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Ketosis and appetite-mediating nutrients and hormones after weight loss


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Background/objectives: Diet-induced weight loss is accompanied by compensatory changes, which increase appetite and encourage weight regain. There is some evidence that ketogenic diets suppress appetite. The objective is to examine the effect of ketosis on a number of circulating factors involved in appetite regulation, following diet-induced weight loss. Subjects/methods: Of 50 non-diabetic overweight or obese subjects who began the study, 39 completed an 8-week ketogenic very-low-energy diet (VLED), followed by 2 weeks of reintroduction of foods. Following weight loss, circulating concentrations of glucose, insulin, non-esterified fatty acids (NEFA), β-hydroxybutyrate (BHB), leptin, gastrointestinal hormones and subjective ratings of appetite were compared when subjects were ketotic, and after refeeding. Results: During the ketogenic VLED, subjects lost 13% of initial weight and fasting BHB increased from (mean±s.e.m.) 0.07±0.00 to 0.48±0.07 mmol/l (P<0.001). BHB fell to 0.19±0.03 mmol/l after 2 weeks of refeeding (P<0.001 compared with week 8). When participants were ketotic, the weight loss induced increase in ghrelin was suppressed. Glucose and NEFA were higher, and amylin, leptin and subjective ratings of appetite were lower at week 8 than after refeeding. Conclusions: The circulating concentrations of several hormones and nutrients which influence appetite were altered after weight loss induced by a ketogenic diet, compared with after refeeding. The increase in circulating ghrelin and subjective appetite which accompany dietary weight reduction were mitigated when weight-reduced participants were ketotic.
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Ketosis and appetite-mediating nutrients and hormones
after weight loss
P Sumithran
, LA Prendergast
, E Delbridge
, K Purcell
, A Shulkes
, A Kriketos
and J Proietto
BACKGROUND/OBJECTIVES: Diet-induced weight loss is accompanied by compensatory changes, which increase appetite and
encourage weight regain. There is some evidence that ketogenic diets suppress appetite. The objective is to examine the effect
of ketosis on a number of circulating factors involved in appetite regulation, following diet-induced weight loss.
SUBJECTS/METHODS: Of 50 non-diabetic overweight or obese subjects who began the study, 39 completed an 8-week ketogenic
very-low-energy diet (VLED), followed by 2 weeks of reintroduction of foods. Following weight loss, circulating concentrations of
glucose, insulin, non-esterified fatty acids (NEFA), b-hydroxybutyrate (BHB), leptin, gastrointestinal hormones and subjective ratings
of appetite were compared when subjects were ketotic, and after refeeding.
RESULTS: During the ketogenic VLED, subjects lost 13% of initial weight and fasting BHB increased from (mean±s.e.m.) 0.07±0.00
to 0.48±0.07 mmol/l (Po0.001). BHB fell to 0.19±0.03 mmol/l after 2 weeks of refeeding (Po0.001 compared with week 8). When
participants were ketotic, the weight loss induced increase in ghrelin was suppressed. Glucose and NEFA were higher, and amylin,
leptin and subjective ratings of appetite were lower at week 8 than after refeeding.
CONCLUSIONS: The circulating concentrations of several hormones and nutrients which influence appetite were altered after
weight loss induced by a ketogenic diet, compared with after refeeding. The increase in circulating ghrelin and subjective appetite
which accompany dietary weight reduction were mitigated when weight-reduced participants were ketotic.
European Journal of Clinical Nutrition (2013) 67, 759–764; doi:10.1038/ejcn.2013.90; published online 1 May 2013
Keywords: appetite; ketosis; very-low-energy diet; weight loss
The increasing prevalence of overweight and obesity has been
widely reported. Ketogenic low-carbohydrate diets are a popular
means of weight loss, and in the short-term, often result in greater
weight loss than low-fat diets.
During fasting or restriction of
dietary carbohydrate intake, fatty acid oxidation in the liver results
in the production of ketones. Although the mechanism of the
efficacy of ketogenic diets has not been definitively established,
it is commonly proposed that ketones suppress appetite,
and it
has been observed that study participants on ad libitum ketogenic
diets spontaneously restrict their energy intake.
In the hypothalamus, signals from several circulating
hormones and nutrients are integrated to regulate appetite and
energy expenditure.
The peripheral modulators of appetite
include glucose,
free-fatty acids
and hormones from the
gastrointestinal tract, pancreas and adipose tissue, such as
leptin, insulin, ghrelin, cholecystokinin (CCK), glucagon-like
peptide 1, peptide YY and pancreatic polypeptide.
Following diet-induced weight loss, a number of compensatory
changes occur, which encourage weight regain and restoration
of energy balance. These include reductions in energy expendi-
and circulating leptin,
and an increase in the orexigenic
hormone ghrelin.
It was recently reported that postprandial
release of CCK, a hormone which increases satiety, was
significantly reduced after diet-induced weight loss.
when weight-reduced subjects were ketotic due to restriction of
dietary carbohydrate, CCK release was maintained at preweight
loss concentrations, raising the possibility of an interaction
between circulating ketones and hormonal mediators of appetite.
The aim of the present study was to examine whether a number
of circulating hormones involved in appetite regulation are altered
in the presence of ketosis following diet-induced weight loss.
The study was approved by the Austin Health Human Research Ethics
Committee, and all subjects provided written informed consent. A detailed
description of methods has previously been published.
In brief,
50 overweight or obese non-diabetic men and postmenopausal women
(mean (±s.d.) age 54.4±10.9 years) undertook a very-low-energy diet
(VLED) for 8 weeks, during which all three daily meals were replaced with a
VLED formulation (Optifast VLCD, Nestle
´Nutrition, Sydney, New South
Wales, Australia) and two cups of low-starch vegetables, according to the
manufacturer’s guidelines, which provided 2.1–2.3 MJ (500–550 kcal) per
day. During the subsequent 2 weeks, subjects who lostX10% of their
starting weight (n¼39) were instructed to gradually substitute the VLED
meal replacements with regular foods, with dietary recommendations
adjusted for individual energy requirements for weight maintenance.
