Appetite regulation and weight loss -
Participants with data at 1Y were considered completers and kept in the analysis. All the analysis was done for completers, except for changes in body weight where an intention to treat analysis with baseline values carried forward was used. The Benjamini—Hochberg method, which controls for the false discovery rate [ 29 ] was used to adjust for the large number of outcome variables.
The association between changes in subjective and objective appetite markers both at Wk13 and 1Y , between the magnitude of WL both at Wk13 and 1Y and the respective changes in both subjective and objective appetite markers and between changes in appetite at Wk13 and WL maintenance at 1Y were investigated with Pearson or Spearmen correlation.
In total 55 females participants fulfilled the study entry criteria and started the study. Of those, 95 participants completed the 8-week VLED 2 did not tolerate the VLED, 1 was excluded due to consumption of extra foods, 1 withdrew for personal reasons and 1 was lost to follow-up , 94 completed Wk 13 measurements 1 withdrew due to family illness and 71 41 females completed the full 1Y 8 withdrew due to own or family related illness, 3 due to work constraints making it difficult to return for measurements, 2 were excluded due to non-compliance as they had started a new VLED, and 10 were lost to follow-up.
Baseline characteristics of the participants who started and completed the study are presented in Table 1. There were no significant differences in any baseline measurement between those who completed and those who did not complete the study.
Moreover, no differences were seen between completers and non-completers regarding changes in appetite with WL Wk13 , even though completers lost more weight at Wk13 No changes in total PA duration or time spent in light, moderate or vigorous activities were measured during the WL phase.
See Supplementary Table 1. Changes in body weight are reported in Fig. Body weight in all participants intention to treat analysis and completers over time.
The changes in absolute FM over time were not statistical significant different between sexes. No significant change overtime were found for rating of fullness, DTE or PFC in fasting see Fig.
Females had overall significant lower ratings of PFC in fasting than males 5. Subjective feelings of hunger a , fullness b , desire to eat c , and prospective food consumption PFC d in fasting, over time, in all participants, males and females.
See Supplementary Table 2 A. Mean fasting and postprandial ratings of hunger a , fullness b , desire to eat c , and prospective food consumption PFC d in all participants over time. See Supplementary Table 3. Basal plasma concentrations of appetite-related hormones: active ghrelin AG a , active glukagon like peptide-1 GLP-1 b , total peptide YY total PYY c , cholecystokinin CCK d and insulin e , over time in all participants, males and females.
See Supplementary Table 2 B. Mean basal and postprandial plasma concentrations of appetite-related hormones; a active ghrelin AG a , b active glucagon-like peptide-1 active GLP-1 b , c total peptide YY total PYY c , d cholecystokinin CCK d , and e insulin e , for all participants over time.
No significant correlation was found between changes in subjective appetite feelings and changes in the plasma concentrations of appetite-related hormones at any time point either at W13 or 1Y. There was also a significant increase in basal and postprandial AG concentrations, a reduction in postprandial CCK and in basal and postprandial insulin.
Basal and postprandial AG remained increased and insulin reduced, while postprandial CCK was increased and PYY decreased at 1Y follow-up, compared to baseline. Few studies have been performed on the long-term sustainability of changes in appetite with WL and, to date, the results have been contradictory [ 15 , 20 , 21 ].
Iepsen et al. Unfortunately, they did not measure changes in subjective feelings of appetite. Adam et al. The present study is the largest evaluating the impact of sustained WL maintenance, employing both subjective and objective appetite markers, and offers a perspective of sex being a mediator of outcome.
Even though ours and other studies tend to consistently show a sustained increase in subjective feelings of hunger, when using VAS, combined with an increase in ghrelin either active or total with long-term WL [ 15 , 21 ], changes in postprandial fullness ratings and plasma concentrations of satiety peptides remain controversial [ 15 , 21 ].
Differences in the magnitude of WL and its sustainability, hormonal fractions measured and methods of analysis of gut peptides [ 32 , 33 , 34 ] are likely to contribute to this inconsistent picture alongside most studies having mixed gender. Moreover, SQ hunger increased with WL, indicating a larger reduction in hunger after the same test meal, which is likely to reflect more accurate appetite sensation responses [ 35 ].
The increase in postprandial fullness with WL and WL maintenance is a novel. Inconsistencies may be due to differences in the magnitude of WL, baseline participant characteristics and sample size.
