“When the diet is extremely low in starches and sugars, blood sugar levels drop substantially so that muscle and brain have to turn to alternative fuels,” explains senior MD, an investigator in the Department of Endocrinology, Diabetes and Metabolism at BIDMC and Associate Professor of Medicine at Harvard Medical School. “Consequently, fatty acids are broken down in the liver and converted to ketones, which then serve as a major fuel source.” The differences in weight gain reflect differences in metabolic rates,”. These, in turn, result in hormonal changes that lead to different disposition of the calories.”

1. Keto- Regulator of fat Metabolism
Abstract
“When the diet is extremely low in starches and sugars, blood sugar levels drop
substantially so that muscle and brain have to turn to alternative fuels,” explains
senior MD, an investigator in the Department of Endocrinology, Diabetes and
Metabolism at BIDMC and Associate Professor of Medicine at Harvard Medical
School. “Consequently, fatty acids are broken down in the liver and converted to
ketones, which then serve as a major fuel source.” The differences in weight gain
reflect differences in metabolic rates,”. These, in turn, result in hormonal changes
that lead to different disposition of the calories.”
It had been fed a ketogenic diet high in both saturated fat and unsaturated fat
and practically devoid of carbohydrates. “Despite the high fat content of this diet,
the study animals maintained normal levels of circulating lipids, “We wanted to
learn what factors might be responsible for creating this state in which consumed
calories were being burned off in the liver rather than being stored as fat.”
Because the physiologic changes in the animals didn't appear to be explained by
typical hormonal regulators – neurotransmitters that normally regulate appetite -
identify which genes were unique to this ketogenic phenotype, exploring the
possibility that hepatocytes were playing an active role in the process.

2. It using microarray gene analysis, they discovered that their hunch was correct:
FGF21, a liver-derived fibroblast growth factor gene, was significantly increased in
the mice that had been fed ketogenic diets.
“FGF21 had previously been identified as a potential metabolic regulator by
scientists at Eli Lilly, who showed that transgenic mice that overexpressed FGF21
were protected from diet-induced obesity, had smaller fat cells and had more
brown adipose tissue, "But little was actually known about FGF21's physiologic
roles. Working with Jeffrey Flier's lab, we were able to show that FGF21 is
essential for fatty acid oxidation.”
Circulating/ Regulating
Furthermore, when FGF21 was inhibited, the mice developed a massive
accumulation of fat in the liver and an extreme increase in circulating lipids.
A second study by Maratos-Flier and colleagues published in the June 2007 issue
of the American Journal of Physiology further elucidates the unique metabolic
changes that occur with the consumption of a ketogenic diet.
“Although the purpose of both of these studies was to glean insights into
metabolic physiology, our findings suggest that increased levels of FGF21 may be
a potential mechanism behind low-carbohydrate diets' beneficial properties when
it comes to lipid metabolism,” says Maratos-Flier. “Diets that limit carbohydrates
and eliminate trans fats, and at the same time emphasize fiber and good fats,
appear to be healthiest, especially among individuals who are predisposed to
developing diabetes.”
Metabolic Pathways
 Modifications in the macronutrient composition of diets or food
components have been shown to affect hormones, metabolic pathways,
gene expression, and appetite control. Several studies have provided
evidence for the appetite suppressant effect of ketogenic diets and shown
that for as long as participants are in a state of ketosis, appetite does not

3. increase, despite weight loss. It has been consistently shown by our
research group and others that under ketogenic conditions, feelings of
hunger, measured using validated visual analogue scales (VASs), do not
increase, even when massive weight loss is achieved (up to 17% or initial
body weight). Studies where hunger feelings have been evaluated through
other methods, such as the Three Factor Eating Questionnaire [14], the
Food Craving Questionnaire [15], Non validated questionnaires, semi-
structured interviews, [19] and case reports [20,21] have also confirmed
that ketogenic diets are associated with diminished or absent feelings of
hunger, a reduced desire to eat and decreased overall appetite.
 From our knowledge, all the available evidence shows that the secretion of
the hunger hormone ghrelin, which is upregulated in response to diet-
induced weight loss, is blunted under ketogenic conditions. Moreover, once
participants are no longer in ketosis, upon refeeding and re-introduction of
CHO, the expected surge in ghrelin secretion and hunger feelings above
baseline levels is seen. The effect of ketogenic diets on the release of
satiety hormones, namely cholecystokinin (CCK), glucagon-like peptide-1
(GLP-1) and peptide YY, remains unfortunately inconclusive. Our group has
found no changes in the postprandial release of these satiety peptides with
a 17% weight loss induced using VLED, independently of the participants
being in or out of ketosis.

4.  Whether appetite responses to ketosis differ between males and females is
yet to be fully determined. However, our research group found that the
basal and postprandial secretion of GLP-1 in response to weight loss
induced by a VLED was modulated by sex, with a decrease in basal GLP-1
concentrations seen only in males, and an increase in postprandial
concentration of GLP-1 happening only in females.
 The threshold of nutritionally induced ketosis needed to achieve appetite
suppression using ketogenic diets has yet to be determined. However, the
results from the systematic review and meta-analysis performed by Gibson
and colleagues indicate that a restriction of CHO below 50 g/day does not
appear to be necessary. This raises the question of whether such a
restriction should be applied in ketogenic diets, because the severity of the
CHO restriction is counterintuitive to healthy eating recommendations.
Entire core food groups, such as whole grains, legumes, reduced-fat dairy,
fruits, and vegetables need to be severely constrained or eliminated due to
the need to significantly reduce CHO intake. This restriction and elimination
may have a negative impact on bone health and increase the risk of
developing certain types of cancer and cardiovascular disease.
Furthermore, in addition to the CHO restriction, fiber intake is also reduced
in ketogenic diets and likely explains why constipation is one of the most
commonly reported side effects of these diets.
 Given that high amounts of circulating ketones have been seen in
participants who followed diets with a CHO intake of up to 192 g/day, a
greater allowance of CHO in ketogenic diets might and should be
considered in future formulations. The literature on this topic seems to

5. suggest that 100 g/day of CHO should be the cut off for ketogenic diets. A
more liberal CHO allowance can, for instance, enable the incorporation of
CHO-rich vegetables that are higher in fiber content pivotal to alleviate
constipation in those undergoing ketogenic diets and allow for the
consumption of calcium-containing dairy products with fortified vitamin D
and calcium to hinder bone loss that has been seen as a long-term side
effect of VLED.
Conclusion: Harvey and colleagues reported recently that equicaloric diets
containing up to 25% total energy from CHO can result in mean ßHB ≥ 0.5
mmol/L, with no clinically relevant differences in symptoms of CHO withdrawal
between diets containing from 5% to 25% total energy from CHO [9].