Data collection
Data was collected at baseline (week 0), at week 8 and after the 2 week
transition to regular foods (week 10). After an overnight fast, measures of
anthropometry were taken with subjects wearing light clothing and
barefoot. Bioelectrical impedance was used to measure body weight and
composition (Tanita TBF-300, Tanita, Perth, Western Australia, Australia)
Department of Medicine (Austin Health), University of Melbourne, Melbourne, Victoria, Australia;
Department of Mathematics and Statistics, La Trobe University, Melbourne,
Victoria, Australia and
Department of Surgery (Austin Health), University of Melbourne, Melbourne, Vict oria, Australia. Correspondence: Professor J Proietto, Department of
Medicine, University of Melbourne, Level 2, Boronia Building, Heidelberg Repatriation Hospital, 300 Waterdale Rd, Heidelberg, Victoria 3081, Australia.
Received 1 October 2012; revised 27 March 2013; accepted 3 April 2013; published online 1 May 2013
European Journal of Clinical Nutrition (2013) 67, 759– 764
2013 Macmillan Publishers Limited All rights reserved 0954-3007/13
using the standard adult mode of measurement. A baseline blood sample
was collected, and subjects were asked to rate their appetite using a
validated visual analogue scale.
A standardized breakfast was provided,
which consisted of a boiled egg, toast, margarine, orange juice, cereal
biscuits (Weet-Bix; Sanitarium, Berkeley Vale, New South Wales, Australia)
and whole milk. This meal contained 2.3 MJ (550 kcal), of which B51%
energy was from carbohydrate, 33% from fat and 16% from protein. Blood
samples and VAS ratings of appetite were collected 30, 60, 120, 180 and
240 min thereafter.
Biochemical assays
Blood was collected into prepared tubes, spun in a refrigerated centrifuge,
and frozen for later analysis. Plasma for b-hydroxybutyrate (BHB), non-
esterified fatty acids (NEFA) and CCK were stored at 801C. All other
aliquots were stored at 20 1C. Fasting and postprandial plasma acylated
ghrelin, active glucagon-like peptide 1, total glucose-dependent insulino-
tropic polypeptide (GIP), pancreatic polypeptide, amylin and peptide YY
concentrations were measured using the human gut hormone panel
Lincoplex kit (Millipore, Sydney, New South Wales, Australia), a multiplex
assay kit, which uses antibody-immobilised beads to simultaneously
quantify peptide hormones. The sensitivity of the assay is 1.8, 5.2, 0.2, 2.4,
3.2 and 8.4 pg/ml respectively, for the hormones as listed above.
Intra-assay and inter-assay variation are o11% and o19% respectively.
Plasma insulin and leptin were measured by commercial radioimmuno-
assay (Millipore). CCK was measured in ethanol-extracted plasma
using antiserum 92128 (generous donation of Prof Jens Rehfeld,
University Hospital, Copenhagen, Denmark) and
label (Perkin Elmer, Melbourne, Victoria, Australia). The antiserum is specific
for CCK-amide with negligible cross-reactivity to gastrin-amide or gly-
extended forms of gastrin and CCK. NEFA was measured by enzymatic
colorimetry (Wako, Osaka, Japan). Glucose was measured by the glucose
oxidase method (GM7 Analox glucose analyzer, Helena Laboratories,
Melbourne, Victoria, Australia). BHB was measured using a colorimetric
assay (Unicel DxC 800 Synchron Clinical System analyzer, Beckman Coulter,
Sydney, New South Wales, Australia). Circulating levels of other ketones
(acetoacetate and acetone) were not measured, as the increase in ketones
during food restriction is predominantly due to BHB.
Statistical analysis
Analyses included the 39 of 50 subjects who completed all three data
collection visits. At baseline, data were missing from one subject for the
gut hormone multiplex, two subjects for CCK and three subjects for NEFA,
due to difficulty obtaining sufficient blood for analysis. Of the remaining
data, o2% was missing at random, and was replaced using linear
interpolation. Analyses were carried out using R version 2.13.1.
measures ANOVA to compare measurements between study visits was
done by fitting a generalized least squares model with an unstructured
error covariance. Comparison between weeks was carried out using Wald
tests applied to the generalized least squares-fitted model. For data which
was not normally distributed, the log or square-root transformation was
used, although means and s.e.m. are reported on the original scale.
The pairwise comparisons between weeks in Tables 1 and 2 were also
adjusted by the Benjamini and Yekutieli method
to account for multiple
comparisons, and P-values which no longer remain significant after
adjustment are indicated on the tables. A table of changes in
anthropometry, fasting and 4-h area under curve (AUC) of nutrients,
hormones and VAS scores between weeks 0– 8, 0–10 and 8–10 showing
P-values for comparisons between weeks before and after adjustment for
multiple comparisons is provided in the Supplementary Data section.
Correlations reported are Spearman rank correlations (r), and 95%
confidence intervals (CI) were calculated using the bootstrap approach.
Insulin resistance was estimated by the homoeostasis model of assessment
of insulin resistance, using the formula homoeostasis model of assessment
of insulin resistance (HOMA-IR) ¼(fasting glucose (mmol/l) fasting
insulin (mU/l))/22.5.
Values are given as means±s.e.m. unless otherwise
Effect of diet on anthropometric measurements
Measures of anthropometry and blood pressure at baseline, and
changes following 8 weeks of VLED and after 2 weeks of
reintroduction of food are shown in Table 1.
Eight weeks on a VLED resulted in a mean loss of 13% initial
body weight, with significant reductions in adiposity, waist and
hip circumferences and blood pressure. There were minor, but
statistically significant, changes in anthropometric parameters
between weeks 8 and 10.
Fasting BHB increased from 0.07±0.00 to 0.48±0.07 mmol/l
after 8 weeks of VLED (Po0.001), and fell to 0.19±0.03 mmol/l
after 2 weeks of food reintroduction (Po0.001, compared with
weeks 0 and 8).
Nutrients and hormones during ketosis (week 8) and after
refeeding (week 10) in weight-reduced participants
Mean fasting and 4-h postprandial values for glucose, NEFA,
ghrelin and amylin at weeks 0, 8 and 10 are depicted in Figure 1.
Mean fasting and 4-h AUC values at baseline, and changes from
baseline at weeks 8 and 10 for nutrients and hormones are shown
in Table 2.