In a study by Delgado-Aros et al. It remains speculative if changes in gastric capacity with WL contributed to increased postprandial fullness in the present study. Increased fullness after acute and sustained WL is unlikely to be explained by changes in CCK secretion, given that a reduction in CCK secretion was measured at Wk13, while an increase was seen with sustained WL at 1Y follow-up.
Another explanation for the increased fullness with WL may be an increased postprandial secretion GLP-1 and PYY. Finally, it is possible that increased fullness reflects the larger relative energy load of the test meal after WL.
To date, there is a dearth of information on the impact of WL on CCK plasma concentrations. The available evidence suggests that acute and rapid WL results in a reduction in postprandial concentrations of CCK [ 15 , 40 ], which is consistent with our results, and probably reflects a lower stimulation due to less food and fat intake.
This could have had an impact on CCK concentrations, and the increased postprandial CCK secretion may reflect a long-term adaptation to substantial WL, but that requires further substantiation. The lack of association between subjective appetite feelings and the plasma concentration of appetite-related hormones seen in this study is not new [ 41 , 42 ] and probably reflects the complexity of the appetite control system and the fact that changes in appetite feelings are unlikely to be attributable to alterations in a single hormone.
It has long been suggested that the increased hunger and reduced satiety seen after WL are part of a compensatory response that tries to bring body weight back to its set point [ 8 , 43 , 44 , 45 ]. However, the findings from the present study: increased fasting hunger and basal AG plasma concentrations, as well as increased postprandial fullness, AG and CCK in response to large sustained WL may suggest otherwise.
It is well known that obese individuals have lower plasma concentration of ghrelin in fasting [ 46 ] and a blunted postprandial secretion of total GLP-1 [ 39 , 47 ], active GLP-1 [ 48 ], total PYY [ 48 , 49 ], and CCK [ 50 ] and lower ghrelin postprandial suppression [ 46 , 48 ].
Therefore, our overall findings, with the exception of PYY, could reflect a normalisation of appetite markers towards those seen in healthy-weight individuals. This is supported by Verdich et al. WL also leads to a reduction in TEE proportional to the new reduced body weight, even though some individuals may experience a larger than predicted reduction—a mechanism known as adaptive thermogenesis AT [ 10 ].
With, the exception of AT, which seems to occur in only some individuals, the changes in appetite and energy expenditure seen with WL could, therefore, be seen as a normalisation towards a lower body weight and not a compensatory mechanism that drives relapse.
This new hypothesis is supported by the fact that neither us, nor Sumithran et al. This study revealed several sex differences in the changes in appetite seen overtime with WL and WL maintenance. Hunger ratings in fasting were increased at Wk13 in females only, while mean postprandial ratings of hunger and fullness were significantly increased, and PFC reduced, in males only at Wk13, and postprandial fullness was increased in females only at 1Y follow-up.
Moreover, mean postprandial CCK plasma concentrations did not change at any time point in females, while in males there was an increase at 1Y follow-up, compared to baseline.
The fact that postprandial fullness was increased at 1Y follow-up in females only may reflect the fact that in males there was a tendency towards weight regain from Wk13 to 1Y, while females continued to lose weight over time. More studies, with larger sample sizes and equal sex distribution, are needed to fully ascertain the potential modulating effect of sex on the changes in appetite seen with WL and WL maintenance and the explanatory mechanisms behind it.
This study has several strengths. First, it is the largest longitudinal study to examine changes in appetite with sustained WL. Second, it included both objective and subjective markers of appetite.
Third, the participants were able to maintain their body weight at 1Y follow-up compared with Wk13 , probably due to on-going and tailored advice provided by dieticians. Finally, both males and females were included in the study in similar numbers.
There are also some limitations. The multiplex assay used for the measurements of appetite hormones except for CCK is likely to result in less accurate and precise measurements compared with optimised assays for each individual hormone.
The fact that the same type of test meal was given to all participants, regardless of their Ereq, constitutes a limitation. Females consumed a larger relative energy load compared with males and the same test meal represented a larger energy load with progressive WL. However, if we had adjusted the test meal accordion to Ereq smaller meals in females compared with females and after WL the appetite response would be blunted, because the nutrient stimuli would also be reduced, independently of the effect of sex or WL on appetite.
