Leptin in Initiation and Maintainance of Ketosis

(Michael - When reality fails to meet expectations, the problem is not reality.) #1

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:

  1. 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]).
  2. 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.
  3. 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.
  4. 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.
  5. 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).
  6. 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).
  7. 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.
  8. 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).

Comment 2 Addition


(A fool and his bacon are soon parted) #2

This paragraph shows signs of uncritical thinking. Bikman has stated that he knows of no evidence showing that the brain requires any glucose at all to function. This doesn’t mean, of course, that the brain needs no glucose, but simply that if it does have a minimum need for glucose, that fact has not yet been documented in the literature. On the other hand, the notion that the brain needs a minimum of 130 g/day of glucose derives from Cahill’s estimate in Starvation in Man (1960’s).

Also, I don’t believe the authors have taken into account the known fact that elevated serum insulin blocks reception of leptin in the ventromedial hypothalamus, one of the reasons that a high-carb diet tends to make us feel constantly hungry.

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

First, this study is not specifically addressing obligate glucose-requiring tissues/organs. I think we can safely assume, unless stated otherwise in the paper, that the authors accept the standard ‘brain requires at least some glucose’ paradigm. Even Dr. Nadir Ali accepts it (see here and here). Maybe Dr Bikman is correct and maybe not. Maybe Cahill was wrong and everyone since him has just accepted his word about it without looking for definitive evidence. I don’t know.

Second, the study addresses specifically how exactly energy ‘substrate’ - either glucose, ketones and/or FFAs - are maintained in relative homeostasis during prolonged low/no carbohydrate intake. In the case of their lab rats starvation was required to get them into ketosis. Of course, for humans just low/no carb will do it. What the authors of this paper are adding is whether or not reduced leptin is required as well as reduced glucose, insulin and glucagon. For that, they build a very strong case.

The particular paragraph you cite claims only that if there is ingested glucose present it will be preferentially utilized for those obligate glucose-requiring tissue/organs rather than used by the liver and/or converted to glycogen. I don’t find that controversial whether or not you think the brain is one of those organs.

Please comment and/or criticize the paper after reading more than the few tidbits I’ve quoted above.

PS: Is there some way to contact Ben Bikman and ask him to take a look and tell us what he thinks about this? I would find that very interesting! Is he a forum member?

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

Hormones and Hunger

Twenty-five years ago, the only known appetite-controlling hormone was insulin. When blood insulin levels are high, glucose gets stored as glycogen and fats get stored in adipose tissue. The resulting reduction in circulating fuels, such as glucose and free fatty acids, then stimulates appetite. This leads to the common experience of being hungry 2-3 hours after a high carbohydrate, low fat meal. In fact, many people are still arguing that increased insulin is the dominant signal that makes us become obese. But in the interim, we have discovered many other circulating and cellular signals that communicate the body’s energy status and regulate energy intake (aka appetite) as well as metabolism. Among these regulatory hormones are leptin (made primarily in adipose tissue), and ghrelin (made in the upper digestive tract). Both have specific receptors in the brain that transmit their biochemical message into behaviors – for leptin it is “eat less” and for ghrelin it is “eat more”.

It turns out that how these signaling hormones interact with insulin is complex. Add the increased underlying inflammation that is characteristic of obesity and diabetes, and the picture gets even more complex in ways that continue to promote obesity. Fortunately, we now know that when you add a well-formulated, sustained ketogenic diet to this picture it changes dramatically for the better, but in a pattern that is hard to explain. Yes, blood insulin levels go down, but the satiety hormone leptin also goes down. In fact, individuals on a low carbohydrate diet who experience weight loss exhibit a significantly greater reduction in leptin levels compared to those on a low-fat diet (10). That would normally be a signal to eat more, but here’s a key fact – the brain’s sensitivity to the leptin signal goes way up when on a well-formulated ketogenic diet . [emphasis in original]

Another key fact – the brain’s response to leptin is inhibited by inflammation (11), resulting in leptin resistance. Since we now know that inflammation is dramatically reduced by sustained nutritional ketosis (12, 13), it appears that the reduction in leptin resistance due to reduced inflammation more than compensates for the lower leptin levels. In other words, on a well-formulated ketogenic diet the brain perceives a greater satiety response to less leptin. This reduction in inflammation and increase in sensitivity to leptin, together with the reduced blood insulin levels characteristic of nutritional ketosis can explain the paradox as to why we see a decrease in appetite with nutritional ketosis.


(Michael - When reality fails to meet expectations, the problem is not reality.) #5

Don’t know just how this fits (yet) but putting it here for reference. Maybe specific only to epilepsy?


The increase in the fat content and the slower growth associated with the ketogenic diet compared to a regular diet should yield changes in some of the neurohormones involved in energy homeostasis. Accordingly, the ketogenic diet increases serum leptin and lowers serum insulin levels to produce a unique metabolic and neurohormonal state. Although evidence for the decrease in insulin having an anticonvulsant effect is lacking, experimental evidence suggests that the increase in leptin could…

Both the OP study and the exerpt from Virta I quoted directly above say the opposite. Leptin gets lowered by a ketogenic diet. Maybe this study has been superceded?