Glucose, insulin. Weight loss led to significant reductions in
fasting glucose and insulin, resulting in a significant improvement
in insulin resistance, estimated by homoeostasis model of
assessment of insulin resistance, from week 0 to 8. There were
no significant changes in these measurements between weeks 8
and 10.
Four-h postprandial AUC for insulin fell significantly with weight
loss, and was not significantly different between weeks 8 and 10.
In contrast, AUC glucose did not change significantly with VLED-
induced weight loss, but fell after refeeding (Table 2). There were
significant correlations between BHB and AUC glucose at week 8
Table 1. Anthropometric and blood pressure measurements at baseline (mean s.d.), and changes after weight loss (mean±s.e.m.) when subjects
were ketotic (week 8) and after refeeding (non-ketotic, week 10)
Measure Week 0 DWeek 0–8
DWeek 0–10
DWeek 8–10 P-value
(week 8 versus 10)
Weight (kg) 96.2 (13.6) 12.5±0.5
0.5±0.1 o0.001
BMI (kg/m
) 34.7 (3.5) 4.5±0.1
0.2±0.1 o0.001
Waist circumferance (cm) 103.3 (10.6) 9.9±0.5
0.7±0.4 0.07
Hip circumferance (cm) 120.3 (8.0) 8.1±0.4
8.9 ±0.4
0.8±0.3 0.002
Fat mass (kg) 49.5 (11.2) 13.4±0.7
1.2±0.3 o0.001
Systolic BP (mmHg) 136.0 (19.8) 17.6±2.4
3.7±1.7 0.03
Diastolic BP (mmHg) 82.7 (11.1) 9.2 ±1.9
0.8±1.8 0.68
Symbols denote significant differences from week 0 (
Pp0.001). Repeated measures ANOVA reported highly significant changes over weeks for all measures
(all P-valueo0.001).
Indicates pairwise comparisons, which did not remain significant after adjustment for multiple comparisons.
Ketosis and appetite after weight loss
P Sumithran et al
European Journal of Clinical Nutrition (2013) 759 – 764 &2013 Macmillan Publishers Limited
(P¼0.40; 95% CI (0.06, 0.67)), and between changes in BHB and
AUC glucose from week 8 to 10 (P¼0.49; 95% CI (0.20, 0.71)).
NEFA. Four-h postprandial AUC for NEFA was elevated at week 8,
but after 2 weeks of refeeding was not significantly different
from baseline values (Table 2). There were significant correlations
between BHB and AUC NEFA at week 8 (P¼0.49; 95% CI
(0.18, 0.69)), and between changes in BHB and AUC NEFA from
week 8 to 10 (P¼0.43; 95% CI (0.11, 0.69)).
Leptin. Fasting leptin fell significantly with weight loss, and
increased slightly following reintroduction of food, even when
adjusted for fat mass. There were inverse correlations between
leptin and BHB at week 8 (P¼0.44; 95% CI ( 0.68, 0.09)),
and between changes in leptin and BHB from weeks 8 to 10
(P¼0.33; 95% CI ( 0.61, 0.01)).
Gastrointestinal peptides. At week 8, weight-reduced subjects
had significantly lower fasting ghrelin, peptide YY, amylin and
pancreatic polypeptide, compared with week 10 values.
Fasting GIP, glucagon-like peptide 1 and CCK were not different
in weight-reduced subjects between weeks 8 and 10 (Table 2).
Four-h AUC values for ghrelin and amylin were significantly
lower at week 8 than at week 10 (Po0.001 for both, Figure 1).
AUC ghrelin increased significantly between weeks 0 and 8 in
participants who did not achieve ketosis (BHB 40.3 mmol/l) at
week 8, but the weight loss induced increase in ghrelin was
completely suppressed in subjects who were ketotic. There were
significant inverse correlations between BHB and AUC ghrelin at
Table 2. Fasting and 4-h AUC of nutrient, hormone and VAS values at week 0 (mean s.d.), and changes from baseline at weeks 8 and 10
Measure Week 0 DWeek 0–8
DWeek 0–10
DWeek 8–10 P-value
(week 8 versus 10)
5.8 (0.9) 0.6±0.1
0.4±0.1w0.2±0.1 0.07
18.1 (9.8) 9.0±1.2
0.7±0.5 0.17
4.7 (2.8) 2.6±0.4
0.3±0.1 0.08
BHB 0.07 (0.0) 0.43±0.08
0.3±0.06 o0.001
0.5 (0.3) 0.3±0.1
0.1±0.05 0.2±0.05 o0.001
33.2 (18.3) 23.4±2.2
2.3±0.6 o0.001
Leptin/fat mass
0.66 (0.3) 0.41±0.04
0.07±0.02 o0.001
122.0 (89.2) 4.4±9.1 52.8±9.0
49.2±9.5 o0.001
68.3 (33.0) 19.7±4.4
13.6±4.2 6.4±3.2 0.02
GIP 18.3 (10.5) 4.1±2.3 1.3±2.5 2.8±1.8 0.12
40.2 (17.2) 6.2±2.1
0.1±2.1 0.88
66.4 (67.5) 19.2±10.2 5.7 ±10.5 24.9±8.0 o0.001
83.1 (52.1) 50.5±7.9
15.5±2.9 o0.001
1.7 (1.0) 0.6±0.2
0.1±0.1 0.19
4-h AUC
Glucose 1487 (262) 25.8±42 66±32*
90.6±30 0.003
12 086 (7728) 4722±974
147±422 0.36
71.9 (29.1) 40.1±6.8
9.4±4.4 30.7±5.5 o0.001
23 034 (16703) 1136±2023 9696±1937
8877±1743 o0.001
18 190 (6384) 2580±665
1771±571w754±602 0.21
18 384 (8471) 9011±2004
6755±2057w2537±1220 0.06
GLP-1 11 471 (4087) 460±608 353±560 130±431 0.97
PP 40 991 (23757) 7358±3404 9384±3775*
834±3160 0.68
35 900 (3340) 16 880±3049
11 875±3170
CCK 730 (317) 64±44 100±47w
29±31 0.36
31.9 (26.3) 2.6±4.7 9.6±4.8*
7.0±3.8 0.03
Full 44.2 (25.9) 0.5±4.3 7.2±4.1 7.2±3.6 0.05
Desire 40.8 (25.1) 0.9±4.5 4.6±4.5 5.4±3.2 0.09
42.8 (18.8) 0.2±3.1 6.0±2.9*
6.2±2.6 0.02
32.7 (23.3) 2.5±3.8 11.1±4.2*
8.5±3.1 0.006
Preoccupied 36.2 (23.3) 4.9±4.0 5.0±4.0 0.0±3.0 1.00
4-h AUC
Hunger 5181 (2538) 847±499 1463±542*
616±397 0.10
Full 12 806 (5326) 491±848 783±853 292±534 0.59
5694 (2902) 796±542 1456±562*
660±334 0.05
Prospective 7125 (2883) 715±525 992±534 277±257 0.40
Urge 5457 (2922) 831±455 1473±533*
642±346 0.07
Preoccupied 5144 (3279) 597±524 880±537 283±293 0.42
Abbreviations: AUC, area under curve; BHB, b-hydroxybutyrate; CCK, cholecystokinin; GLP-1, glucagon-like peptide 1; GIP, glucose-dependent insulinotropic
polypeptide; HOMA-IR, homeostasis model of assessment of insulin resistance; NEFA, non-esterified fatty acids; PP, pancreatic polypeptide; PY Y, peptide YY.