This study was not powered to examine sex differences per se, so we are unable to draw firm conclusions about sex differences in responses to WL. Our findings have some important practical implications. Patients with obesity who have lost and maintained significant amounts of weight via dieting, and benefited in terms of metabolic and overall health markers [ 30 , 31 ], should expect a sustained increase in hunger feelings in the fasting state and to be prepared for these feelings to occur.
This increased drive to eat in fasting may impact on food selection, eating rate and total energy intake, despite increased postprandial fullness, and thus lead to positive energy imbalance and increase the risk of weight regain.
Health professionals working with this patient group, should be aware of the sustained increase in the drive to eat in the fasting state and help individuals develop management strategies to reduce the risk of overeating.
However, the changes in appetite seen with WL increased hunger and AG were not associated with long-term relapse, which likely reflects the complexity of body weight regulation [ 51 ].
Some sex differences were revealed, but larger studies are needed to support these findings. Future studies should evaluate if changes in appetite markers with WL are part of a compensatory response or a simple normalisation towards healthy-weight values, its relationship with actual food intake and its real impact on long-term WL maintenance.
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Int J Obes Relat Metab Disord. Third, although patients were instructed to follow a healthy normocaloric diet, we were not able to exactly determine to what degree patients had complied with the intervention regime. Finally, the limited sample size of our study may have resulted in to type 1 errors and our results should thus be replicated in a larger cohort.
The limited sample size of the current study prevented us from investigating potential synergistic effects of changes in multiple hormones in a single statistical model.
This could be included in future large-scale studies. It would also be highly interesting to prospectively compare the hormonal alterations in response to a normocaloric CLI to a control group and other interventions as well as single components of the intervention e.
very-low energy diets; vs. healthy diet only; vs. CBT only; vs. exercise only. Finally, future studies should investigate potential sex differences in this context which we could not assess in view of a sample size of only eight males. Modest weight loss in response to a 1.
The clinical impact of alterations in levels of appetite-regulating hormones on long-term weight loss maintenance during modest weight loss remains questionable.
Especially changes in levels of long-term adiposity-related hormones seem to rather follow weight loss instead of governing it. Future studies should investigate the potential association of changes in FGF21 and adiponectin levels with subsequent weight gain in a larger sample, ideally including measures of adipocyte distribution and health.
The studies involving human participants were reviewed and approved by Dutch Medical Ethics Review Committee MERC. SK was responsible for developing the research question, performing the statistical analyses and writing the manuscript.
She also planned and coordinated the hormone analyses of the blood samples and assisted in the laboratory work. EV contributed to developing the research question, helped with discussing the statistical analysis and gave feedback on the manuscript.
AS helped with interpreting the results as well as writing the manuscript, whereby he provided substantial input regarding the theoretical framework. RL has helped with the statistical analysis, interpretation of the results and gave feedback on the manuscript.
JV, AI, and MM helped with the interpretation of the results and have given feedback on the manuscript. SB was involved in organizing the laboratory analyses in his laboratory and in the interpretation of the results from a technical as well as theoretical perspective.
He also gave feedback on the manuscript. ER was involved in the development of the research question, clinical care of the patients, and has supervised the coordination of the blood analyses, the statistical analyses, the interpretation of the results as well as the writing of the manuscript.
This work was funded by the Netherlands organization for scientific research NWO Vidi grant No. We would like to thank Mariëtte Boon for sharing her expertise on hormonal regulators of energy homeostasis.
In addition, we would like to thank Mila Welling, Bibian van der Voorn, Hilguin Ruinemans, Kirsten Berk, Eva van Eijk, Arlette Vergunst for their medical treatments and professional guidance of the patients during the lifestyle intervention.
We are also thankful to all patients included in the study as well as for the support of Renate Meeusen and Annemieke van der Zwaan regarding data management and study coordination.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers.
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Citation: Kuckuck S, van der Valk ES, Scheurink AJW, Lengton R, Mohseni M, Visser JA, Iyer AM, van den Berg SAA and van Rossum EFC Levels of hormones regulating appetite and energy homeostasis in response to a 1. doi: Received: 03 August ; Accepted: 30 January ; Published: 20 February Copyright © Kuckuck, van der Valk, Scheurink, Lengton, Mohseni, Visser, Iyer, van den Berg and van Rossum.
This is an open-access article distributed under the terms of the Creative Commons Attribution License CC BY.
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