I introduced this particular study earlier in another forum topic. As I read it more thoroughly, however, I decided it merits a discussion of its own.
There are some remarkable and new data to consider regarding the process of initiating and maintaining ketosis. So I’d like to discuss. Starting with the following points from the conclusion of the study’s final Discussion section.
First, just to get it off the plate - yes, rat study. Yes, they had to put the rats into starvation to get them into ketosis (hence the study’s name) - so questions about applicability to human nutritional ketosis. Still, I think the mechanics of going from a glucose-based energy state to a fat/ketone-based energy state are likely valid and applicable.
In summary, these data reveal several new concepts regarding leptin biology and the regulation of whole-body and tissue-specific substrate metabolism from the transition from the fed to fasted state in normal lean free-ranging rats, specifically:
- Progressive decreases in plasma glucose (9 to 6 mM)and insulin (500 to 100 pM) concentrations during early starvation (6–16 hr) can mostly be ascribed to reduced rates of net hepatic glycogenolysis (25 to 4 mmol/[kg , min]).
- Reductions in plasma leptin concentrations (150 to 60 pM) stimulate the HPA axis, thus increasing plasma corticosterone concentrations (100 to 450 nM), which, in the presence of hypoinsulinemia, results in stimulation of WAT lipolysis and the shift from whole-body carbohydrate oxidation to fat/ketone oxidation.
- Increases in WAT lipolysis increase hepatic acetyl-CoA content and allosterically stimulate hepatic pyruvate carboxylase flux, which is essential for the maintenance of hepatic glucose production and euglycemia during starvation.
- Insulinopenia is necessary, but not sufficient, for increased rates of WAT lipolysis, increased hepatic acetyl-CoA content, increased rates of hepatic ketogenesis, and the shift from carbohydrate oxidation to fat/ketone oxidation during starvation.
- Decreased glucose-alanine cycling, due to hepatic glycogen depletion, results in marked (~50%) reductions in rates of hepatic pyruvate carboxylase flux (VPC) and hepatic mitochondrial oxidative metabolism (VCS).
- Reductions in rates of hepatic mitochondrial oxidation (VCS) during prolonged (48 hr) starvation can be attributed in part to reductions in rates of hepatic anaplerosis (VPC).
- Physiologic replacement of plasma leptin concentrations (30 to 60 pM) during prolonged (48 hr) starvation inhibits WAT lipolysis and results in decreased rates of hepatic gluconeogenesis through reductions in HPA axis activity. In contrast, supraphysiologic plasma leptin concentrations stimulate WAT lipolysis and result in increased rates of hepatic gluconeogenesis and hyperglycemia through activation of the sympathetic nervous system and increased catecholamine secretion.
- Increased rates of WAT lipolysis promote increased hepatic fat (DAG) accumulation and PKCε activation during prolonged (48 hr) starvation.
Regarding this last point, it is interesting to speculate that fasting-induced hepatic steatosis and lipid-induced hepatic insulin resistance may also play an important role in promoting survival during famine by minimizing hepatic glucose uptake and energy storage as glycogen, therefore sparing any ingested carbohydrate for the central nervous system and other obligate glucose-requiring tissues, thus providing an evolutionary basis for DAG-PKCε induced hepatic insulin resistance.
Taken together, these data show that both insulinopenia and hypoleptinemia are necessary for maintenance of euglycemia during short-term (6–16 hr) starvation in lean rats, with insufficient anaplerosis from glucose-alanine cycling limiting both hepatic gluconeogenesis and mitochondrial oxidation in prolonged (48 hr) starvation. These data further identify a novel leptin-mediated glucose-fatty acid cycle that integrates responses of the muscle, white adipose tissue, and liver to maintain adequate substrate supply to the brain to promote survival during starvation.
Update to Apr 20, 2018
Comment 1 Addition
This study begs the question: is simply activation of the HPA-axis sufficient to induce ketogenesis, or do insulin and leptin (and thus, glucagon) really need to be low?
We can look at exercise for some hints at this hypothesis. Acute exercise seems to be a stimulant of the HPA-axis in humans while having little effects on leptin. If we hold the Perry study above to be true (that carb restrict → ↓ glucose → ↓ insulin:glucagon ratio AND ↓ leptin → ↓ glycogen → ↑ ketones) in a sense that decreases in glycogen, glucose and leptin are all necessary for the production of ketones, then it would be the case the exercise itself would not induce ketogenesis. The evidence states the contrary (just look at Volek above), as exercise has long been known to increase the amount ketones in the blood (also known as the Courtice-Douglas Effect).