Units are as follows: insulin mU/l; HOMA-IR units; leptin ng/ml; PYY, GIP, GLP-1, PP pg/ml; CCK fmol/ml, VAS millimetres (mm), with possible range 0–100 mm
for fasting values. Repeated measures ANOVA reported significant changes over weeks for measures denoted by
Symbols denote significant differences from
week 0 (
Pp0.01, * Po0.05).
Indicates pairwise comparisons, which did not remain significant after adjustment for multiple comparisons.
Ketosis and appetite after weight loss
P Sumithran et al
&2013 Macmillan Publishers Limited European Journal of Clinical Nutrition (2013) 759 – 764
week 8 (P¼0.34; 95% CI ( 0.62, 0.04)), and between
changes in BHB and AUCs for ghrelin (P¼0.48, 95% CI ( 0.70,
0.22)) and amylin (P¼0.43, 95% CI ( 0.68, 0.12)) from
week 8 to 10. AUC GIP tended to be higher at week 8 compared
with week 10. AUC CCK was not significantly different from
baseline at week 8, but was significantly lower than baseline
values at week 10. At week 8, there was a significant correlation
between BHB and AUC CCK (P¼0.38; 95% CI (0.11, 0.61)).
AUCs for peptide YY, glucagon-like peptide 1 and pancreatic
polypeptide were not significantly different between weeks
8 and 10.
Appetite during ketosis and after refeeding in weight-reduced
Appetite ratings at week 0, and changes from baseline at
weeks 8 and 10 are presented in Table 2.
At week 8, fasting and AUC ratings of appetite were unchanged
compared with baseline. However, after 2 weeks of refeeding
(week 10), fasting scores for hunger, urge to eat and prospective
consumption rose significantly, and fullness tended to decrease.
At week 10, AUCs for hunger, urge and desire to eat were
significantly higher than preweight loss levels (P¼0.02, 0.02 and
0.04 respectively; all P40.05 after adjustment for multiple
Although an inhibitory effect of ketosis on appetite is widely
assumed, there is little information regarding the effect of
ketosis on circulating factors involved in mediating hunger
and satiety.
It is well-established that diet-induced weight loss is accom-
panied by changes in energy expenditure and concentrations of
appetite-regulating hormones, in a manner which encourages
weight regain and restoration of energy balance.
It has
been shown that postprandial release of CCK is maintained at the
preweight loss level following an 8-week ketogenic VLED, but
reduced when weight-reduced subjects are no longer ketotic.
The present study confirms this finding, and uncovers several
other factors, which are altered in ketotic weight-reduced
subjects. Subjective ratings of appetite were significantly lower
when weight-reduced subjects were ketotic than following
In mildly ketotic participants, the increase in the circulating
concentration of ghrelin, a potent stimulator of appetite, which
otherwise occurs as a result of diet-induced weight loss, was
suppressed. The present findings are in keeping with a recent
report of a 12-week carbohydrate-restricted diet, during which 28
overweight subjects lost B6.5% of their starting weight without a
significant change in fasting plasma ghrelin.
In our study,
postprandial ghrelin concentrations were also measured, and
found to remain unchanged following weight loss as long as
subjects were ketotic. After refeeding, fasting and postprandial
ghrelin concentrations rose significantly.
Our findings of elevated NEFA after 8 weeks on a
low-carbohydrate VLED with return to baseline values after
carbohydrate reintroduction are not surprising, as carbohydrate
restriction stimulates adipocyte lipolysis and ketogenesis. In
rodents, intracerebroventricular administration of a long-chain
fatty acid markedly reduced food intake and hypothalamic
expression of neuropeptide Y, a potent stimulator of appetite,
and peripheral infusion of lipids has been shown to reduce
voluntary food intake in humans.
It has been hypothesized that
fatty acids may provide a signal to the hypothalamus of nutrient
and this may contribute to the appetite-reducing
effects of ketogenic low-carbohydrate diets.
The observation that ketosis did not affect fasting glucose,
but was associated with elevated postprandial blood glucose
concentrations is interesting. As postprandial reductions in blood
glucose may increase hunger,
(the ‘glucostatic theory’ of
food intake regulation, first proposed by Mayer more than
60 years ago
), the effect of ketosis on postprandial glucose
may contribute to appetite reduction. Reports of ketogenic low-
carbohydrate diets having beneficial effects on insulin sensitivity
in humans
have used the homoeostasis model assessment of
insulin resistance or quantitative insulin sensitivity check index
(QUICKI), which take into account only fasting glucose and insulin
measurements. Conversely, using hyperinsulinemic euglycemic
clamps, it was demonstrated that a ketogenic diet reduces the
ability of insulin to suppress endogenous glucose production, and
impairs insulin-stimulated glucose oxidation.
Elevated NEFA may
also contribute to insulin resistance.
