacity to excrete alkaline urine as well as deal with the sodium overload.

Essentially, any cell challenged by low oxygen availability or by a toxin interfering with mitochondrial function should benefit by utilizing β-hydroxybutyrate in preference to any other substrate, including glucose, lactate, pyruvate, or fatty acids. In a very simple experiment, mice given β-hydroxybutyrate exposed to 4% oxygen survived longer (37, 72). Likewise, neurons in models of Alzheimer’s and Parkinson’s disease survive better with β-hydroxybutyrate in the system (36). Recent studies have shown that rats fatigued on an exercise wheel perform better after βOHB addition to the diet and, more interestingly, subsequently are able to improve in psychological tests (R.L. Veech and K. Clarke, personal communication).