In rats, intracerebroventricular infusion of BHB reduces food
intake and body weight,
and there is recent in vitro evidence
Time (mins)
Glucose (mmol/L)
Week 0
Time (mins)
NEFA (mEq/L)
Ghrelin (pg/ml)
Amylin (pg/ml)
30 60 120 180 240
30 60 120 180 240
30 60 120 180 240
30 60 120 180 240
Week 8 Week 10
Week 0 Week 8 Week 10
Week 0 Week 8
Week 10
Week 0 Week 8
Week 10
Figure 1. Mean fasting and postprandial glucose (a), NEFA (b), ghrelin (c) and amylin (d) at weeks 0, 8 and 10. Symbols indicate significant
differences in AUCs compared with week 0 (*Po0.05;
Ketosis and appetite after weight loss
P Sumithran et al
European Journal of Clinical Nutrition (2013) 759 – 764 &2013 Macmillan Publishers Limited
that BHB may directly reduce central orexigenic signalling.
Peripheral injection of BHB also reduces food intake, and this
effect is eliminated by transection of the common hepatic branch
of the vagus nerve.
Of note, this branch primarily contains
afferent fibres originating in the proximal small intestine, stomach
and pancreas, which have been shown to be sensitive to
stimulation by CCK.
Ghrelin also conveys its orexigenic signal
to the brain via the vagus nerve.
The preservation of preweight-
loss profiles of ghrelin and CCK release may thereby contribute to
the suppressive effect of ketosis on appetite.
It is interesting to note that not all hormones changed in a
direction which would contribute to appetite suppression by
ketosis. Leptin was lower after 8 weeks on a VLED than following 2
weeks of refeeding, even when adjusted for fat mass. This is
consistent with previous reports of a lower plasma leptin during
dynamic weight loss than after maintenance of the reduced
and is in keeping with the hypothesis that the role of
leptin is more as an emergency signal of energy depletion than
an inhibitor of food intake.
Amylin is cosecreted with insulin
by pancreatic b-cells, and reduces food intake directly in the area
and also via mediation of the anorexic effects of other
hormones including CCK.
GIP, an incretin hormone, appears to
promote energy storage.
The weight loss induced reduction
in amylin and increase in GIP, which would be expected to
encourage regain of lost body weight, were somewhat attenuated
following refeeding. It is difficult to explain the seemingly
contradictory effects of ketosis on different hormones and
nutrients involved in appetite regulation. Nonetheless, subjective
ratings of appetite were lower when participants were ketotic. It is
possible that central sensitivity to the anorexic effect of hormones
such as leptin and amylin may be altered by ketosis, or that
interaction between various hormones is affected. The relative
potency of the multitude of factors involved in appetite regulation
is also unknown, and it may be that the increase in hunger
following the reduction in ketosis reflects the strength of ghrelin
as an orexigenic signal.
It should be noted that although the majority of randomized
controlled trials comparing ad libitum ketogenic low-carbohydrate
diets with low-fat diets have found greater weight loss over
6 months on the ketogenic diets, the difference is no longer
observed at 12 months.
In one of these studies, urinary ketones
were significantly higher in the low-carbohydrate group compared
with the low-fat group over the first 12 weeks, but no relationship
was found between urinary ketones and weight loss.
Only a
minority of people have detectable urinary ketones after
3–6 months on low-carbohydrate diets.
This study has limitations. Subjects were undergoing active
weight loss after 8 weeks on the VLED, compared with relative
weight stability after 2 weeks of food reintroduction, which could
have influenced the concentration of measured hormones and
nutrients. However, compensatory mechanisms aimed at restoring
energy balance would be expected to be more pronounced
during dynamic weight loss, so this is likely to minimize the
predominantly anorexigenic changes detected while subjects
were ketotic. There was a small but statistically significant
reduction in body weight and adiposity between weeks 8 and
10. This difference, representing a reduction in initial weight of
13.6% (week 10) compared with 13.1% (week 8), is unlikely to be
of sufficient magnitude to affect the hormone and appetite
results. It has previously been shown that circulating ghrelin
increases significantly following a diet-induced loss of 8.5% of
initial body weight.
Perhaps due to fear of weight regain, it is
likely that not all participants consumed the prescribed amount of
carbohydrates during the period of food reintroduction, and
although BHB concentrations decreased significantly between
week 8 and 10, they did not return to baseline values by week 10.
This is likely to underestimate the effect of ketosis on the appetite-
regulating hormones and nutrients measured. Although we have
demonstrated associations between ketones and appetite-
regulating hormones, this does not indicate causality. However,
it has been shown in mice that infusion of BHB increases
circulating CCK and reduces food intake.
A similar study
with measurement of other appetite-regulating hormones would
be informative.
In conclusion, following diet-induced weight loss, the circulat-
ing concentrations of several hormones and nutrients which
influence appetite were altered when participants were ketotic,
compared with after refeeding. The increases in circulating ghrelin
and subjective appetite which accompany dietary weight reduc-
tion were mitigated when weight-reduced participants were
ketotic. Further research is needed to determine the precise
mechanism of this effect.
JP was chairman of the Optifast medical advisory board at the time the study was
conducted. The other authors have no conflict of interest.
This work was supported by NHMRC project grant (508920), Endocrine Society of
Australia scholarship (PS), Royal Australasian College of Physicians Shields Research
Entry scholarship (PS), and Sir Edward Dunlop Medical Research Foundation (JP). We
thank Celestine Bouniu, John Cardinal, Sherrell Cardinal, Christian Rantzau, Rebecca
Sgambellone, Sherley Visinoni and Mildred Yim for technical assistance.
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Supplementary Information accompanies this paper on European Journal of Clinical Nutrition website (
Ketosis and appetite after weight loss
P Sumithran et al
European Journal of Clinical Nutrition (2013) 759 – 764 &2013 Macmillan Publishers Limited
... Nutritional-induced ketosis has been shown to modulate the concentrations of GI hormones, particularly ghrelin [17,18], with the increased drive to eat otherwise seen with diet-induced weight loss being attenuated, or even absent, under ketogenic conditions [17,19,20]. Interestingly, it has been reported that patients who undergo bariatric surgery develop mild ketosis shortly after surgery [21]. ...
... EFFECT OF DIET OR BARIATRIC SURGERY ON APPETITE weight loss [17,18,20], which might explain these findings. The main production site of ghrelin is the fundus of the stomach, which is removed during the SG procedure. ...
... This is in line with the present Despite supposedly less beneficial alterations in GI hormonal concentrations with weight loss induced by diet alone, an overall reduction in ratings of postprandial hunger, as well as an overall increase in postprandial fullness, was seen in the present study. It has previously been demonstrated that the expected increase in hunger that follows weight loss is prevented and postprandial fullness sometimes increased when participants are ketotic [20,36]. Even though ketosis has been associated with a greater weight loss 1 year post SG [37], the impact of ketosis on appetite in the context of bariatric surgery is underinvestigated [21,37]. ...
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Objective The aim of this study was to compare changes in gastrointestinal hormones and appetite ratings after a similar weight loss induced by a very low-energy diet alone or in combination with sleeve gastrectomy (SG) or Roux-en-Y gastric bypass (RYGB). Methods Patients with severe obesity scheduled for SG (n = 15) and RYGB (n = 14) and 15 controls (very low-energy diet alone) were recruited. Body weight/composition, plasma concentrations of ß-hydroxybutyric acid, acylated ghrelin, total glucagon-like peptide-1, total peptide YY, cholecystokinin, and ratings of hunger, fullness, desire to eat, and prospective food consumption were measured pre- and postprandially, before and after 10 weeks of intervention. Results Changes in body weight/composition and level of ketosis were similar across groups. In SG and RYGB, basal and postprandial acylated ghrelin declined, and postprandial glucagon-like peptide-1 increased, both significantly more compared with controls. Postprandial peptide YY increased in all groups. Overall, postprandial hunger decreased, and postprandial fullness increased. But ratings of desire to eat and prospective food consumption were more favorable after both surgeries compared with controls. Conclusions Weight loss with SG and RYGB leads to more favorable changes in gastrointestinal hormones compared with diet alone, although ratings of appetite were reduced across all groups.
... obesity, polycystic ovary syndrome, autism, acne, asthma, multiple sclerosis, alzheimer's, Parkinson's) in which the severity of inflammation affects the course of the disease. 5,23,[31][32][33][34][35][36][37][38][39][40][41][42][43] it may also contribute to brain function and cognitive performance. 42,43 One of the potential reasons for the neuron-protective effect is that antioxidant mechanisms are thought to be enhanced by ketogenic nutrition. ...
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BaCKgrOuND: anastomotic leaks cause major problems in colorectal surgeries increase morbidity and mortality. The idea that ketogenic diet reduces inflammation and free oxygen radicals in the body, as well as its effects on intestinal microbiota, suggests that this diet may have a positive effect on colon anastomosis and wound healing. METhODS: Thirty adult male albino Wistar rats were used in the study. animals in group 1 were fed standard rodent food. group 2 was fed with standard rodent food before the operation and a ketogenic diet after the operation. in the third group, a ketogenic diet was started 7 days before the operation and continued after the operation. Anastomotic bursting pressures and hydroxyproline levels were measured, and the specimens were evaluated histopathologically. RESULTS: No statistically significant difference regarding anastomotic bursting pressures and hydroxyproline levels was found between the groups. When the neovascularization in the anterior abdominal wall was evaluated, the rate of high-level neovascularization was 40% in group 1, and 0% in group 2 and group 3. Low-level neovascularization rate was 20%, 50% and 80%, respectively. This difference between the groups was found to be statistically significant. CONCLUSIONS: We thought that the antioxidant and anti-inflammatory effect of ketogenic diet may have a beneficial effect on wound healing and intestinal anastomotic strength. However, we found no significant difference on behalf of the diet between the groups in this study. A better understanding of the mechanisms underlying the positive effects of ketogenic diet will enable better planning of future studies.
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Background: Weight loss can induce changes in appetite-regulating hormone levels, possibly linked to increases in appetite and weight regain. However, hormonal changes vary across interventions. Here, we studied levels of appetite-regulating hormones during a combined lifestyle intervention (CLI: healthy diet, exercise and cognitive behavioral therapy). Methods: We measured levels of long-term adiposity-related hormones (leptin, insulin, high-molecular-weight (HMW) adiponectin) and short-term appetite hormones (PYY, cholecystokinin, gastric-inhibitory polypeptide, pancreatic polypeptide, FGF21, AgRP) in overnight-fasted serum of 39 patients with obesity. Hormone levels were compared between T0 (baseline), T1 (after 10 weeks) and T2 (end of treatment, 1.5 years). T0-T1 hormone changes were correlated with T1-T2 anthropometric changes. Results: Initial weight loss at T1 was maintained at T2 (−5.0%, p < 0.001), and accompanied by decreased leptin and insulin levels at T1 and T2 (all p < 0.05) compared to T0. Most short-term signals were not affected. Only PP levels were decreased at T2 compared to T0 (p < 0.05). Most changes in hormone levels during initial weight loss did not predict subsequent changes in anthropometrics, except for T0-T1 decreases in FGF21 levels and T0-T1 increases in HMW adiponectin levels tended to be associated with larger T1-T2 increases in BMI (p < 0.05 and p = 0.05, respectively). Conclusion: CLI-induced weight loss was associated with changes in levels of long-term adiposity-related hormones towards healthy levels, but not with orexigenic changes in most short-term appetite signals. Our data indicates that the clinical impact of alterations in appetite-regulating hormones during modest weight loss remains questionable. Future studies should investigate potential associations of weight-loss-induced changes in FGF21 and adiponectin levels with weight regain.
The aim of this review was to investigate in the literature the application of strategies such as low carbohydrate diet (LCD), ketogenic diet (KD) and intermittent fasting (IF) and their effects on the CNS. We performed a narrative review of the literature. The search was specifically carried out in PubMed, selecting articles in English, which had the following keywords: obesity, central nervous system, low carb diet, ketogenic diet and intermittent fasting, using the narrative review methodology. The studies found show that the benefits of the LCD, KD and IF strategies, at the CNS level, have a strong influence on the mechanisms of hunger and satiety, as well as on the reduction of food reward and show improvement in memory and mood influenced by the interventions.
Background: Low-carbohydrate high-fat (LCHF) diets may suppress the increase in appetite otherwise seen after diet-induced fat loss. However, studies of diets without severe energy restriction are lacking, and the effects of carbohydrate quality relative to quantity have not been directly compared. Objectives: To evaluated short- (3 mo) and long-term (12 mo) changes in fasting plasma concentrations of total ghrelin, β-hydroxybutyrate (βHB), and subjective feelings of appetite on 3 isocaloric eating patterns within a moderate caloric range (2000-2500 kcal/d) and with varying carbohydrate quality or quantity. Methods: We performed a randomized controlled trial of 193 adults with obesity, comparing eating patterns based on "acellular" carbohydrate sources (e.g., flour-based whole-grain products; comparator arm), "cellular" carbohydrate sources (minimally processed foods with intact cellular structures), or LCHF principles. Outcomes were compared by an intention-to-treat analysis using constrained linear mixed modeling. This trial was registered at as NCT03401970. Results: Of the 193 adults, 118 (61%) and 57 (30%) completed 3 and 12 mo of follow-up. Throughout the intervention, intakes of protein and energy were similar with all 3 eating patterns, with comparable reductions in body weight (5%-7%) and visceral fat volume (12%-17%) after 12 mo. After 3 mo, ghrelin increased significantly with the acellular (mean: 46 pg/mL; 95% CI: 11, 81) and cellular (mean: 54 pg/mL; 95% CI: 21, 88) diets but not with the LCHF diet (mean: 11 pg/mL; 95% CI: -16, 38). Although βHB increased significantly more with the LCHF diet than with the acellular diet after 3 m (mean: 0.16 mmol/L; 95% CI: 0.09, 0.24), this did not correspond to a significant group difference in ghrelin (unless the 2 high-carbohydrate groups were combined [mean: -39.6 pg/mL; 95% CI: -76, -3.3]). No significant between-group differences were seen in feelings of hunger. Conclusions: Modestly energy-restricted isocaloric diets differing in carbohydrate cellularity and amount showed no significant differences in fasting total ghrelin or subjective hunger feelings. An increase in ketones with the LCHF diet to 0.3-0.4 mmol/L was insufficient to substantially curb increases in fasting ghrelin during fat loss.
Scope: The primary aim of the present study was to study the effect of acute ketosis on parameters of appetite regulation in prediabetes. The secondary aim was to investigate whether the effect is influenced by eating behaviours. Methods and results: This was a randomised controlled trial. After an overnight fast, 18 adults with prediabetes (defined in line with the American Diabetes Association criteria) were assigned to consume either a ketone monoester (D-β-hydroxybutyrate-(R)-1,3 butanediol) drink (energy content 123 kcal) or a placebo drink (containing virtually no calories) in cross-over fashion. Blood samples were collected every 30 mins, from baseline to 150 minutes. Paired t-test was used to compare the total area under the curve (AUC) for the changes in parameters of appetite regulation (acylated ghrelin, peptide YY (PYY), and hunger) following both drinks. Eating behaviours were determined with the use of the three-factor eating questionnaire. Significant elevation in blood β-hydroxybutyrate from 0.2 mmol/L to 3.5 mmol/L (p < 0.001) was achieved within 30 minutes. Acute ketosis did not result in statistically significant differences in the AUCs for ghrelin, PYY, and hunger. No statistically significant difference in the AUCs was also observed when participants were stratified by their eating behaviours. Conclusion: Acute ketosis consistently did not affect both objective and subjective parameters of appetite regulation in prediabetes. No subset of people with prediabetes according to eating behaviours had a significant effect of acute ketosis on appetite regulation. This article is protected by copyright. All rights reserved.
Background Key underlying metabolic pathologies are thought to play a role in bipolar disorder (BD), including dysfunctions in energy metabolism. This review highlights underlying metabolic mechanisms of BD and potential therapeutic effects of a low carbohydrate ketogenic diet (KD) on mood symptoms. Based on its robust effectiveness in treating epilepsy, the KD has garnered recent interest in its application for mood disorders as it may imitate the pharmacological effects of mood stabilizers, commonly prescribed agents in the treatment of both BD and epilepsy, amongst other effects on stabilizing neural networks in the brain. Methods A literature review was conducted on current metabolic mechanisms of BD and clinical developments in KD. Results Recent findings support the idea that BD may have roots of metabolic dysfunction: cerebral glucose hypometabolism, oxidative stress, as well as mitochondrial and neurotransmitter dysfunction. A KD provides alternative fuel to the brain and is believed to contain beneficial neuroprotective effects, including neural network stabilization and inflammation reduction. Several beneficial metabolic effects on insulin resistance, weight, and lipid composition have been shown. Limitations Limited case studies on KD treatment in BD have been reported to date. Conclusions Preliminary data support further testing of a low carbohydrate KD as a potential therapeutic tool in repairing energy metabolism in bipolar illness. Additionally, it may repair deficits in energy metabolism often seen in BD. Further research and clinical trials are needed to evaluate the efficacy of a KD as a supplemental or co-treatment of bipolar illness and an open-label pilot trial testing the diet in bipolar illness is currently underway at Stanford.
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Circadian rhythm is an inherent endogenous biological rhythm in living organisms. However, with the improvement of modern living standards, many factors such as prolonged artificial lighting, sedentarism, short sleep duration, intestinal flora and high-calorie food intake have disturbed circadian rhythm regulation on various metabolic processes, including GLP-1 secretion, which plays an essential role in the development of various metabolic diseases. Herein, we focused on GLP-1 and its circadian rhythm to explore the factors affecting GLP-1 circadian rhythm and its potential mechanisms and propose some feasible suggestions to improve GLP-1 secretion.
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Liver fructose-1,6-bisphosphatase (FBPase) is a regulatory enzyme in gluconeogenesis that is elevated by obesity and dietary fat intake. Whether FBPase functions only to regulate glucose or has other metabolic consequences is not clear; therefore, the aim of this study was to determine the importance of liver FBPase in body weight regulation. To this end we performed comprehensive physiologic and biochemical assessments of energy balance in liver-specific transgenic FBPase mice and negative control littermates of both sexes. In addition, hepatic branch vagotomies and pharmacologic inhibition studies were performed to confirm the role of FBPase. Compared with negative littermates, liver-specific FBPase transgenic mice had 50% less adiposity and ate 15% less food but did not have altered energy expenditure. The reduced food consumption was associated with increased circulating leptin and cholecystokinin, elevated fatty acid oxidation, and 3-β-hydroxybutyrate ketone levels, and reduced appetite-stimulating neuropeptides, neuropeptide Y and Agouti-related peptide. Hepatic branch vagotomy and direct pharmacologic inhibition of FBPase in transgenic mice both returned food intake and body weight to the negative littermates. This is the first study to identify liver FBPase as a previously unknown regulator of appetite and adiposity and describes a novel process by which the liver participates in body weight regulation.
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β-Hydroxybutyric acid (BHBA) acts in the brain to influence feeding behaviour, but the underlying molecular mechanisms are unclear. GT1-7 hypothalamic cells expressing orexigenic agouti-related peptide (AGRP) were used to study the AMP-activated protein kinase (AMPK) pathway known to integrate dietary and hormonal signals for food intake regulation. In a 25 mM glucose culture medium, BHBA increased intracellular calcium concentrations and the expression of monocarboxylate transporter 1 (MCT1 (SLC16A1)). Phosphorylation of AMPK-α (PRKAA1 and PRKAA2) at Thr(172) was diminished after 2 h but increased after 4 h. Its downstream target, the mammalian target of rapamycin, was increasingly phosphorylated on Ser(2448) after 2 h but not changed after 4 h of BHBA treatment. After 4 h, BHBA treatment also increased Agrp mRNA expression. This increase was prevented by preincubation with the AMPK inhibitor Compound C. The inhibition of MCT1 activity by p-hydroxymercuribenzoate suppressed BHBA-stimulated AMPK phosphorylation but did not prevent BHBA-induced Agrp mRNA expression. This finding demonstrates that BHBA triggers the AMPK pathway resulting in orexigenic signalling under 25 mM glucose culture conditions. Under conditions of 5.5 mM glucose, however, BHBA marginally increased intracellular calcium but significantly decreased AMPK phosphorylation and Agrp mRNA expression, demonstrating that under physiological conditions BHBA reduces central orexigenic signalling.
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After weight loss, changes in the circulating levels of several peripheral hormones involved in the homeostatic regulation of body weight occur. Whether these changes are transient or persist over time may be important for an understanding of the reasons behind the high rate of weight regain after diet-induced weight loss. We enrolled 50 overweight or obese patients without diabetes in a 10-week weight-loss program for which a very-low-energy diet was prescribed. At baseline (before weight loss), at 10 weeks (after program completion), and at 62 weeks, we examined circulating levels of leptin, ghrelin, peptide YY, gastric inhibitory polypeptide, glucagon-like peptide 1, amylin, pancreatic polypeptide, cholecystokinin, and insulin and subjective ratings of appetite. Weight loss (mean [±SE], 13.5±0.5 kg) led to significant reductions in levels of leptin, peptide YY, cholecystokinin, insulin (P<0.001 for all comparisons), and amylin (P=0.002) and to increases in levels of ghrelin (P<0.001), gastric inhibitory polypeptide (P=0.004), and pancreatic polypeptide (P=0.008). There was also a significant increase in subjective appetite (P<0.001). One year after the initial weight loss, there were still significant differences from baseline in the mean levels of leptin (P<0.001), peptide YY (P<0.001), cholecystokinin (P=0.04), insulin (P=0.01), ghrelin (P<0.001), gastric inhibitory polypeptide (P<0.001), and pancreatic polypeptide (P=0.002), as well as hunger (P<0.001). One year after initial weight reduction, levels of the circulating mediators of appetite that encourage weight regain after diet-induced weight loss do not revert to the levels recorded before weight loss. Long-term strategies to counteract this change may be needed to prevent obesity relapse. (Funded by the National Health and Medical Research Council and others; number, NCT00870259.).
Background: Low-carbohydrate diets remain popular despite a paucity of scientific evidence on their effectiveness. Objective: To compare the effects of a low-carbohydrate, ketogenic diet program with those of a low-fat, low-cholesterol, reduced-calorie diet. Design: Randomized, controlled trial. Setting: Outpatient research clinic. Participants: 120 overweight, hyperlipidemic volunteers from the community. Intervention: Low-carbohydrate diet (initially, <20 g of carbohydrate daily) plus nutritional supplementation, exercise recommendation, and group meetings, or low-fat diet (<30% energy from fat, <300 mg of cholesterol daily, and deficit of 500 to 1000 kcal/d) plus exercise recommendation and group meetings. Measurements: Body weight, body composition, fasting serum lipid levels, and tolerability. Results: A greater proportion of the low-carbohydrate diet group than the low-fat diet group completed the study (76% vs. 57%; P = 0.02). At 24 weeks, weight loss was greater in the low-carbohydrate diet group than in the low-fat diet group (mean change, -12.9% vs. -6.7%; P < 0.001). Patients in both groups lost substantially more fat mass (change, -9.4 kg with the low-carbohydrate diet vs. -4.8 kg with the low-fat diet) than fat-free mass (change, -3.3 kg vs. -2.4 kg, respectively). Compared with recipients of the low-fat diet, recipients of the low-carbohydrate diet had greater decreases in serum triglyceride levels (change, -0.84 mmol/L vs. -0.31 mmol/L [-74.2 mg/dL vs. -27.9 mg/dL]; P = 0.004) and greater increases in high-density lipoprotein cholesterol levels (0.14 mmol/L vs. -0.04 mmol/L [5.5 mg/dL vs. -1.6 mg/dL]; P < 0.001). Changes in low-density lipoprotein cholesterol level did not differ statistically (0.04 mmol/L [1.6 mg/dL] with the low-carbohydrate diet and -0.19 mmol/L [-7.4 mg/dL] with the low-fat diet; P = 0.2). Minor adverse effects were more frequent in the low-carbohydrate diet group. Limitations: We could not definitively distinguish effects of the low-carbohydrate diet and those of the nutritional supplements provided only to that group. In addition, participants were healthy and were followed for only 24 weeks. These factors limit the generalizability of the study results. Conclusions: Compared with a low-fat diet, a low-carbohydrate diet program had better participant retention and greater weight loss. During active weight loss, serum triglyceride levels decreased more and high-density lipoprotein cholesterol level increased more with the low-carbohydrate diet than with the low-fat diet.